{"publication_id":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","content_hash":"sha256:4d31b0add9f60d2757a5fc192fbc286c43bf36326f01518faf0ce1db58358bb3","nodes":[{"id":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","type":"publication","title":"Adjacent Evidence Brief: Telomere Measurement Methods"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on telomere measurement methods across the retained source corpus and high-confidence extracted claim set [bundle:5]."},{"id":"claim_2","type":"claim","text":"This paper synthesizes evidence on telomere measurement methods across the retained source corpus and high-confidence extracted claim set [bundle:5]."},{"id":"claim_3","type":"claim","text":"The geroscience hypothesis proposes that targeting fundamental aging biology, rather than individual diseases, could be a more efficient strategy to extend healthspan. Within this framework, telomere maintenance has been proposed as a key modifiable hallmark of aging. Interventions ranging from lifestyle modifications to pharmacological agents are being investigated for their potential to influence telomere dynamics. This variability underscores the complexity of telomere biology and suggests that broad lifestyle-based interventions may have modest or context-dependent effects on telomere length, necessitating a more targeted approach."},{"id":"claim_4","type":"claim","text":"The human randomized controlled trial (RCT) landscape for telomere-focused interventions is characterized by diverse study designs, populations, and endpoints, leading to a mixed and sometimes contradictory evidence base. Many trials are mechanistic or biomarker-focused, assessing TL change as a primary or secondary endpoint without clinical outcomes. This diversity of trial contexts and populations makes it difficult to synthesize a unified narrative about the efficacy of interventions aimed at modifying telomere length."},{"id":"claim_5","type":"claim","text":"This synthesis aims to contribute by systematically examining the tensions between mechanistic plausibility and clinical evidence within the telomere measurement and intervention literature. A central challenge is the separation of clinical from mechanistic evidence, as findings from different outcome domains cannot be directly compared. The review will therefore weight the evidence by separating these layers: mapping the landscape of human RCTs that have directly measured telomere length change, examining the observational associations with longevity and specific diseases, and evaluating the mechanistic studies that inform biological plausibility. The goal is to identify where the evidence is consistent, where it is contradictory, and where the most significant gaps remain, particularly concerning the functional consequences of modifying telomere length and the boundary conditions for any potential clinical benefit."},{"id":"claim_6","type":"claim","text":"Risk-of-bias honesty note: No populated per-source public appraisal ratings are reported in this artifact. Risk-of-bias language is therefore descriptive of source design and directness, not a claim that formal framework-specific scoring was completed."},{"id":"claim_7","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_8","type":"claim","text":"A source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources."},{"id":"claim_9","type":"claim","text":"Risk-of-bias framework assignment follows study design (risk-of-bias appraisal for RCTs, non-randomized-study appraisal for non-randomised studies, review-quality appraisal for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_10","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, frailty, immune and inflammation, longevity, mortality and survival, muscle function); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_11","type":"claim","text":"| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |"},{"id":"claim_12","type":"claim","text":"| Telomere Measurement Methods / Contextual Adjacent Evidence | n=25; claims=319 | positive=1, negative=2, null=2, mixed=1, unclear=19 (n=25) | 17 direct; 5 indirect; 3 review | limited corpus depth in this outcome class |"},{"id":"claim_13","type":"claim","text":"| Telomere Measurement Methods / Cardiometabolic | n=4; claims=30 | positive=0, negative=0, null=0, mixed=0, unclear=4 (n=4) | 3 direct; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"| Telomere Measurement Methods / Immune and Inflammation | n=4; claims=72 | positive=0, negative=0, null=2, mixed=0, unclear=2 (n=4) | 2 direct; 1 indirect; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_15","type":"claim","text":"| Telomere Measurement Methods / Longevity | n=2; claims=44 | positive=1, negative=0, null=0, mixed=0, unclear=1 (n=2) | 1 direct; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_16","type":"claim","text":"| Telomere Measurement Methods / Animal/Preclinical Context | n=1; claims=11 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 mechanistic | single-source slice; hypothesis-generating |"},{"id":"claim_17","type":"claim","text":"| Telomere Measurement Methods / Deficiency Prevalence | n=1; claims=14 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_18","type":"claim","text":"| Telomere Measurement Methods / Frailty | n=1; claims=10 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_19","type":"claim","text":"| Telomere Measurement Methods / Mortality and Survival | n=1; claims=13 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_20","type":"claim","text":"| Telomere Measurement Methods / Muscle Function | n=1; claims=7 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 review | single-source slice; hypothesis-generating |"},{"id":"claim_21","type":"claim","text":"Ribeiro 2021 [bundle:1] (Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in; representative statistic p ≤ 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_22","type":"claim","text":"Jaeger 2024 [bundle:4] (A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized; representative statistic p = 0.01; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_23","type":"claim","text":"Salvador 2016 [bundle:34] (A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo; representative statistic p = 0.005; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_24","type":"claim","text":"Sindi 2020 [bundle:7] (Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial; representative statistic p = .039; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_25","type":"claim","text":"Kalstad 2019 [bundle:36] (Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and; 8 extracted claim(s); receipt-level direction is the coded finding; outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_26","type":"claim","text":"Su 2025 [bundle:8] (Effects of TA-65 on telomere length, functional outcomes, and inflammation: a systematic review and meta-analysis; representative statistic p < 0.00001; source-level statistic reported; outcome=Biomarker/Adjacent Immune and Inflammation; direction=null; directness=review; tier=B1)."},{"id":"claim_27","type":"claim","text":"Nanda 2025 [bundle:2] (Chronic inflammation mediates the relationship between physical activity and telomere length; 30 extracted claim(s); receipt-level direction is the coded finding; outcome=Biomarker/Adjacent Immune and Inflammation; direction=null; directness=indirect; tier=B2)."},{"id":"claim_28","type":"claim","text":"Liu 2025 [bundle:18] (representative non-significant statistic p>0.05; not treated as positive or negative directional support unless source direction is coded; outcome=Biomarker/Adjacent Frailty; direction=unclear; directness=indirect; tier=B2)."},{"id":"claim_29","type":"claim","text":"Thesis:** Across 40 curated reference papers, the evidence base for Telomere shows a context-dependent profile. Positive signals appear in: longevity, Contextual Adjacent Evidence. Negative signals appear in: Contextual Adjacent Evidence. Null findings dominate: immune inflammation, Contextual Adjacent Evidence. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Telomere broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile."},{"id":"claim_30","type":"claim","text":"Threat 1: Several randomized controlled trials reporting telomere maintenance or lengthening also report concurrent improvements in cardiometabolic, hormonal, or inflammatory biomarkers, suggesting that the disconnect between elongation and function may be an artifact of short follow-up or underpowered functional endpoints rather than a true mechanistic disconnect. These findings appear consistent with a model in which the temporal horizon required for telomere elongation to manifest as functional improvement may exceed the 12- to 24-month windows most trials employ, and the evidence suggests that caloric restriction confers benefits through pathways that do not necessarily pass through measurable telomere length change."},{"id":"source_1","type":"source","study":"Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study","year":2021,"doi":"10.3390/ijerph182111274","url":"https://doi.org/10.3390/ijerph182111274","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Ribeiro 2021","evidence_span":"The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women","excerpt":"The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT."},{"id":"source_2","type":"source","study":"Chronic inflammation mediates the relationship between physical activity and telomere length","year":2025,"doi":"10.1007/s11357-025-01818-z","url":"https://doi.org/10.1007/s11357-025-01818-z","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Nanda 2025","evidence_span":"1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72","excerpt":"1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif"},{"id":"source_3","type":"source","study":"Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank","year":2026,"doi":"10.1007/s00415-025-13479-1","url":"https://doi.org/10.1007/s00415-025-13479-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Chen 2026","evidence_span":"Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).","excerpt":"Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001)."},{"id":"source_4","type":"source","study":"A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study","year":2024,"doi":"10.3390/nu16172963","url":"https://doi.org/10.3390/nu16172963","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Jaeger 2024","evidence_span":"Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated","excerpt":"Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004)."},{"id":"source_5","type":"source","study":"Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial","year":2025,"doi":"10.3390/nu17182974","url":"https://doi.org/10.3390/nu17182974","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Farhat 2025","evidence_span":"Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and","excerpt":"Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category."},{"id":"source_6","type":"source","study":"Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis","year":2024,"doi":"10.1111/acel.14149","url":"https://doi.org/10.1111/acel.14149","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Hastings 2024","evidence_span":"This is similar to patterns observed in the smaller SHINE trial, where average TL for weight loss maintainers decreased in the first 3 months of the intervention, but then increased between 3 months and 1 year (Mason et al., 2018 ). Thus, TL may exhibit a hormesis‐like response to CR wherein the stress of weight loss that accompanies early‐phase CR accelerates TL attrition, which is thereafter mitigated or ablated altogether as new homeostatic norms are established. We acknowledge limitations. There is no gold standard of telomere measurement applicable for population‐based studies. This","excerpt":"This is similar to patterns observed in the smaller SHINE trial, where average TL for weight loss maintainers decreased in the first 3 months of the intervention, but then increased between 3 months and 1 year (Mason et al., 2018 ). Thus, TL may exhibit a hormesis‐like response to CR wherein the stress of weight loss that accompanies early‐phase CR accelerates TL attrition, which is thereafter mitigated or ablated altogether as new homeostatic norms are established. We acknowledge limitations. There is no gold standard of telomere measurement applicable for population‐based studies. This investigation included two distinct approaches toward TL quantification, direct measurement of aTL using qPCR and indirect estimation of TL from DNA methylation data (DNAmTL). The moderate agreement ( r = 0.29) between the two measurements is in line with previous reports (Doherty et al., 2023 ; Hastings et al., 2022 ), as are cross‐sectional per year TL attrition rates (Ye et al., 2023 ) and differences between White and Black Americans (Hansen et al., 2016 ; Hunt et al., 2008 ). The capacity to detect change in TL is dependent on measurement precision, follow‐up duration, and the number of longitudinal assessments. The DNA extraction approached utilized by CALERIE™ (i.e., Qiagen Puregene) has also been shown to increase the variability in qPCR‐based method of TL assessments (Lin et al., 2022 ). Although we took care to correct aTL measurements using metrics of DNA integrity (Wolf et al., 2024 ), it remains possible that pre‐analytical factors could have contributed to variability in aTL measurements and change scores. Average within‐person changes in aTL across 2 years, 510 bp, is larger than would be expected based upon chronological age associated differences in aTL observed in linear models (87 bp/year). This difference is partly attributable to intervention effects on aTL but does not preclude the possibility of measurement error contributing to observed findings. In particular, the reversed directionality of aTL attrition in the CR group between the weight loss and weight maintenance phases could also result from regression to the mean. Even so, the strong reliability of aTL measurements (ICC >0.80), consistency of attrition in the AL group, and use of three time points decreases the likelihood that effects are artifacts resulting from measurement error or regression to the mean (Steenstrup et al., 2013 ). DNAmTL is not a perfect proxy for TL, reflecting an algorithm of CpG sites trained to predict TL measured using southern blot. Sex differences in DNAmTL presented in the direction opposite expectations, with females exhibiting shorter DNAmTL at all time points. This could be attributed to bias in the predominately female CALERIE™ sample, however, DNAmTL was constructed in a similarly skewed dataset (75% female), and effects in test datasets were in the expected direction (i.e., shorter DNAmTL in men) (Lu et al., 2019 ). Recent evidence has highlighted how DNAmTL measures trained in disparate datasets (Doherty et al., 2023 ) can exhibit similar concordance with qPCR‐based measurements of TL despite having low overlap in their CpG composition (<2%), suggesting a broader set of global CpGs related to TL than is comprised in a single DNAmTL algorithm. Given that effects of CR were differential between DNAmTL and aTL measurements, it is possible that the DNAmTL measure utilized in our work registered telomere dynamics especially sensitive to CR (via unique CpGs) that may not replicate to other DNA‐methylation based predictors of TL. TL is not a static measure, representing an average across chromosome ends and various cell types. Although we took care to control for differences in immune cell distribution, it is possible that CR‐mediated effects could translate differentially across one or many chromosomes. This will be a future avenue of research as approaches toward chromosome‐specific TL measurement continue to develop. Cohen's f 2 effect sizes for significant group differences observed using CALERIE™ multiple regression frameworks were small for aTL ( f 2 12 months = 0.027; f 2 Maintenance = 0.036) and very small for DNAmTL ( f 2 12 months = 0.001). Power analyses suggest the study sample size was insufficient to reliably detect effects of this size ( β aTL , 12 months = 0.54; β aTL , Maintenance = 0.62; β DNAmTL , 12 months = 0.07). Thus, results should be taken as exploratory, and effects of CR on TL observed in very healthy, predominately white, majority female participants without obesity may not extend to a more heterogenous general population. In conclusion, we observed mixed evidence for effects of the CALERIE™ intervention on TL attrition. Intervention group status was not significantly associated with TL attrition across the first year, although there were trends toward increased attrition in the CR group for both TL measurement approaches. Using TOT analysis, which estimated impacts of CR across both intervention groups, increased CR was associated with accelerated DNAmTL attrition between baseline and the 12‐month follow‐up. By contrast, both CR group status and increased CR were associated with slower aTL attrition over the second year of weight maintenance. No differences were observed for either measure when considering TL change across the full study duration from baseline to 24 months, leaving it unclear whether CR‐related impacts"},{"id":"source_7","type":"source","study":"Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial","year":2020,"doi":"10.1093/gerona/glaa279","url":"https://doi.org/10.1093/gerona/glaa279","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Sindi 2020","evidence_span":"Between September 7, 2009 and November 24, 2011, 2654 individuals were screened and 1260 were randomly assigned to the intensive intervention group ( n = 631) or control group ( n = 629). The full trial profile has been previously described ( 17 ). There were no significant differences in baseline characteristics between intervention and control groups in the LTL subpopulation ( Table 1 ). The LTL subpopulation ( n = 756) had a higher education level ( p = .039), lower systolic blood pressure ( p = .003), and better cognitive performance on the total NTB ( p = .001), executive functioning ( p","excerpt":"Between September 7, 2009 and November 24, 2011, 2654 individuals were screened and 1260 were randomly assigned to the intensive intervention group ( n = 631) or control group ( n = 629). The full trial profile has been previously described ( 17 ). There were no significant differences in baseline characteristics between intervention and control groups in the LTL subpopulation ( Table 1 ). The LTL subpopulation ( n = 756) had a higher education level ( p = .039), lower systolic blood pressure ( p = .003), and better cognitive performance on the total NTB ( p = .001), executive functioning ( p ≤ .001), and processing speed ( p = .035) domains compared with the rest of the FINGER participants ( n = 504; Supplementary Table S1 ). Baseline Characteristics of Participants in the FINGER LTL Exploratory Substudy Notes: FINGER = Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; NTB = Neuropsychological Test Battery. Values are means ± SD unless otherwise specified. Differences between intervention and control groups were analyzed with chi-square and t tests as appropriate. *Scores on the NTB total score, executive functioning, processing speed, memory, and long-term memory are mean values of z -scores of the cognitive tests included in each cognitive outcome. Higher scores indicate better performance. Mean relative LTL ( SD ) at baseline was 1.075 (0.325) for participants aged 60–70 years and 1.042 (0.338) for participants aged 70–77 years. Because there is no “general reference scale” for the size of change in relative LTL values over time, and LTL decreases with age, these mean baseline values per age decade are provided as reference. FINGER is so far the largest clinical trial investigating the effects of a multidomain lifestyle intervention on change in LTL and the first to relate the change in LTL to change in cognition in older adults at risk for dementia from the general population. Overall, LTL change during 2 years was not significantly different between the intervention and control groups."},{"id":"source_8","type":"source","study":"Effects of TA-65 on telomere length, functional outcomes, and inflammation: a systematic review and meta-analysis","year":2025,"doi":"10.1007/s10565-025-10115-6","url":"https://doi.org/10.1007/s10565-025-10115-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Su 2025","evidence_span":"TA-65 supplementation induced moderate telomere elongation (SMD = 0.47, 95% CI: 0.31–0.62; p < 0.00001), with amplified effects in adults > 60 years (SMD = 0.63 vs. 0.36; p = 0.03). Industry-funded trials reported inflated efficacy (SMD = 0.63 vs. 0.40; p = 0.03). Critically, telomere elongation did not translate to functional improvements in frailty (SMD = 0.09, p = 0.15) or inflammation (CRP/IL-6 SMD = − 0.11, p = 0.07), revealing a telomere-function disconnect. Safety analysis (n = 487) identified mild gastrointestinal toxicity (12.4% incidence; nausea: 7.1%, abdominal discomfort: 5.3%)","excerpt":"TA-65 supplementation induced moderate telomere elongation (SMD = 0.47, 95% CI: 0.31–0.62; p < 0.00001), with amplified effects in adults > 60 years (SMD = 0.63 vs. 0.36; p = 0.03). Industry-funded trials reported inflated efficacy (SMD = 0.63 vs. 0.40; p = 0.03). Critically, telomere elongation did not translate to functional improvements in frailty (SMD = 0.09, p = 0.15) or inflammation (CRP/IL-6 SMD = − 0.11, p = 0.07), revealing a telomere-function disconnect. Safety analysis (n = 487) identified mild gastrointestinal toxicity (12.4% incidence; nausea: 7.1%, abdominal discomfort: 5.3%) but no severe adverse events (e.g., oncogenesis) over 12 months. Dose–response relationships (10–50 mg/day) and measurement-method variations were non-significant (p > 0.05). While TA-65 demonstrates telomerase-activating efficacy, particularly in older adults, its failure to improve functional aging metrics underscores limitations of unimodal biomarker targeting. The absence of dose-dependent toxicity or short-term oncogenic risk is notable, yet long-term carcinogenic potential remains unaddressed. Rigorous, independent trials must evaluate TA-65’s chronic toxicity, telomere-independent mechanisms, and utility within multidimensional aging frameworks. Clinical application may consider older adults with immunosenescence, incorporating safety surveillance for gastrointestinal and oncological endpoints. This graphical abstract summarizes the design, key findings, and conclusion of our meta-analysis on TA-65's effects on telomere length and functional aging outcomes. The online version contains supplementary material available at 10.1007/s10565-025-10115-6. Keywords: TA-65, Telomere paradox, Biomarker-function disconnect, Translational gerontology, Industry bias, Anti-aging pharmacology Telomere attrition represents a fundamental pillar of cellular aging, driving genomic instability, senescence, and systemic functional decline across organ systems (Ly et al. 2018 ; Martínez and Blasco 2015 ; De Rosa and Opresko 2023 ). Shortened leukocyte telomere length (LTL) is consistently linked to age-associated pathologies—from cardiovascular disease to neurodegeneration—imposing staggering societal burdens in aging populations worldwide (Lu and Pickett 2022 ; Cheng et al. 2021 ; Haycock et al. 2017 ; Guo et al. 2022 ). While telomerase activation offers a promising strategy to counteract this process, its paradoxical role in carcinogenesis poses critical safety concerns: constitutive telomerase upregulation may fuel malignant transformation, as evidenced by TERT promoter mutations in diverse cancers (Shim et al. 2024 ; Gao and Pickett 2022 ; Tsoukalas et al. 2019 ). This delicate balance between anti-aging efficacy and oncogenic risk underscores the urgent need for toxicologically informed evaluations of telomerase-targeting compounds. TA-65® ( cycloastragenol ), a small-molecule telomerase activator derived from Astragalus membranaceus, exemplifies this translational challenge. Preclinical studies demonstrate its capacity to elongate telomeres and improve metabolic parameters in aging models (Fernandez et al. 2018 ; Liu et al. 2017 ; Bawamia et al. 2023 ; Bernardes de Jesus et al. 2011 ). However, the mechanism underlying telomere elongation remains uncertain. While TA-65 is proposed to act as a telomerase activator, the evidence in humans is inconsistent (13), and its effects may alternatively involve a redistribution of immune cell populations toward naïve cells with inherently longer telomeres, rather than direct telomerase activation (Salvador et al. 2016 ; Muscari et al. 2023 ). These discrepancies stem from methodological heterogeneity, commercial bias (78% industry funding) (Huang et al. 2024 ), and insufficient attention to tissue-specific bioavailability and off-target effects. Crucially, the absence of integrated analyses reconciling molecular efficacy, functional outcomes, and toxicological risks hinders evidence-based clinical translation (Table S1 ). Our study addresses these gaps through the first systematic meta-analysis quantitatively dissecting TA-65’s dual roles in cellular aging and toxicity. Leveraging PRISMA-guided methodology across 8 randomized trials (n = 750), we integrate three innovative dimensions: (1) simultaneous assessment of telomere dynamics and functional aging metrics (frailty, inflammation), (2) toxicological profiling of dose-dependent adverse events and oncogenic risks, and (3) rigorous bias adjustment for commercial funding confounders. By employing GRADE evidence grading and meta-regression, we establish a biologically stratified risk–benefit framework—enabling identification of responsive subpopulations while mitigating safety hazards. This approach transcends prior reviews through its mechanistic focus on the telomere-function disconnect and proactive safety surveillance protocol. Throughout this paper, 'telomere length' refers to LTL unless otherwise specified. The societal imperative for this work is unequivocal: with global populations aging rapidly, ineffective or unsafe \"anti-aging\" interventions exacerbate healthcare costs and erode public trust. Our findings provide urgently needed evidence to guide regulatory policies, clinical practice, and future research—prioritizing independent validation of TA-65’s long-term safety, multidimensional aging endpoints, and tailored implementation for high-risk geriatric cohorts. By resolving the tension between TA-65’s molecular promise and its functional-toxicological realities, this work redefines standards for evaluating aging therapeutics in the precision medicine era. The aim of this systematic review is to evaluate the effects of TA-65 on LTL, functional outcomes, and inflammatory markers in adults aged ≥ 40 years, using PICOS criteria: Participants (adults ≥ 40 years), Intervention (TA-65 monotherapy), Comparison (placebo or no treatment), Outcomes (telomere length, functional metrics, inflammation), and Study design (RCTs and observational studies). Several primary limitations temper the interpretation of our findings. First, methodological heterogeneity in telomere measurement techniques (e.g., qPCR vs. Southern blot) may obscure true effect sizes, though our subgroup analyses suggested this was not a major source of bias. Second, the median follow-up of 12 months precludes a robust assessment of long-term oncological risks—a critical gap given telomerase's dual role in aging and carcinogenesis. and Third, several important subgroup analyses (e.g., by age and funding source) were conducted post-hoc rather than being pre-specified in our PROSPERO protocol. While these analyses provide valuable exploratory insights into potential sources of heterogeneity, their findings should be interpreted as hypothesis-generating and require confirmation in future pre-specified studies. Fourth, a key methodological concern is that none of the included studies controlled for or reported changes in immune cell distribution (e.g., the ratio of naïve to memory T-cells). As shifts in leukocyte subsets can significantly influence the average telomere length measured in bulk samples, the observed telomere elongation attributed to TA-65 could be partially confounded by changes in cell population composition rather than true telomere elongation within individual cells. Fifth, observed funnel plot asymmetry (p = 0.02, Egger's test) suggests the potential for unpublished negative studies, which may inflate the overall efficacy estimate. Finally, our initial subgroup analysis of dosage was limited by an imbalanced distribution of studies, with only one trial in the highest dose category. However, we mitigated this concern by performing supplementary analyses, including meta-regression and an alternative binary split, which consistently reinforced the conclusion of a non-significant dose–response relationship. Future trials should prioritize the standardization of telomere quantification, extend safety monitoring beyond 5 years, adopt open-data practices to minimize publication bias, and pre-specify key subgroup hypotheses to allow for more confirmatory analyses (Table 4 ). GRADE evidence profile TA-65 epitomizes the challenges of translational gerontology: while it may elongate telomeres, the absence of functional improvements questions the utility of telomerase activation as a standalone anti-aging strategy and underscores the inadequacy of single-biomarker approaches. Industry sponsorship biases exacerbate the stark molecular-clinical dichotomy. Until robust longitudinal evidence emerges, TA-65 remains investigational. Clinicians should restrict use to older adults (> 60 years) with biomarker-confirmed immunosenescence, enforcing strict stopping rules due to the telomere-function disconnect."},{"id":"source_9","type":"source","study":"Shorter leukocyte telomere length protects against NAFLD progression in children","year":2023,"doi":"10.1038/s41598-023-31149-y","url":"https://doi.org/10.1038/s41598-023-31149-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wojcicki 2023","evidence_span":"The Treatment of NAFLD in Children Trial (TONIC) was a NIH sponsored randomized, double-blind, placebo-controlled trial that was conducted at 10 research centers in the US with 173 patients (age 8–17) with biopsy confirmed NAFLD to assess the impact of vitamin E (400 IU twice daily) compared with 500 mg metformin twice daily versus placebo over 96 weeks (ClinicalTrials.gov identifier: NCT00063635 , 03/07/2003). The primary outcome was reduction in serum alanine aminotransferase (ALT) levels 12 and has been previously described in protocol and result publications including full CONSORT","excerpt":"The Treatment of NAFLD in Children Trial (TONIC) was a NIH sponsored randomized, double-blind, placebo-controlled trial that was conducted at 10 research centers in the US with 173 patients (age 8–17) with biopsy confirmed NAFLD to assess the impact of vitamin E (400 IU twice daily) compared with 500 mg metformin twice daily versus placebo over 96 weeks (ClinicalTrials.gov identifier: NCT00063635 , 03/07/2003). The primary outcome was reduction in serum alanine aminotransferase (ALT) levels 12 and has been previously described in protocol and result publications including full CONSORT checklist 13 , 14 . Different study sites each had the respective institutional review board approve the study. Informed consent was obtained from all children (subjects) and/or their legal guardians. For this secondary data analysis of study results, the University of California, San Francisco (UCSF) institutional review board (IRB) provided approval for this study and all guidelines and regulations were followed as indicated by the IRB. As part of the TONIC trial, whole blood was collected from children to collect DNA samples for potential genetic testing. DNA was extracted using the Qiagen Autopure LS DNA extractors using PUREGENE reagents using a modified salting out procedure. DNA was rehydrated by incubating at 56 °C for 1 h in a shaking incubator and placed on orbital shakers for 36–48 h prior to stock transfer. In the event a sample had a 260/280 ratio less than 1.7 (indicative of protein contamination), it was re-precipitated to improve its purity. DNA extraction was performed as soon as samples were received by the lab. Samples that were processed for DNA extraction and passed quality control were assigned storage locations by RUCDR STARLIMS in a − 80 °C freezer until LTL assay. Liver biopsies were obtained at study entry and subsequently after 96 weeks of therapy for all children enrolled in the TONIC trial. For all biopsies, the NASH Clinical Research Network (CRN) recommended a 16-gauge biopsy needle and a specimen length of at least 1.5 cm. The liver tissue was prepared locally for light microscopy with stains including hematoxylin and eosin, Masson’s trichrome and iron stain. All slides were sent to the data coordinating center for central reading by the study pathologists 15 . Slides were assessed for steatohepatitis, fibrosis and NAFLD Activity Score (NAS) (consisting of steatosis, lobular inflammation, and hepatocyte ballooning) using previously defined criteria 16 . Other specifics that were extracted from the biopsy included factors associated with metabolic disease and obesity (e.g., megamitochondria, glycogen nuclei, large lipogranulomas, microvesicular steatosis) and others associated with cell death and hepatic injury (e.g., acidophil bodies, Mallory bodies, microgranulomas, and pigmented macrophages). At baseline and 96 weeks of follow-up liver function tests and biomarkers of metabolic health including lipids and insulin resistance were also evaluated in the children. Anthropometrics including body mass index (BMI) and waist circumference were also assessed. Additionally, at baseline, autoantibodies associated with autoimmune hepatitis were assessed including anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA) and anti-mitochondrial antibody (AMA). This is the first study to evaluate the role of LTL as a predictive biomarker in pediatric patients with NAFLD including a high proportion with NASH. The mean value of 1.33 ± 0.23 T/S units in our population group is longer than that in other studies with children of roughly the same age including a study of Mexican children (1.03 ± 0/74) 18 and Brazilian ones (1.05 ± 0.42 T/S) in whites and 1.18 ± 0.57 T/S in black or mixed children) 19 . As described below, it is possible that the NAFLD disease process in children activates telomerase or other mechanisms to maintain telomere length, and this process may be indicative of a more severe liver disease process in children. Indeed, NAFLD is often more severe in children than adults with estimates of 18% of children diagnosed with stage 3 fibrosis 20 , 21 and the portal-based injury that is typical of"},{"id":"source_10","type":"source","study":"Unsuppressed Viremia and Lower CD4 Count Associated With Faster Telomere Attrition in African Children With Perinatal Human Immunodeficiency Virus on Long-term Antiretroviral Therapy","year":2026,"doi":"10.1093/infdis/jiag060","url":"https://doi.org/10.1093/infdis/jiag060","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Shellard 2026","evidence_span":"Remarkably, within just 48 weeks, we measured an increased rate of telomere attrition in participants who had VL >1000 RNA copies/mL across visits compared with those who had VL <1000 RNA copies/mL across visits. There is a dearth of longitudinal telomere data in CWH; however, our data are consistent with adult studies that have demonstrated that HIV seropositivity [ 33 ] and detectable VL [ 34 ] are associated with a greater rate of attrition. The timeframes for data collection in these studies ranged from 2 years [ 33 ] to 17 years [ 34 ], compared with the 48-week period between baseline","excerpt":"Remarkably, within just 48 weeks, we measured an increased rate of telomere attrition in participants who had VL >1000 RNA copies/mL across visits compared with those who had VL <1000 RNA copies/mL across visits. There is a dearth of longitudinal telomere data in CWH; however, our data are consistent with adult studies that have demonstrated that HIV seropositivity [ 33 ] and detectable VL [ 34 ] are associated with a greater rate of attrition. The timeframes for data collection in these studies ranged from 2 years [ 33 ] to 17 years [ 34 ], compared with the 48-week period between baseline and follow-up in the VITALITY cohort. Given that telomere attrition naturally occurs at a higher rate in children than in adults [ 35 ], our longitudinal analysis therefore highlights the distinct urgency to address accelerated immune degradation in African CWH, as they may be the most vulnerable population. Achieving long-term suppression could prevent and potentially reverse accelerated TL shortening in CWH, as demonstrated in adult populations [ 34 ]. Despite cART for at least 6 months before the study, 19.5% of the VITALITY cohort had an HIV VL >60 RNA copies/mL at baseline, of which 11.6% had VL >1000 RNA copies/mL. Most participants (79%) were on a highly potent INSTI-based cART regimen, yet 4.7% of participants had VL >1000 RNA copies/mL across both visits 1 year apart, ostensibly leading to faster HIV disease progression in this subgroup. HIV disease progression has been shown to accompany an accelerated immune aging phenotype, with characteristics such as T-cell regenerative failure, genotoxicity, mitochondrial dysfunction, and chronic inflammation [ 5 ]. These changes are in turn thought to underpin the increased risk of cardiovascular [ 36 ] and renal disease [ 37 ], malignancy [ 38 ], and neurological impairments [ 39 ] in people with HIV. Therefore, this study underscores the importance of maintaining sustained viral suppression among CWH as a priority to avert or prevent progression of HIV-associated comorbidities and to promote healthy aging among CWH. Previous clinical trials have demonstrated how community-based support [ 40 ] and injectable antiretroviral therapy [ 41 ] can improve adherence and reduce virological failure in Africa. Combined with a greater emphasis on HIV drug resistance screening and cART regimen adjustments [ 42 ], these interventions could produce a dynamic multipronged approach that may achieve better outcomes in CWH. Lower baseline CD4 T-cell count was associated with shorter TL and greater telomere attrition rate. Compared with HIV seropositivity and VL, there are fewer studies of relationships between CD4 T cells and TL, several of which have found no association [ 31 , 32 ]. In some studies, proportion of CD4, rather than CD4 count, was used as the indication of disease progression, which alongside the differences in study populations may explain discrepant results. Our data imply that immune aging may be a function of disease progression as well as the current status of viral control. Our study benefits from the inclusion of participants from 2 countries and in univariate analysis we found that Zimbabwean CWH had shorter TL than their Zambian counterparts. However, we did not adjust for the fact that Zimbabwean children were older, more often male, but less virally suppressed than Zambian children. Although evaluating differences between countries was not a primary objective, our data open the possibility that a separate biological factor might explain the relationship between HIV VL and TL that differs between study sites. There is a dearth of research into the variation of TL distribution, drivers of telomere attrition, and drug resistance mutations between countries in Africa, and this study gives the first indication that there may be heterogeneity that is relevant to how we address accelerated immune aging in these populations. There is accumulating evidence that CMV seropositivity reduces TL among T cells [ 27 ] and is associated with an increased risk of severe non-AIDS morbidities, particularly cardiovascular and cerebrovascular events, in adults with HIV [ 43 ]. Many children in Africa are CMV seropositive within 1 year of age [ 12 ], so we investigated CMV IgG among Zimbabwean VITALITY participants as an indication of the scale of CMV infection in our cohort. We found that CMV IgG was not associated with TL or the rate of attrition. It may be the case that CMV IgG does not fully capture the effect of CMV on immune aging, so other markers, such as CMV reactivation, should be considered in future studies. Alternatively, CMV infection may not have any effect on TL in this population, but we additionally note that our statistical power was halved in this sensitivity analysis. Given its anti-inflammatory and immunomodulatory effects, vitamin D supplementation has been proposed as an adjunct to cART [ 5 ]. This may specifically ameliorate heightened immune activation and could therefore preserve TL. A randomized controlled trial among American adults (>50 years) showed that daily vitamin D supplementation over a 5-year period significantly reduced telomere attrition at each f"},{"id":"source_11","type":"source","study":"Leukocyte Telomere Length Variants Are Independently Associated with Survival of Patients with Colorectal Cancer","year":2026,"doi":"10.3390/cancers18030490","url":"https://doi.org/10.3390/cancers18030490","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Sarkar 2026","evidence_span":"Telomere length was shorter in stage II patients compared to stage III ( p = 0.0005). However, this difference was mainly driven by the difference in age distribution. The median follow-up time for our study population was 6.98 (IQR = 2.13, 11.4) years. A total of 32.2% ( n = 324) patients died during the follow-up period. Overall survival after diagnosis was 0.882 (95% CI = 0.861–0.904) at 3 years and 0.791 (95% CI = 0.764–0.820) at 5 years and was higher for stage II patients ( p = 0.09, log-rank test). Disease-free survival estimates were 0.819 (95% CI = 0.794–0.845) at 3 years and 0.726","excerpt":"Telomere length was shorter in stage II patients compared to stage III ( p = 0.0005). However, this difference was mainly driven by the difference in age distribution. The median follow-up time for our study population was 6.98 (IQR = 2.13, 11.4) years. A total of 32.2% ( n = 324) patients died during the follow-up period. Overall survival after diagnosis was 0.882 (95% CI = 0.861–0.904) at 3 years and 0.791 (95% CI = 0.764–0.820) at 5 years and was higher for stage II patients ( p = 0.09, log-rank test). Disease-free survival estimates were 0.819 (95% CI = 0.794–0.845) at 3 years and 0.726 (95% CI = 0.696–0.757) at 5 years and were higher for stage II patients ( p = 0.002, log-rank test)."},{"id":"source_12","type":"source","study":"Leukocyte telomere length as a compensatory mechanism in vitamin D metabolism","year":2022,"doi":"10.1371/journal.pone.0264337","url":"https://doi.org/10.1371/journal.pone.0264337","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Agirbasli 2022","quote":"The study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation and seasonal changes on vitamin D related parameters, including 25(OH)D, 1,25(OH) 2 D parathormone (PTH), Vitamin D binding protein (VDBP), vitamin D receptor (VDR), and telomere length in a cohort of postmenopausal women (n = 102). The group was divided as supplementation (n = 52) and placebo groups (n = 50).","evidence_span":"The study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation and seasonal changes on vitamin D related parameters, including 25(OH)D, 1,25(OH) 2 D parathormone (PTH), Vitamin D binding protein (VDBP), vitamin D receptor (VDR), and telomere length in a cohort of postmenopausal women (n = 102). The group was divided as supplementation (n = 52) and placebo groups (n = 50).","excerpt":"The study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation and seasonal changes on vitamin D related parameters, including 25(OH)D, 1,25(OH) 2 D parathormone (PTH), Vitamin D binding protein (VDBP), vitamin D receptor (VDR), and telomere length in a cohort of postmenopausal women (n = 102). The group was divided as supplementation (n = 52) and placebo groups (n = 50). All parameters were measured before and after treatment. Serum VDBP levels were measured by ELISA method and VDR , GC (VDBP) gene expressions and relative telomere lengths were measured in peripheral blood mononuclear cells (PBMC) using a quantitative real-time PCR method. The results demonstrate that baseline levels were similar between the groups. After vitamin D supplementation 25(OH)D, 1,25(OH) 2 D, PTH and VDBP levels were changed significantly compared to the placebo group. At the end of the study period, LTL levels were significantly increased in both groups and this change was more prominent in placebo group. The change in GC expression was significant between treatment and placebo groups but VDR expression remained unchanged. Even though the study was designed to solely assess the effects of vitamin D supplementation, LTL was significantly increased in the whole study group in summer months suggesting that LTL levels are affected by sun exposure and seasonal changes rather than supplementation. The study displayed the short-term effect of Vitamin D supplementation on vitamin D, PTH levels, LTL and vitamin D associated gene expressions. The relation between Vitamin D and LTL is not linear and could be confounded by several factors such as the population differences, regional and seasonal changes in sun exposure. Vitamin D is a steroid hormone synthesized in the skin via sunlight. It plays an important role in biological systems including mineralization of bones, stabilization of blood calcium levels, modulating the innate and adaptive immune responses, and nerve conduction. Vitamin D deficiency is defined as 25-hydroxy-vitamin D (25(OH)D) concentrations lower than 20 ng/ml (50 nmol/l) whereas insufficiency is defined as levels ranging from 20 to 29.9 ng/ml [ 1 ]. Population studies indicate that 25(OH)D deficiency is a risk factor for common chronic complex diseases such as cardiovascular disease, diabetes mellitus, neuropsychiatric disorders, and autoimmune diseases. Obesity and vitamin D deficiency in women are important public health problems [ 2 , 3 ]. Vitamin D deficiency can be seen at any age and is highly prevalent in postmenopausal women due to the decrease in estrogen levels [ 4 ]. Aging, insufficient exposure to sunlight, obesity, diet, and hyperlipidemia are also risk factors for vitamin D deficiency. For instance, among the elderly population, 61% in the United States, 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran are vitamin D deficient [ 5 ]. Although there is still controversy about the amount and duration of vitamin D supplementation, vitamin D deficient adults require 6000 IU/day of vitamin D 3 for 8 weeks or 50,000 IU of vitamin D 3 once weekly for 8 weeks [ 1 ]. Seasonal variations affect vitamin D levels but as a carrier protein for vitamin D metabolites; vitamin D binding protein (VDBP) levels remain mostly stable [ 6 ]. Telomere length is an important parameter in chromosome stability and chronic diseases. Telomeres are repetitive DNA sequences at the ends of the chromosomes and protect the chromosomal integrity. Telomeres maintain the genomic and cellular stability. Telomere length decreases with aging, inflammation and oxidative stress. Telomere length shortening is associated with many chronic diseases [ 7 , 8 ]. Vitamin D is known to be protective for aging and age-related chronic diseases. It also plays a role in the cell’s vital activities such as differentiation, proliferation and apoptosis [ 9 ]. Vitamin D levels are related to aging and telomere length as it reduces inflammation and is related to genomic stability [ 10 , 11 ]. 1,25- Dihydroxyvitamin D (1,25(OH) 2 D) receptors are present in leukocytes and this may support the effect of vitamin D in leukocyte telomere length (LTL) [ 12 ]. There are numerous studies investigating the LTL in postmenopausal women. Although ethnicity does not play a role in LTL, age and gender are among the determinants of LTL [ 13 , 14 ]. Decreased estrogen levels after menopause, a pivotal factor in the biology of aging, were positively associated with LTL [ 13 ]. Studies also indicate from the premenopausal period through the perimenopausal period to the postmenopausal period there is gradual attrition in LTL which then turned out to be more stable after the postmenopausal period [ 15 ]. Previous studies demonstrated the association between telomere length and vitamin D levels in cross sectional studies [ 16 ]; however, the short-term effects of vitamin D supplementation on telomere length remain to be elucidated. The effects of Vitamin D supplementation or seasonal changes on telomere length remain largely unknown. Therefore, this study was designed as a placebo-controlled study to investigate the short-term effects of vitamin D supplementation on vitamin D related parameters, including 25(OH)D, 1,25(OH) 2 D and PTH, VDBP, VDR, and telomere length in a cohort of postmenopausal women. This study included healthy 102 postmenopausal women (25(OH)D<20 ng/ml (<50 nmol/l)) who had never used vitamin D supplements or hadn’t used vitamin supplements for at least a year. Subjects were divided into two groups as Vitamin D group taking vitamin D supplements (n = 52) and the placebo group (n = 50). Subjects were randomly selected for allocating vitamin D supplement/placebo by toss of a coin method. Enrollment of subjects started in October 2017, ended in June 2018. Demographic variables were displayed in Table 2 . Baseline characteristics were similar between the groups. The distribution between Vitamin D and placebo groups was similar for smoking and physical activity status ( Table 2 ). Baseline biochemical parameters were distributed homogenously in both groups and were shown in Table 3 . Mean values ± standard deviations were shown when parameters were distributed normally. Median and (IQR) were shown when the parameters were in abnormal distribution. *Significance between groups is shown as p-value <0.05. Mean values ± standard deviations were shown when parameters were distributed normally. Median and (IQR) were shown when the parameters were in abnormal distribution. *Significance between groups is shown as p-value <0.05 and labeled as bold. Vitamin D supplementation and placebo groups have similar 25(OH)D levels before vitamin D treatment ( Table 4 ). The change in vitamin D levels was statistically significant both in the placebo (11.8 ± 4.2 vs 15.2 ± 5.9 before and after treatment, respectively, p <0.001) and in the vitamin D"},{"id":"source_13","type":"source","study":"Combined physical and cognitive training enhances telomere length in mild cognitive impairment patients","year":2026,"doi":"10.1186/s12877-026-07380-3","url":"https://doi.org/10.1186/s12877-026-07380-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Borghini 2026","evidence_span":"MCI patients had shorter LTL than controls ( p = 0.02), and short LTL was associated with a higher risk of MCI (OR adjusted = 2.6; 95%CI, 1.1–6.0; p = 0.03). Training improved ADAS-cog scores (T 0 = 15.1 ± 4.8 to T 7 = 13.4 ± 5.0, p = 0.01) and increased LTL (T 0 = 0.97 ± 0.21 to T 7 = 1.04 ± 0.23, p = 0.04). hTERT mRNA levels were negligible in MCI patients at T0 and T7, indicating inactive telomerase. TERRA expression increased in untrained MCI ( p = 0.02), which may reflect impaired telomere homeostasis.","excerpt":"MCI patients had shorter LTL than controls ( p = 0.02), and short LTL was associated with a higher risk of MCI (OR adjusted = 2.6; 95%CI, 1.1–6.0; p = 0.03). Training improved ADAS-cog scores (T 0 = 15.1 ± 4.8 to T 7 = 13.4 ± 5.0, p = 0.01) and increased LTL (T 0 = 0.97 ± 0.21 to T 7 = 1.04 ± 0.23, p = 0.04). hTERT mRNA levels were negligible in MCI patients at T0 and T7, indicating inactive telomerase. TERRA expression increased in untrained MCI ( p = 0.02), which may reflect impaired telomere homeostasis."},{"id":"source_14","type":"source","study":"Impact of a nutritional supplement during gestation and early childhood on child salivary cortisol, hair cortisol, and telomere length at 4–6 years of age: a follow-up of a randomized controlled trial","year":2020,"doi":"10.1080/10253890.2020.1728528","url":"https://doi.org/10.1080/10253890.2020.1728528","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Oaks 2020","evidence_span":"Our objective was to evaluate the long-term effect of nutritional supplementation during gestation and early childhood on child cortisol and buccal telomere length (a marker of cellular aging) at 4–6 years of age. We conducted a follow-up study of children born to women who participated in a nutritional supplementation trial in Ghana. In one group, a lipid-based nutrient supplement (LNS) was provided to women during gestation and the first 6 months postpartum and to their infants from age 6 to 18 months. The control groups received either iron and folic acid (IFA) during gestation or multiple","excerpt":"Our objective was to evaluate the long-term effect of nutritional supplementation during gestation and early childhood on child cortisol and buccal telomere length (a marker of cellular aging) at 4–6 years of age. We conducted a follow-up study of children born to women who participated in a nutritional supplementation trial in Ghana. In one group, a lipid-based nutrient supplement (LNS) was provided to women during gestation and the first 6 months postpartum and to their infants from age 6 to 18 months. The control groups received either iron and folic acid (IFA) during gestation or multiple micronutrients during gestation and the first 6 months postpartum, with no infant supplementation. At age 4–6 years, we measured hair cortisol, buccal telomere length, and salivary cortisol before and after a stressor. Salivary cortisol was available for 364 children across all three trial arms and hair cortisol and telomere length were available for a subset of children ( n = 275 and 278, respectively) from the LNS and IFA groups. Telomere length, salivary cortisol, and hair cortisol did not differ by supplementation group. Overall, these findings suggest that nutritional supplementation given during gestation and early childhood does not have an effect on child stress response or chronic stress in children at 4–6 years. Trial registration: ClinicalTrials.gov Identifier NCT00970866 . This study addressed a research gap about whether improved nutrition during pregnancy and early childhood impacts telomere length and cortisol in preschool children. There was no difference in child telomere length or cortisol between two trial arms of a nutritional supplementation trial that began during pregnancy. The research outcomes indicate lipid-based nutrient supplements, a relatively new form of supplementation, do not have an effect on markers of stress or cellular aging measured in later childhood. Keywords: Cortisol, telomere length, pregnancy, nutrition, child Cortisol is a hormone released by the hypothalamic-pituitary-adrenal (HPA) axis in response to mental and physical stressors (Dickerson & Kemeny, 2004 ). Additionally, cortisol has a diurnal pattern in which cortisol concentrations typically peak 30–40 min after awakening and then decline throughout the day, with lowest concentrations in the evening (Hucklebridge, Hussain, Evans, & Clow, 2005 ). Previous studies have demonstrated that the regulation of both the stress response and diurnal pattern of cortisol can be impacted by a wide range of factors (Cohen et al., 2006 ; Danese & McEwen, 2012 ; Liu et al., 2017 ), including nutrition (Keenan et al., 2016 ; Oaks et al., 2016 ). Recent research suggests that permanent dysregulation of the HPA axis can occur during gestation and early childhood (Alexander et al., 2012 ). Whether nutrition during this critical time period can have a long-term impact on the HPA axis of the offspring is unknown. Perceived stress and cortisol reactivity to stress are associated with shorter telomere length (Parks et al., 2009 ; Puterman et al., 2010 ), a biomarker of cellular aging (Collado, Blasco, & Serrano, 2007 ). Telomeres are structures at the end of chromosomes that become shorter with each cell division until reaching a limit at which point cell apoptosis or loss of cell function occurs. Shorter telomere length is associated with cardiovascular disease (Fitzpatrick et al., 2006 ), cancer (Ennour-Idrissi, Maunsell, & Diorio, 2017 ), and mortality (Cawthon, Smith, O'Brien, Sivatchenko, & Kerber, 2003 ). A meta-analysis of seven trials studying the impact of nutrition on telomere length reported no significant relationship; however, all trials have been conducted in adult populations and the meta-analysis noted strong heterogeneity among the studies in terms of type and duration of dietary intervention (Pérez et al., 2017 ). We previously conducted a three-armed nutrition supplementation trial in Ghana, located in West Africa, to determine the effect of a LNS on maternal and child health outcomes when given during gestation, the first 6 months postpartum, and to the offspring from 6–18 months of age. In addition to greater birth weight and child growth in the LNS trial arm (Adu-Afarwuah et al., 2015 ), we found that among younger women, those provided with LNS during gestation had lower morning salivary cortisol in late gestation than those receiving iron and folic acid (IFA) capsules or multiple micronutrients (MMNs) capsules (Oaks et al., 2016 ). LNS and MMN had identical amounts of 18 micronutrients, but LNS also had four additional micronutrients and essential fatty acids, including the omega-3 fatty acid, alpha-linolenic acid, a necessary component for pathways that produce the anti-inflammatory response. As cortisol can cross the placenta, we now aim to determine if there was a lasting effect on their children. The present study is part of a follow-up study conducted when the children were 4–6 years of age. We investigated whether the nutritional supplementation provided during gestation and early childhood had an impact on child stress response, hair cortisol (a measurement of cumulative cortisol), and buccal telomere length. We hypothesized that children in the LNS trial arm would have lower mean hair cortisol concentrations and a longer mean telomere length than children who received no supplementation and were born to mothers receiving IFA. We also hypothesized that the LNS children would have a better regulated stress response compared with children who received no supplementation and were born to mothers receiving IFA or MMN. Our previous research from the main trial in Ghana showed that among younger women, late pregnancy morning salivary cortisol concentration was lower among those receiving LNS compared with those receiving IFA or MMN (Oaks et al., 2016 ). In this follow-up study, we examined the hypothesis that provision of LNS during gestation and early childhood would alter offspring salivary and hair cortisol concentrations and buccal telomere length at 4–6 years of age. Buccal telomere length, hair cortisol concentrations, and salivary cortisol concentrations before and after a finger prick were similar across supplementation groups, thus our results do not support our primary hypothesis. We did find evidence of an interaction between the nutrition supplement and maternal age: among children born to older mothers, those in the LNS group had longer telomere length than those in the IFA group, with the opposite seen among children born to younger mothers. However, it is possible that this finding was due to chance, as the interaction did not remain significant after correcting for multiple hypothesis testing. To our knowledge, this is the first study to examine the long-term effect of a nutrition supplement given during both gestation and early childhood on either child telomere length or cortisol concentration. Previous studies have shown that nutrition supplementation during gestation modulates the offspring salivary cortisol response to a stressor in both animals (Grissom, George, & Reyes, 2017 ) and humans (Keenan et al., 2016 ). In the present study, salivary cortisol concentration generally did not exhibit a stress response to the finger prick. Previous studies have reported that 4–6 year olds are one of the more challenging groups in which to elicit the stress response (Gunnar, Talge, & Herrera, 2009 ). Future studies would benefit from exploring other stressors. In terms of child telomere length, our results are consistent with a prenatal omega-3 supplementation trial that showed no effect on child telomere length at 12 years of age (See et al., 2016 ) and a study of the Dutch famine birth cohort in which undernutrition during gestation was not associated with offspring telomere length at 68 years of age (de Rooij et al., 2015 ). However, two other cohort studies have reported that higher serum folate and vitamin D concentrations during pregnancy are associated with longer telomere length in newborns (Entringer et al., 2015 ; Kim et al., 2018 ). In our study, all three groups received folate so it is possible that folate has an impact on telomere length that we could not examine in this study. However, only the LNS and MMN groups received vitamin D as part of the assigned supplement and we did not find a difference in telomere length between the IFA and LNS groups, so our study does not support a focus on maternal vitamin D supplementation for impacting offspring telomere length in this study setting. It is possible that the nutritional status of the mother during gestation has an effect on newborn telomere length that then is not evident at older ages, although research is still limited in this area and further investigation is needed. There are several biological mechanisms that could underlie effects of a maternal or early childhood nutritional supplement on child cortisol and telomere length. Omega-3 fatty acids can facilitate the anti-inflammatory response. As inflammation is associated with both higher cortisol (Silverman & Sternberg, 2012 ) and shorter telomere length (Wong, Vivo, Lin, Fang, & Christiani, 2014 ), it is possible that omega-3 supplementation may lead to lower cortisol concentrations and longer telomeres. This is particularly relevant during pregnancy, which is a state of chronic inflammation. Folate acts as a methyl donor and is necessary for fetal DNA synthesis and cell proliferation. Folate deficiency can lead to a compromised DNA structure that may affect the telomere sequence (Entringer et al., 2015 ). Vitamin D can upregulate telomerase activity, an essential enzyme for telomere maintenance. Additionally, Vitamin D promotes the expression of Klotho, a protein associated with cellular aging. An in vitro study using human umbilical cells demonstrated that Klotho deficiency induces telomere shortening (Buendía et al., 2015 ). Our study has several strengths and limitations worth noting. We had relatively low loss-to-follow-up, enrolling approximately 80% of children from the main trial in the follow-up study. While any loss-to-follow-up can contribute to attrition bias, the likelihood of attrition bias for this study is low. We found baseline characteristics to be similar between those with and without a saliva sample at 4–6 years of age aside from a slight difference in maternal age."},{"id":"source_15","type":"source","study":"Effects of Hawthorn Fruit Supplementation on Facial Skin Phenotypes and Leukocyte Telomere Length Stratified by TERT Polymorphisms","year":2025,"doi":"10.3390/nu17121983","url":"https://doi.org/10.3390/nu17121983","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kim 2025","evidence_span":"Results: The HF supplementation group exhibited significantly improved hydration scores compared to the control group; the mean changes (follow-up measure—baseline measure) [standard deviation] in hydration scores over 6 months were 1.71 [8.18] and −3.00 [8.42] for the supplementation group and control group, respectively ( p < 0.05) (Cohen’s d = 0.57). However, changes in other phenotypes and leukocyte TL were similar between groups. The genotype-specific analysis revealed that the improvement of hydration state was most noticeable among carriers with the CC genotype of rs7705526 ( p < 0.05)","excerpt":"Results: The HF supplementation group exhibited significantly improved hydration scores compared to the control group; the mean changes (follow-up measure—baseline measure) [standard deviation] in hydration scores over 6 months were 1.71 [8.18] and −3.00 [8.42] for the supplementation group and control group, respectively ( p < 0.05) (Cohen’s d = 0.57). However, changes in other phenotypes and leukocyte TL were similar between groups. The genotype-specific analysis revealed that the improvement of hydration state was most noticeable among carriers with the CC genotype of rs7705526 ( p < 0.05) (Cohen’s d = 1.50) and that the HF supplementation group exhibited reduced wrinkle scores while the control group showed increased scores among carriers of the AA genotype of rs2853669 ( p < 0.05) (Cohen’s d = 1.40). In correlation analysis for all participants, hydration scores were positively correlated with leukocyte TL (Spearman correlation coefficient: 0.36; p < 0.05). Conclusions: These findings suggest that HF consumption may have potential anti-skin-aging effects. Future studies may need to elucidate the biological mechanisms underlying these effects. Skin changes related to aging include wrinkles, dryness, pigmentation, and loss of elasticity. These phenotypes of skin aging are determined by multiple risk factors, such as age, gender, ethnicity, genetic factors, ultraviolet (UV) radiation from sunlight, exposures to air pollution or toxic substances, smoking, and inadequate diet [ 1 ]. Particularly, modifiable factors including diet or nutraceuticals are of interest to peoples who want to improve their skin. A number of clinical trials have attempted to evaluate the effects of nutraceutical components, such as collagen peptide, polysaccharides, and botanical extracts on skin improvement [ 2 ]. Hawthorn is a deciduous tree, belonging to the Crataegus genus in the Rosaceae family, with a well-established history as a medicinal herb. Hawthorn fruit (HF) contains various bioactive compounds, such as polyphenolic compounds, fatty acids, and organic acids [ 3 ]. In an experimental study, in which mouse models with skin damage were treated with a high dose of HF extract, their skin moisture increased by 34% [ 4 ]."},{"id":"source_16","type":"source","study":"Selenium and Coenzyme Q 10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality—Sub-Study of a Randomized Clinical Trial","year":2022,"doi":"10.3390/nu14163346","url":"https://doi.org/10.3390/nu14163346","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Opstad 2022","evidence_span":"Our aim was to determine whether 42 months of selenium and coenzyme Q 10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium ( n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group ( p = 0.23). At 42","excerpt":"Our aim was to determine whether 42 months of selenium and coenzyme Q 10 supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium ( n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group ( p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL ( p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival ( p = 0.03)."},{"id":"source_17","type":"source","study":"Shortened Telomere Length as a Risk Factor for Idiopathic Pulmonary Fibrosis: A Meta-Analysis","year":2026,"doi":"10.2174/0118743064421488251017061020","url":"https://doi.org/10.2174/0118743064421488251017061020","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Fachrucha 2026","evidence_span":"The pooled standard mean difference (SMD) with 95% confidence interval (CI) of telomere length was calculated using a random-effect model. Six original studies containing 622 IPF patients and 544 controls were included in the meta-analysis. The study designs were case control and cohort. Pooled analysis showed shorter telomere length in IPF patients compared to controls (SMD: -0.84, 95%CI -1.21 to -0.48, Z = 4.55, p < 0.00001). Subgroup analysis showed that steeper telomere shortening was found in lung tissue compared to peripheral blood sample. The findings suggested that telomere length may","excerpt":"The pooled standard mean difference (SMD) with 95% confidence interval (CI) of telomere length was calculated using a random-effect model. Six original studies containing 622 IPF patients and 544 controls were included in the meta-analysis. The study designs were case control and cohort. Pooled analysis showed shorter telomere length in IPF patients compared to controls (SMD: -0.84, 95%CI -1.21 to -0.48, Z = 4.55, p < 0.00001). Subgroup analysis showed that steeper telomere shortening was found in lung tissue compared to peripheral blood sample. The findings suggested that telomere length may be closely associated with the pathogenesis of pulmonary fibrosis. Repeated cell divisions gradually shorten telomeres that lead to senescence and apoptosis. Premature senescence disrupts the balance of lung epithelial cells, potentially activating lung remodeling processes that result in fibrotic damage through senescence-associated secretory phenotype (SASP). This study shows significant shorter telomere lengths in IPF patients compared to healthy controls that suggest telomere as a risk factor for IPF occurrence. These findings highlight the value of telomere assessment not only for early detection but also as a potential predictive biomarker for clinical outcomes. Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease with limited life expectancy after diagnosis. The disease is characterized by continuous scarring of the lung parenchyma, leading to a decline in pulmonary function [ 1 , 2 ]. These injuries stimulate alveoli to release cytokines and growth factors that promote recruitment, proliferation, and differentiation of lung fibroblasts into myofibroblasts [ 3 , 4 ]. This cascade creates a loop that leads to excessive collagen deposition [ 5 ], along with alveolar reepithelialization failure [ 6 ]. IPF is recognized as a rare disease [ 7 ]; however, its incidence has increased in recent years [ 8 ]. This rise is due to improvements in diagnostic methods and the aging of the population [ 1 ]. IPF is the most prevalent and morbid disease among Idiopathic Interstitial Pneumonias (IIPs) [ 9 ]. The median survival time ranges from 2 to 4 years, indicating a poor prognosis [ 10 ]. Pulmonary function can rapidly decline, leading to respiratory failure, whereas 10-15% of patients experience an unusually rapid decline within months [ 10 ]. Epidemiological studies in North American and European populations report 3 to 9 cases per 100,000 people per year [ 10 ]. The Incidence in Asia and South America is estimated to be lower, around 0.5 to 4.2 cases per 100,000 people per year [ 11 ]. However, these numbers continue to rise, mainly among elderly individuals over 65 years [ 12 ]. Additionally, male gender is also a prominent risk factor for IPF incidence [ 13 ]. Multiple telomere-related genes that cause telomere shortening have been associated with a significant percentage of IPF cases [ 14 ]. Mutations in telomere genes are found in 25% of familial cases and 1% to 3% of sporadic cases [ 15 ]. Moreover, shortened telomeres are also observed in sporadic cases without mutations [ 15 ]. It is reported that 10% of the patients have telomeres as short as those in mutation carriers. These findings lead to a poor prognosis due to impaired tissue repair [ 16 ]. Telomere shortening has also been observed in studies of other lung diseases with fibrosis phenotypes [ 17 ]. Given the fragmented evidence on telomere length and IPF, a meta-analysis is warranted to synthesize available findings; however, such an effort must be conducted with rigorous methodology to ensure the representativeness and reliability of the results [ 18 ]. This review aims to analyze the association between short telomere length and IPF incidence. This study conducted a systematic review and meta-analysis to determine the influence of telomere length on IPF occurrence, with the goal of providing new insights into early-stage diagnosis and effective therapeutic strategies [ 19 ]. The initial search produced 678 potentially relevant articles, and 260 records were retrieved after removing duplicates (Fig. 1 ). A total of 379 articles were excluded due to the discordance with the inclusion/exclusion criteria, resulting in 39 eligible articles for full-text screening. After careful evaluation, 33 articles were removed. Eventually, six articles were included in this current systematic review and entered the meta-analysis process. This study shows significantly shorter telomere length in IPF patients compared to healthy controls (p < 0.00001), observed in both peripheral blood and lung tissue."},{"id":"source_18","type":"source","study":"Association between human herpesvirus 6 status and sarcopenia risk: a UK biobank cohort study with sex-specific patterns and telomere length modification","year":2025,"doi":"10.3389/fimmu.2025.1623291","url":"https://doi.org/10.3389/fimmu.2025.1623291","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Liu 2025","evidence_span":"Individuals with DR-only positive HHV-6 status exhibited significantly elevated odds of sarcopenia at baseline (OR = 3.77, 95% CI: 1.44-8.08) and approximately fivefold increased risk during follow-up (HR = 4.76, 95% CI: 1.19-19.10). Sex-stratified analyses revealed pronounced male vulnerability to DR-only positivity (OR = 5.23, 95% CI: 1.74-12.60), while females showed associations only with typical positive status (OR = 1.63, 95% CI: 1.00-2.49). Telomere length significantly modified these relationships, with stronger associations among males with longer telomeres (OR = 6.57, 95% CI:","excerpt":"Individuals with DR-only positive HHV-6 status exhibited significantly elevated odds of sarcopenia at baseline (OR = 3.77, 95% CI: 1.44-8.08) and approximately fivefold increased risk during follow-up (HR = 4.76, 95% CI: 1.19-19.10). Sex-stratified analyses revealed pronounced male vulnerability to DR-only positivity (OR = 5.23, 95% CI: 1.74-12.60), while females showed associations only with typical positive status (OR = 1.63, 95% CI: 1.00-2.49). Telomere length significantly modified these relationships, with stronger associations among males with longer telomeres (OR = 6.57, 95% CI: 1.43-30.16) and females with shorter telomeres (OR = 1.94, 95% CI: 1.08-3.49). Results remained consistent across sensitivity analyses using alternative sarcopenia definitions. This study identifies novel associations between HHV-6 status, particularly DR-only positivity, and increased sarcopenia risk in a sex-specific manner. These associations are further modified by telomere length, indicating potential interactions between viral integration, cellular senescence, and muscle health. Our findings contribute to emerging research on infectious correlates of age-related muscle deterioration and may inform future investigations into preventive strategies. Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, represents a significant global health concern affecting approximately 10% of older adults worldwide ( 1 , 2 ). Recognized as a geriatric syndrome with substantial clinical implications, sarcopenia contributes to increased risk of falls, functional decline, disability, poor quality of life, and premature mortality ( 3 , 4 ). The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) diagnostic algorithm defines sarcopenia through the concurrent presence of reduced muscle strength and diminished skeletal muscle mass, with severe sarcopenia further characterized by impaired physical performance ( 5 ). While age-related physiological changes remain the primary driver of sarcopenia development, growing evidence suggests that various modifiable and non-modifiable factors—including chronic inflammation, metabolic disorders, malnutrition, and genetic predisposition—significantly influence its pathogenesis ( 6 , 7 ). In recent years, increasing attention has focused on the potential role of infectious agents, particularly viruses with persistent or latent infection profiles, in age-related degenerative conditions ( 8 , 9 ). Human herpesvirus 6 (HHV-6), a ubiquitous beta-herpesvirus with a high global seroprevalence exceeding 90% in adults, exhibits distinct biological characteristics that may have implications for chronic health conditions ( 10 ). HHV-6 exists in two closely related variants (HHV-6A and HHV-6B) and demonstrates unique genomic integration capabilities, with approximately 1% of the population carrying chromosomally integrated HHV-6 (ciHHV-6) ( 11 , 12 ). This integration can manifest as different molecular phenotypes, including “typical positive” (with integration of both the direct repeat [DR] and unique [U] regions) and “DR-only positive” (with selective integration or amplification of DR sequences) ( 13 , 14 ). Chronic viral infections may contribute to sarcopenia pathophysiology through several biological mechanisms. Persistent viral presence can induce sustained low-grade inflammation, characterized by elevated pro-inflammatory cytokines (IL-6, TNF-α) that promote protein catabolism and impair muscle regeneration ( 15 ). Viral infections may also accelerate cellular senescence processes through oxidative stress pathways and telomere attrition, potentially connecting viral burden with accelerated biological aging ( 16 , 17 ). HHV-6, specifically, has been associated with altered immune function, systemic inflammation, and tissue-specific pathologies that could theoretically influence muscle homeostasis ( 18 , 19 ). Furthermore, emerging evidence suggests sex-specific differences in both viral immune responses and sarcopenia manifestation, highlighting the importance of gender-stratified analyses in investigating such associations ( 20 , 21 ). Despite these potential mechanistic links, the relationship between HHV-6 infection status and sarcopenia remains largely unexplored. Previous investigations have examined associations between cytomegalovirus (another herpesvirus) seropositivity and frailty or physical function ( 22 ), but specific studies addressing HHV-6 and skeletal muscle health are notably absent from the literature. Additionally, the potential modifying effects of important biological factors—such as systemic inflammation, body composition, genetic susceptibility, and telomere length—on virus-mediated muscle pathology have not been adequately characterized ( 23 , 24 ). Given these knowledge gaps, this study aimed to comprehensively investigate the association between HHV-6 status and sarcopenia using the UK Biobank cohort. Specifically, we sought to: 1) determine whether different HHV-6 integration profiles are associated with sarcopenia risk; 2) explore potential sex-specific differences in these associations; 3) examine the modifying effects of biological factors including inflammation markers, body mass index, genetic predisposition, and telomere length; and 4) establish temporal relationships through both cross-sectional and longitudinal analyses. By elucidating these relationships, this study contributes to the growing understanding of potential infectious determinants of sarcopenia and may inform future preventive and therapeutic strategies. This study provides novel evidence of a significant association between HHV-6 status and sarcopenia risk, with distinctive patterns observed across different viral integration profiles and between sexes. Our findings demonstrate that individuals with DR-only positive HHV-6 status exhibited nearly fourfold higher odds of sarcopenia at baseline and approximately fivefold elevated risk during follow-up after comprehensive adjustment for confounding factors. Notably, these associations were predominantly driven by pronounced effects in males, where DR-only positivity conferred over fivefold increased sarcopenia risk, while females showed significant associations only with typical positive status. Furthermore, telomere length significantly modified the HHV-6-sarcopenia relationship, with distinct interaction patterns observed between sexes. The observed association between HHV-6 DR-only positive status and sarcopenia represents a novel finding in the field of muscle health. Previous investigations have primarily focused on CMV in relation to physical function and frailty ( 29 , 30 ), with limited attention to other herpesviruses. Wang et al. demonstrated that CMV seropositivity was associated with increased frailty risk in older people ( 22 ), while Matheï et al. reported associations between CMV infection and inflammatory markers linked to physical decline ( 31 ). Our results extend this emerging field by identifying HHV-6, particularly the DR-only phenotype, as a potential viral determinant of muscle health. The selective association with DR-only positivity, rather than typical positive status, suggests that specific molecular mechanisms related to partial viral genome integration may contribute to muscle pathology. The marked sexual dimorphism observed in our analyses aligns with growing evidence of sex-specific immunological responses to viral infections ( 32 , 33 ). The pronounced association between DR-only positivity and sarcopenia in males may reflect sex-based differences in immune responses to latent viral infections. Testosterone has been shown to modulate pro-inflammatory cytokine production ( 34 ), potentially exacerbating muscle catabolism in the presence of persistent viral triggers. Conversely, the female-specific association with typical positive status suggests distinct pathophysiological pathways. Estrogen’s immunomodulatory effects may alter viral reactivation patterns ( 35 ), triggering different inflammatory cascades associated with complete viral integration. These findings underscore the importance of sex-stratified analyses in investigations of infectious determinants of age-related conditions. Particularly intriguing was the interaction between telomere length and HHV-6 status in modifying sarcopenia risk. In males, DR-only positivity conferred elevated sarcopenia risk regardless of telomere length, though the effect was slightly more pronounced among those with longer telomeres. This counterintuitive finding challenges the traditional view that shorter telomeres, typically associated with cellular senescence and aging ( 36 ), would exacerbate pathological processes. One potential explanation involves the relationship between telomere biology and viral integration. HHV-6 demonstrates a unique tropism for telomeric regions ( 37 , 38 ), potentially disrupting telomere function even when length appears preserved. Michael L Wood et al. found that HHV-6 integration can lead to telomere lengthening at DRL-T2 ( 39 ). The HHV-6 genome can be excised and reactivated in this manner. Therefore, the DR-only group may represent those with reactivation. Furthermore, viral integration into telomeric regions may impair the recruitment of telomere-associated proteins necessary for proper telomere maintenance ( 40 ), creating functional deficits independent of measured length. However, measured telomere length reflects only one aspect of telomere biology, and the association reported here is observational and does not establish causation. These observed interactions may reflect an underlying confounding factor or biological synergy that has yet to be identified. The biological mechanisms underlying the observed associations likely involve complex interactions between viral persistence, inflammation, and muscle homeostasis. DR-only positivity, representing selective integration or amplification of direct repeat viral sequences, may disrupt host genomic stability through insertional mutagenesis ( 41 , 42 ). Such genomic alterations could potentially affect genes involved in myogenesis or muscle protein synthesis. Additionally, viral integration may trigger chronic low-grade inflammation—a well-established contributor to sarcopenia pathogenesis ( 43 ). HHV-6 has been shown to induce pro-inflammatory cytokines including IL-6 and TNF-α ( 44 ), which promote protein catabolism and impair muscle regeneration. The sex-specific patterns observed may reflect differential inflammatory responses, with males typically exhibiting more pronounced pro-inflammatory profiles following immune challenges ( 29 , 45 ). Mitochondrial dysfunction represents another potential mechanistic link between HHV-6 and sarcopenia. HHV-6 proteins have been shown to localize within mitochondria, altering respiratory function and promoting oxidative stress ( 46 , 47 ). Mitochondrial impairment is increasingly recognized as a central feature of sarcopenia ( 48 ), potentially explaining how viral integration contributes to muscle deterioration. Furthermore, cellular senescence, a biological process characterized by irreversible cell cycle arrest and pro-inflammatory secretory phenotype, may be accelerated by chronic viral presence ( 49 ), contributing to impaired satellite cell function and compromised muscle regenerative capacity. While no significant associations were found between EBV/CMV serostatus and sarcopenia in our cohort (both p>0.05), these results must be interpreted with caution."},{"id":"source_19","type":"source","study":"An Anthocyanin- and Anti-Ageing Amino Acids-Enriched Pigmented Rice Innovation Promotes Healthy Ageing Through the Modulation of Telomere, Oxidative Stress and Inflammation Reduction: A Randomized Clinical Trial","year":2025,"doi":"10.3390/ijms262210911","url":"https://doi.org/10.3390/ijms262210911","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wattanathorn 2025","evidence_span":"Thus, the reduction in AIP which was observed in subjects who consumed high doses of “Zuper rice” for 12 weeks may be partly associated with oxidative stress.","excerpt":"Thus, the reduction in AIP which was observed in subjects who consumed high doses of “Zuper rice” for 12 weeks may be partly associated with oxidative stress."},{"id":"source_20","type":"source","study":"Longer leukocyte telomere length increases the odds of premature rupture of membranes: a cross-sectional study based on UK Biobank","year":2026,"doi":"10.1038/s41598-026-46566-y","url":"https://doi.org/10.1038/s41598-026-46566-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Xiao 2026","evidence_span":"For every 1 unit increase in the original LTL, the odds of PROM significantly increases by 1.97 times (OR = 1.97, 95% CI:1.30–2.95).","excerpt":"For every 1 unit increase in the original LTL, the odds of PROM significantly increases by 1.97 times (OR = 1.97, 95% CI:1.30–2.95)."},{"id":"source_21","type":"source","study":"Effects of Randomized Controlled Infancy-Onset Dietary Intervention on Leukocyte Telomere Length—The Special Turku Coronary Risk Factor Intervention Project (STRIP)","year":2021,"doi":"10.3390/nu13020318","url":"https://doi.org/10.3390/nu13020318","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Pitkanen 2021","quote":"Healthy 7-month-old children were randomized to the intervention group ( n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group ( n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years ( n = 232; intervention n = 108, control n = 124).","evidence_span":"Healthy 7-month-old children were randomized to the intervention group ( n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group ( n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years ( n = 232; intervention n = 108, control n = 124).","excerpt":"Healthy 7-month-old children were randomized to the intervention group ( n = 540) receiving dietary counseling mainly focused on dietary fat quality and to the control group ( n = 522). Leukocyte TL was measured using the Southern blot method from whole blood samples collected twice: at a mean age of 7.5 and 19.8 years ( n = 232; intervention n = 108, control n = 124). Yearly TL attrition rate was calculated. The participants of the intervention group had slower yearly TL attrition rate compared to the controls (intervention: mean = −7.5 bp/year, SD = 24.4 vs. control: mean = −15.0 bp/year, SD = 30.3; age, sex and baseline TL adjusted β = 0.007, SE = 0.004, p = 0.040). The result became stronger after additional adjustments for dietary fat quality and fiber intake, serum lipid and insulin concentrations, systolic blood pressure, physical activity and smoking (β = 0.013, SE = 0.005, p = 0.009)."},{"id":"source_22","type":"source","study":"TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis","year":2021,"doi":"10.1136/bmjresp-2021-001127","url":"https://doi.org/10.1136/bmjresp-2021-001127","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Mackintosh 2021","quote":"A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib).","evidence_span":"A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib).","excerpt":"A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population. Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences. NCT04638517 ; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p). Keywords: interstitial fibrosis Progressive pulmonary fibrosis (PF) is a relatively rare condition that leads to substantial morbidity and mortality. The treatment of progressive PF, particularly in its idiopathic form (IPF), has undergone dramatic change over the last decade. In 2012, a major shift in the management of IPF occurred, with the publication of the Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Reponse in Idiopathic Pulmonary Fibrosis (PANTHER-IPF) trial which demonstrated harm from this combination, which had been the standard of care until that point. 1 Subsequently two agents, nintedanib and pirfenidone, jointly coined antifibrotics, have proved efficacious to slow disease progression, reduce the frequency of acute exacerbation and improve survival. 2–4 However, these medications are not a cure, and do not completely halt disease progression. While they both have demonstrated broad activity across the spectrum of fibrosing interstitial lung diseases, 5–7 their activity targets down-stream pathways of lung fibrosis. Disease modifying therapies in their truest sense, require activity at the very origins of disease pathogenesis. Recent discoveries have begun to unravel fundamental genetic abnormalities in a significant proportion of patients with PF. The most frequent genetic abnormalities are found in genes involved in telomere maintenance. Telomeres are nucleoprotein complexes consisting of long, TTAGGG repeat segments, which protect chromosomes from loss of genomic material during cell replication. Telomere length is regulated by the enzyme telomerase and shortening occurs naturally with age. Mutations in telomere-maintenance genes cause extreme shortening, and were first recognised to lead to fatal PF in children with dyskeratosis congenita (DC). 8 Subsequently, similar mutations were identified in adults with PF. 9 Telomere shortening is frequently identified in adult PF and defines disease behaviour. 10 11 In IPF, telomere length is directly proportionate to survival—those with the shortest telomere lengths have the worst survival. 12–15 Additionally, post-hoc evaluation of the pivotal PANTHER trial suggests that a proportion of the adverse outcomes with immunosuppression was attributable to the treatment’s impact in patients with short telomeres. 16 In chronic hypersensitivity pneumonitis, the presence of shortened telomeres predicts a survival identical to IPF. 17 Shortened telomeres and their associated genetic mutations (TERT, TERC, RTEL1 and PARN) predict adverse outcomes among families with inherited interstitial lung diseases (ILDs), despite heterogeneous radiology and histology. 12 Finally, the presence of telomere shortening impacts lung transplantation complications and survival, and data are emerging to suggest that such patients should be managed differently in the post-transplantation period. 18 The evidence above suggests that the telomere apparatus is a potential treatment target in PF. Preserving, and potentially elongating telomere length may help to prevent progressive PF. Danazol, a synthetic androgen, has demonstrated potential efficacy in this regard. 19 In 27 subjects with a variety of short telomere related blood disorders, telomeres were lengthened with danazol. 19 Ten participants with PF had stable lung function over 2 years of treatment. A case report from our group demonstrated similar benefit with danazol. 20 Moreover, in 17 patients, including 6 with PF, a similar androgen (intramuscular nandrolone) resulted in telomere elongation by 1119 base pairs (bp) at 12 months, and resolution of respiratory failure in 1 patient. 21 Further support for a potential role of androgens in PF stems from data demonstrating lower testosterone levels in males with IPF, which correlated with shorter telomere length. 22 However, previous trials have significant limitations, including missing data, no comparator group, and the majority of participants had extremely short telomeres (less than first centile). Additionally a study in 10 haematology patients failed to confirm an effect of danazol on telomere length. 23 Ongoing studies of androgens highlight the worldwide interest in this therapy for short telomere syndromes. However, these studies either have a haematological (USA, NCT03312400 ; France, EudraCT 2018-001686-17, South America, NCT02055456 ) or paediatric (Boston, NCT01001598 ) focus. The TELO-SCOPE Study: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial of Danazol for Short Telomere Related Pulmonary Fibrosis, will be the first study to specifically study danazol in PF associated with short telomeres and has been deliberately designed to align with international protocols so that subsequent meta-analyses are facilitated. The primary endpoint of the study is change in telomere length over 12 months of treatment, allowing the study to be adequately powered."},{"id":"source_23","type":"source","study":"A Systematic Review and Meta-analysis Highlights a Link Between Aerobic Fitness and Telomere Maintenance","year":2025,"doi":"10.1093/gerona/glaf068","url":"https://doi.org/10.1093/gerona/glaf068","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Ryall 2025","evidence_span":"Relative to individuals with below-average VO 2max based on age- and sex-adjusted norms, fit participants with relative VO 2max values in the 70th percentile or higher possessed longer telomeres (standardized mean difference [95% confidence interval {CI}]: 0.36 [0.14–0.59], p = .002). A similar difference was observed between individuals with below-average VO 2max and those above the 90th percentile (0.28 [0.03–0.53], p = .03). However, no statistically significant telomere length differences were observed between individuals in the 70th to 90th percentile compared to those above the 90th","excerpt":"Relative to individuals with below-average VO 2max based on age- and sex-adjusted norms, fit participants with relative VO 2max values in the 70th percentile or higher possessed longer telomeres (standardized mean difference [95% confidence interval {CI}]: 0.36 [0.14–0.59], p = .002). A similar difference was observed between individuals with below-average VO 2max and those above the 90th percentile (0.28 [0.03–0.53], p = .03). However, no statistically significant telomere length differences were observed between individuals in the 70th to 90th percentile compared to those above the 90th (−0.08 [−0.40 to 0.24], p = .62)."},{"id":"source_24","type":"source","study":"The association of periodontitis with telomere length: a meta-analysis","year":2026,"doi":"10.1186/s12920-026-02323-8","url":"https://doi.org/10.1186/s12920-026-02323-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Sun 2026","evidence_span":"The differences in mean TL between those with and without periodontitis were measured using standardized mean difference (SMD) with 95% confidence intervals (CIs), while standardized beta coefficients (β) and their 95% CIs were applied to assess the strength of the association using a random effects model. Ten observational studies including 22,625 participants were analyzed. The overall results indicated no significant difference in mean TL between individuals with and without periodontitis (SMD = -0.03, 95% CI = -0.09 to 0.03). Additionally, no significant association was observed between","excerpt":"The differences in mean TL between those with and without periodontitis were measured using standardized mean difference (SMD) with 95% confidence intervals (CIs), while standardized beta coefficients (β) and their 95% CIs were applied to assess the strength of the association using a random effects model. Ten observational studies including 22,625 participants were analyzed. The overall results indicated no significant difference in mean TL between individuals with and without periodontitis (SMD = -0.03, 95% CI = -0.09 to 0.03). Additionally, no significant association was observed between periodontitis and TL (β = -0.001, 95% CI = -0.01 to 0.01). Subgroup analysis revealed that patients under 50 years old (SMD = -0.25, 95% CI = -0.41 to -0.09) and Asian patients (SMD = -0.44, 95% CI = -0.82 to -0.06) had significantly shorter TL compared to those without periodontitis. Additionally, periodontitis was significantly inversely associated with TL in these groups (age < 50: β = -0.07, 95% CI = -0.11 to -0.03; Asians: β = -0.20, 95% CI = -0.38 to -0.03). Periodontitis may be linked to shorter TL, indicating that TL could potentially serve as a biomarker for periodontal health. The online version contains supplementary material available at 10.1186/s12920-026-02323-8. Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of the supporting structures of the teeth, including the periodontal ligament and alveolar bone [ 1 ]. Periodontitis is recognized as a significant public health challenge worldwide [ 2 ]. It is the leading cause of tooth loss among adults [ 3 ] and is linked to a higher risk of systemic conditions including cardiovascular disease, diabetes, chronic respiratory illnesses, and cancer [ 4 ]. About 50% of adults experience some degree of periodontitis [ 5 ], with higher prevalence among males, racial or ethnic minorities, individuals of lower socioeconomic status, and older adults [ 6 ]. The pathogenesis of periodontitis involves a complex interplay between genetic, microbial infection and host immune-inflammatory responses, which can induce oxidative stress and cellular damage [ 7 ]. Additionally, obesity, diabetes mellitus, alcohol use, cigarette smoking, and psychological stress are possible risk factors contributing to the incidence and severity of periodontitis [ 8 – 10 ]. Aging is regarded as a key risk factor for periodontitis, as it facilitates the colonization of pathogenic microorganisms, triggers a pro-inflammatory environment, and exacerbates bone loss [ 11 ]. Multiple prospective cohort studies have consistently reported that periodontal attachment loss increases with advancing age [ 12 , 13 ]. Several experimental studies have demonstrated significant individual differences in aging, influenced by a combination of genetic factors and environmental exposures [ 14 ]. Ageing is typically measured by chronological age; however, research indicates that people of the same chronological age can differ in their vulnerability to age-related diseases, implying that chronological age does not completely or accurately represent the actual aging process [ 15 ]. Telomere length (TL), consisting of TTAGGG nucleotide repeats at chromosome ends, serves as an indicator of biological aging [ 16 ]. Telomeres play a crucial role in maintaining genomic stability and cellular replicative capacity [ 17 ] and play a key role in the progression of age-related chronic diseases [ 18 ]. TL gradually decreases with every cell division because the DNA replication process cannot completely replicate the 5’ end of the lagging DNA chain [ 19 ]. This process ultimately leads to cellular senescence, a condition that can be hastened by inflammation, oxidative stress, and aging [ 5 ]. The variation in the prevalence of periodontitis among populations of the same age may be attributed to differences in TL [ 6 ]. Emerging evidence suggests a potential link between periodontitis and telomere attrition. Regarding the association between TL and periodontitis, three studies demonstrated that individuals with chronic periodontitis had shorter TL than healthy individuals [ 6 , 20 , 21 ]. Conversely, two other studies found that TL was comparable in periodontitis patients and healthy subjects [ 13 , 22 ], and another study found a positive correlation between TL and periodontitis [ 23 ]. The inconsistent results are possibly due to differences in study design, population characteristics, and the level of adjustment for covariates. This meta-analysis aims to systematically synthesize existing research to clarify the relationship between periodontitis and TL, thereby providing insights into the potential factors contributing to the heterogeneity across the studies. This study was carried out and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 24 ]. Since this study did not use original data of patients, ethical approval as not required. This meta-analysis examined the relationship between periodontitis and TL. While no significant association was found in the overall analysis, the results showed that periodontitis is inversely related to TL in patients younger than 50 years old, Asian p"},{"id":"source_25","type":"source","study":"Unraveling the telomere-mitochondrial axis in colorectal cancer: Results from a prospectively followed cohort","year":2026,"doi":"10.1186/s10020-026-01423-6","url":"https://doi.org/10.1186/s10020-026-01423-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gil-Korilis 2026","evidence_span":"Higher relative mtDNA-CN in blood was associated with a lower risk of disease recurrence even after adjusting for multiple covariates (HR = 0.43, 95% CI 0.20–0.97, p = 0.041), highlighting its potential use as a prognostic tool.","excerpt":"Higher relative mtDNA-CN in blood was associated with a lower risk of disease recurrence even after adjusting for multiple covariates (HR = 0.43, 95% CI 0.20–0.97, p = 0.041), highlighting its potential use as a prognostic tool."},{"id":"source_26","type":"source","study":"Association of life’s essential 8 with leukocyte telomere length and mitochondrial DNA copy number: Findings from the population-based UK Biobank study","year":2025,"doi":"10.1016/j.jnha.2025.100557","url":"https://doi.org/10.1016/j.jnha.2025.100557","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Tian 2025","quote":"After adjusting for confounders, a higher LE8 score is associated with longer LTL (Beta = 0.075, P < 0.05) and increased mtDNA-CN (Beta = 0.094, P < 0.05). We also observed that this association was evident in the health behavior score (diet, physical activity, nicotine exposure, and sleep) and the health factors score (BMI, non-HDL cholesterol, blood glucose, and blood pressure), with a stronger positive association of health factors with LTL and mtDNA-CN (Beta = 0.019, P < 0.05; Beta = 0.037, P < 0.05).","evidence_span":"After adjusting for confounders, a higher LE8 score is associated with longer LTL (Beta = 0.075, P < 0.05) and increased mtDNA-CN (Beta = 0.094, P < 0.05). We also observed that this association was evident in the health behavior score (diet, physical activity, nicotine exposure, and sleep) and the health factors score (BMI, non-HDL cholesterol, blood glucose, and blood pressure), with a stronger positive association of health factors with LTL and mtDNA-CN (Beta = 0.019, P < 0.05; Beta = 0.037, P < 0.05).","excerpt":"After adjusting for confounders, a higher LE8 score is associated with longer LTL (Beta = 0.075, P < 0.05) and increased mtDNA-CN (Beta = 0.094, P < 0.05). We also observed that this association was evident in the health behavior score (diet, physical activity, nicotine exposure, and sleep) and the health factors score (BMI, non-HDL cholesterol, blood glucose, and blood pressure), with a stronger positive association of health factors with LTL and mtDNA-CN (Beta = 0.019, P < 0.05; Beta = 0.037, P < 0.05)."},{"id":"source_27","type":"source","study":"Reverse causal relationship between periodontitis and shortened telomere length: Bidirectional two-sample Mendelian random analysis","year":2022,"doi":"10.3389/fimmu.2022.1057602","url":"https://doi.org/10.3389/fimmu.2022.1057602","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Hu 2022","quote":"In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR.","evidence_span":"In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR.","excerpt":"In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR. No pleiotropy was detected in sensitivity analysis (all P>0.05). Our MR studies showed a reverse causal relationship, with shorten TL being linked to a higher risk of periodontitis, rather than periodontitis shorten that TL. Future research is needed to investigate the relationship between cell senescence and the disease. Periodontitis is an inflammatory immune condition brought on by problems with mouth microbes ( 1 ). If periodontitis is not control in time, with the continuous development of inflammation, it may eventually destroy the tooth supporting tissue, leading to tooth loss ( 2 , 3 ). Being a very common non-communicable disease, it has negatively impacted people’s quality of life and added to society’s financial burden ( 4 ).It is the sixth most common diseased in the globe. A person with many missing teeth may appear older, lose their ability to chew and have pronunciation issues. Periodontitis has significant systemic effects in addition to local ones, and prior studies have demonstrated a relationship between periodontitis and cardiovascular, respiratory, hypertensive, and diabetes disorders ( 5 – 7 ). Treatment of periodontitis is made more challenging by the interaction of multiple systemic diseases, and vice versa. Under the accumulation of plaque, inflammation, and a bad lifestyle, the occurrence of periodontitis seems to be closely related to age ( 8 ). According to figures from epidemiological surveys, periodontitis affects 50% of adults in varying degrees, and incidence and severity have both sharply increased in the group over"},{"id":"source_28","type":"source","study":"Aerobic exercise and telomere length in patients with systolic heart failure: protocol study for a randomized controlled trial","year":2022,"doi":"10.1186/s13063-022-06257-1","url":"https://doi.org/10.1186/s13063-022-06257-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Franzoni 2022","quote":"In an attempt to fill this gap, we designed a study to determine the effects of 16 weeks of aerobic training (32 sessions) on telomere length in HFrEF patients. In this single-center randomized controlled trial, men and women between 50 and 80 years old will be allocated into two different groups: a moderate-intensity aerobic training and a control grouTelomere length, functional capacity, echocardiographic variables, endothelial function, and walking ability will be assessed before and after the 16-week intervention period.","evidence_span":"In an attempt to fill this gap, we designed a study to determine the effects of 16 weeks of aerobic training (32 sessions) on telomere length in HFrEF patients. In this single-center randomized controlled trial, men and women between 50 and 80 years old will be allocated into two different groups: a moderate-intensity aerobic training and a control grouTelomere length, functional capacity, echocardiographic variables, endothelial function, and walking ability will be assessed before and after the 16-week intervention period.","excerpt":"In an attempt to fill this gap, we designed a study to determine the effects of 16 weeks of aerobic training (32 sessions) on telomere length in HFrEF patients. In this single-center randomized controlled trial, men and women between 50 and 80 years old will be allocated into two different groups: a moderate-intensity aerobic training and a control grouTelomere length, functional capacity, echocardiographic variables, endothelial function, and walking ability will be assessed before and after the 16-week intervention period. Understanding the role of physical exercise in biological aging in HFrEF patients is relevant. Due to cell senescence, these individuals have shown a shorter telomere length. AERO can delay biological aging according to a balance in oxidative stress through antioxidant action. Positive telomere length results are expected for the aerobic training group. ClinicalTrials.gov NCT03856736 . Registered on February 27, 2019 HF affects more than 26 million people worldwide. It is considered a global public health problem and is expected to increase substantially with the aging of the population. Globally, HFrEF is the most prevalent form of HF syndrome, affecting at least 60% of all patients [ 1 , 2 ]. Despite the different strategies for its management, most individuals with this syndrome will experience some limitation in exercise capacity during the natural course of the disease [ 3 , 4 ]. In fact, exercise intolerance dominates the clinical presentation of moderate to severe HFrEF and is a major determinant of overall prognosis [ 5 – 7 ]. On the other hand, patients who exercise regularly have a better prognosis than sedentary ones [ 8 ], since AERO improves VO 2 peak [ 9 – 11 ] and TL [ 12 ]. TL is a complex DNA sequence located at the ends of chromosomes [ 13 – 15 ]. It is important to point out that oxidative stress is the main factor that shortens TL in HFrEF [ 16 – 19 ] and accelerates the aging process [ 20 – 22 ]. Studies have shown that exercise can promote a reverse profile in oxidative stress, increasing TL or preventing telomere shortening [ 23 – 26 ]. However, changes in TL depend on exercise intensity. HIIT is described as short periods of exercise performed at a high intensity (> 80–85% heart rate reserve), with active recovery intervals at a moderate intensity (30–40% of HRR) [ 27 ]. MIAT (40–60% HRR), however, is the most commonly used AERO modality, and different HF guidelines recommended it [ 28 – 30 ]. Physiologically, very-high intensity exercise can lead to decreased TL due to an imbalance between severe oxidative stress and reduced antioxidant mechanisms [ 31 , 32 ]. In contrast, MIAT can lead to a reduction in oxidative stress through higher antioxidant activity, which can have beneficial effects on TL [ 33 – 37 ]. In individuals who have not been diagnosed with HFrEF, conflicting results have been found regarding the effects of MIAT on TL. Some studies have shown that MIAT may increase TL [ 12 , 24 , 33 , 34 ], while others have not observed any modification in these outcomes [ 38 – 40 ]. In patients with HFrEF, MIAT can improve functional capacity and has been demonstrated to be safe, effective, and reproducible outside the hospital environment [ 41 – 43 ]. However, as far as we know, no studies have investigated MIAT and TL in the HFrEF setting, and since there is a gap in the literature, the main goal of this manuscript is to describe the study protocol of this unique randomized controlled trial. We will compare TL in a MIAT group and a CG of HFrEF patients before and after 16 weeks of an exercise-based cardiac rehabilitation program. In addition, the secondary outcomes of this randomized controlled trial are to correlate TL with the following: Different CPET parameters such as VE/VCO 2 , oxygen pulse, and oxygen uptake efficiency slope Changes in echocardiographic variables by Doppler echocardiogram Changes in endothelial function measured by FMD of the brachial artery Changes in walking ability measured by SWSS Telomere and its length have been studied as a biological marker of aging and are considered a therapeutic target, not only in patients, but also in healthy individuals [ 51 , 52 ]. The larger the telomere, the greater the life expectancy of the individual [ 53 ]. Acute AERO can promote the upregulation of telomeres and the expression of white blood cell microRNAs, improving immune function and physical health [ 54 ]. In its turn, chronic physical training plays an important role in maintaining or increasing the TL [ 23 ]. Some evidence suggests that only AERO (moderate or high intensity) can increase the TL after 6 months of intervention in healthy individuals [ 12 ] and there is already some evide"},{"id":"source_29","type":"source","study":"Telomere length dynamics in adults living with HIV: A systematic review","year":2026,"doi":"10.1186/s12879-026-13243-4","url":"https://doi.org/10.1186/s12879-026-13243-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Massamba 2026","evidence_span":"Of the 59 included studies, the majority (62.7%) were cross-sectional, providing snapshots of TL at specific stages, while a smaller number (22%) were longitudinal, tracking how T","excerpt":"Of the 59 included studies, the majority (62.7%) were cross-sectional, providing snapshots of TL at specific stages, while a smaller number (22%) were longitudinal, tracking how T"},{"id":"source_30","type":"source","study":"Telomere length as biomarker of nutritional therapy for prevention of type 2 diabetes mellitus development in patients with coronary heart disease: CORDIOPREV randomised controlled trial","year":2024,"doi":"10.1186/s12933-024-02175-5","url":"https://doi.org/10.1186/s12933-024-02175-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Ojeda-Rodriguez 2024","evidence_span":"In our study, we observed a higher percentage of patients at risk of short telomeres (< 20th percentile) among Incident-T2DM patients compared to Non-T2DM patients, with an 84% higher risk of developing T2DM in those subjects having shortened TL. Similarly, large longitudinal studies have demonstrated that healthy individuals at risk of shorter telomeres have a 30–50% independent and significantly higher risk of developing T2DM [ 9 – 11 ].","excerpt":"In our study, we observed a higher percentage of patients at risk of short telomeres (< 20th percentile) among Incident-T2DM patients compared to Non-T2DM patients, with an 84% higher risk of developing T2DM in those subjects having shortened TL. Similarly, large longitudinal studies have demonstrated that healthy individuals at risk of shorter telomeres have a 30–50% independent and significantly higher risk of developing T2DM [ 9 – 11 ]."},{"id":"source_31","type":"source","study":"A Systematic Review of Telomere Length and Telomerase Activity in Preeclampsia: Maternal, Placental, and Cord Blood Perspectives","year":2026,"doi":"10.3390/medsci14010100","url":"https://doi.org/10.3390/medsci14010100","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Gerede 2026","evidence_span":"Ultimately, a study conducted by Hwang et al. revealed that telomerase activity in mesenchymal stem cells derived from umbilical cord blood was approximately 40% lower in women di","excerpt":"Ultimately, a study conducted by Hwang et al. revealed that telomerase activity in mesenchymal stem cells derived from umbilical cord blood was approximately 40% lower in women di"},{"id":"source_32","type":"source","study":"Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial","year":2018,"doi":"10.3390/nu10121907","url":"https://doi.org/10.3390/nu10121907","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Freitas-Simoes 2018","evidence_span":"2 years) and intervention (control vs. walnut), obtained by two-way repeated measures ANCOVA.","excerpt":"2 years) and intervention (control vs. walnut), obtained by two-way repeated measures ANCOVA."},{"id":"source_33","type":"source","study":"The relationship between telomere length and mortality risk in non-model vertebrate systems: a meta-analysis","year":2018,"doi":"10.1098/rstb.2016.0447","url":"https://doi.org/10.1098/rstb.2016.0447","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Wilbourn 2018","evidence_span":"Overall, the hazard ratio associated with TL was significantly negative, supporting a decreased mortality risk with increasing TL across studies (mean ln HR = −0.205 ± 0.049 s.e., p < 0.001, figure 2 ). However, there was evidence for publication bias (Kendall's tau = −0.310; p = 0.016; figure 3 ). Visual inspection of a funnel plot relating effect size to s.e. ( figure 3 ) revealed that this bias was primarily driven by three qPCR-based studies with small sample sizes with strongly negative hazard ratios (ln HR > −1: [ 31 , 34 , 44 ]). To establish whether this bias influenced the overall","excerpt":"Overall, the hazard ratio associated with TL was significantly negative, supporting a decreased mortality risk with increasing TL across studies (mean ln HR = −0.205 ± 0.049 s.e., p < 0.001, figure 2 ). However, there was evidence for publication bias (Kendall's tau = −0.310; p = 0.016; figure 3 ). Visual inspection of a funnel plot relating effect size to s.e. ( figure 3 ) revealed that this bias was primarily driven by three qPCR-based studies with small sample sizes with strongly negative hazard ratios (ln HR > −1: [ 31 , 34 , 44 ]). To establish whether this bias influenced the overall association between TL and mortality risk, we re-ran the models without these three studies; the overall association remained significant (−0.162 ± 0.044; p < 0.001) and the Kendall's tau statistic became non-significant (−0.134; p = 0.341). We also applied the ‘trim and fill’ method [ 55 ] to examine the sensitivity of the results to publication bias and found that the overall association became substantially weaker and remained marginally significant (−0.108 ± 0.062 s.e.; p = 0.083). Forest plot of effect sizes (natural logarithm of the hazard ratio for standardized telomere length) and associated 95% confidence intervals."},{"id":"source_34","type":"source","study":"A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study","year":2016,"doi":"10.1089/rej.2015.1793","url":"https://doi.org/10.1089/rej.2015.1793","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Salvador 2016","evidence_span":"Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner.","excerpt":"Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner. Keywords: : telomere length, TA-65, Astragalus , telomerase, randomized, placebo controlled trial T A -65 was discovered as a chemically defined small molecule activator of telomerase in the year 2000 from an empirical screen of natural product extracts from traditional Chinese medicines. 1 , 2 (Patent number: US7846904). Since that time, there have been research and observational studies on TA-65 in humans and animal models supporting improvements in biomarkers of aging, including immune, cardiovascular, metabolic, bone, and inflammatory markers, without significant signs of toxicity. 2–4 The formulation (TA-65MD) is manufactured under the regulations of current good manufacturing practice (cGMP); it is designated as GRAS (generally recognized as safe) for use in a medical food and is sold as a dietary supplement by the company TA Sciences. Interest in TA-65 as a telomerase activator is largely driven by the potential health benefit of telomere maintenance. Without telomerase, telomeres gradually shorten with each cell division due to the “end replication problem,” oxidative stress, and other natural DNA processing at chromosome ends, ultimately triggering cell senescence, that is, the loss of cell replication capacity and ensuing tissue degeneration when telomeres become critically short. 5 There is abundant evidence that telomerase activation can help maintain and/or lengthen telomeres 6–8 and in some cases restore tissue and organ function that has been compromised by critical telomere shortening. 9 However, to date, there have been no blinded, placebo controlled human studies of TA-65. This report provides the first evidence from a randomized, double blind, placebo controlled study that dietary supplementation with TA-65 has the ability to lengthen telomeres and potentially improve health outcomes in humans, with no observed safety concerns. Cytomegalovirus (CMV) infects the majority of the population worldwide asymptomatically. Seventy to eighty percent of individuals by the age of 50 are infected with CMV. CMV has been implicated in decreased T-cell immunity, associated immunosenescence, and decrease in the T-cell receptor repertoire, causing clonal expansion of senescent CD8 + CD28 − T cells with a proinflammatory profile. 10 Recent studies also suggest that CMV infections are associated with increased mortality in the elderly and are a potential factor in the development of cardiovascular disease among immuno-compromised individuals. 11 , 12 Here we investigated whether TA-65 can alleviate telomere attrition in CMV + subjects, to support our previous observational study finding that TA-65 appears to preferentially lengthen critically short telomeres in CMV + subjects. 1 This study is aimed at understanding telomere length (TL) changes in CMV + subjects taking the telomerase activator TA-65 in comparison with the placebo group. In a previous observational study, subjects taking TA-65 along with other supplements showed improvements from baseline in health biomarkers, especially in CMV + subjects. 1 Since the subjects were blind to their CMV status while taking TA-65, it is unlikely that the positive effects of TA-65 were due to a placebo effect. To confirm that there was in fact no significant placebo effect, this study was designed to be randomized, double blind, and placebo controlled. We tested a cohort of CMV + subjects for the effect of TA-65 on TL. The TLs were measured using HT Q-FISH with automation to handle a large number of human samples and to improve consistency. The cross-sectional analysis of TL at baseline indicates a decline of 50 ± 21 bp/year, which is higher than in some studies, but consistent with other published data. 5 , 16 , 17 The rate of telomere loss has been reported to be exacerbated in CMV + individuals, 18 which may also contribute to the relatively high rate of change in the cross-sectional analysis. The rate of loss reported in this study 18 was 94 ± 9 bp/year in CMV + subjects and 77 ± 9 bp/year in CMV − subjects. In this study, the placebo group had an average telomere attrition of 290 ± 100 bp/year ( p = 0.01), whereas the low-dose TA-65 (250 U) group had net increase of 530 ± 180 bp/year ( p = 0.005). Interestingly there were no statistically significant changes in TL in the high-dose TA-65 (1000 U) group. Loss of 290 bp/year in the placebo group is indeed large, but a large loss is to be expected in a group that is 100% CMV + and consists of older individuals aged >60 years. The accelerated attrition is supported by: (1) CMV infection that causes significant shortening of TL in the age group of >60 years 18 and (2) CMV seropositivity increases the oligoclonal expansion of the immune cells with age. 19 Although variation in the rate of TL loss over time cannot be ruled out, there are limited studies on TLs in CMV subjects. In the previous observational study, 1 the subjects who took a very low starting dose of 5–10 mg/day of unformulated TA-65 ( i.e. , active ingredient alone) had no significant change in TL. In this study, with an improvement in formulation (TA-65MD) to enhance bioavailability, the TA-65 250 U (with 8 mg of active ingredient) increased TL, whereas TA-65 1000 U (with 3"},{"id":"source_35","type":"source","study":"Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial","year":2019,"doi":"10.1093/ajcn/nqz048","url":"https://doi.org/10.1093/ajcn/nqz048","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Canudas 2019","evidence_span":"After excluding those who declined to participate ( n = 30) and those who did not meet the inclusion criteria ( n = 24), 54 participants were randomly assigned to 1 of the 2 intervention sequences (i.e., PD–CD or CD–PD). Five participants dropped out for personal reasons and no nucleic acid samples were available (either at baseline or follow-up). Thus a total of 49 subjects successfully completed the study and are included in the analysis ( Supplemental Figure 1 ). The baseline characteristics of these 49 study participants are shown in Table 1 . No significant differences were observed","excerpt":"After excluding those who declined to participate ( n = 30) and those who did not meet the inclusion criteria ( n = 24), 54 participants were randomly assigned to 1 of the 2 intervention sequences (i.e., PD–CD or CD–PD). Five participants dropped out for personal reasons and no nucleic acid samples were available (either at baseline or follow-up). Thus a total of 49 subjects successfully completed the study and are included in the analysis ( Supplemental Figure 1 ). The baseline characteristics of these 49 study participants are shown in Table 1 . No significant differences were observed between dietary interventions at baseline in any of the analyzed parameters. Similarly, baseline DNA oxidation and TL did not differ between dietary interventions ( P = 0.458 and P = 0.452, respectively) ( Supplemental Table 2 )."},{"id":"source_36","type":"source","study":"Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients","year":2019,"doi":"10.1186/s12877-019-1383-9","url":"https://doi.org/10.1186/s12877-019-1383-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Kalstad 2019","evidence_span":"[ 21 ] demonstrated a significant reduced shortening with higher baseline levels of eicoapentaenoic acid (EPA) and docosahexaenoic acid (DHA) over a period of 6 years in a CVD population [ 21 ]. Reduced shortening of telomeres was also reported with decreasing n-6/n-3 ratio in a supplementation study in a healthy middle-aged population [ 22 ]. The aim of the present study was to further explore the relationship between LTL and selected commonly studied LCPUFAs and diet in elderly survivors of myocardial infarction (MI). In addition, any associations of LTL with risk cardiovascular risk","excerpt":"[ 21 ] demonstrated a significant reduced shortening with higher baseline levels of eicoapentaenoic acid (EPA) and docosahexaenoic acid (DHA) over a period of 6 years in a CVD population [ 21 ]. Reduced shortening of telomeres was also reported with decreasing n-6/n-3 ratio in a supplementation study in a healthy middle-aged population [ 22 ]. The aim of the present study was to further explore the relationship between LTL and selected commonly studied LCPUFAs and diet in elderly survivors of myocardial infarction (MI). In addition, any associations of LTL with risk cardiovascular risk factors, MI characteristics and markers of myocardial injury and dysfunction were explored. Baseline characteristics of the patient cohort ( n = 299) are presented in Table 1 .The median age of was 75 (72, 78) years. Males comprised 70.2% of the population. All patients were of Caucasian ethnicity. Other cardiovascular risk factors were prevalent, with 60.9% diagnosed with hypertension or used anti-hypertensive medications, 47.8% diagnosed with hyperlipidemia or on lipid-lowering agents and 23.1% were diagnosed with diabetes mellitus. Pre-existing coronary artery disease was reported in 45.2% of patients prior to the index MI. A total of 40 patients (13.4%) had diagnosis of heart failure, either preexisting or diagnosed during or after the index hospitalization. LVEF < 50% was recorded in 52 patients (32.1% of 162). NSTEMIs constituted 68.6% of cases and STEMIs the remaining 31.4%. Table 1 Characteristics of the study cohort. Data are presented as number (%) or median values (25, 75 percentiles) Age (years)(range) 75 (70,82) Males 210 (70.2) BMI (kg/m 2 ) 25.6 (23.8, 28.3) Systolic BP (mmHg) 140 (125, 151) Diastolic BP (mmHg) 74 (67, 80) Current smokers 41 (13.7) Previous hyperlipidemia 156 (47.8) Previous hypertension 182 (60.9) Diabetes mellitus 69 (23.1) Previous chronic kidney disease 1 15 (5.1) Previous heart failure 16 (5.4) Previous coronary artery disease 135 (45.2) Previous ischaemic stroke 21 (7.0) NSTEMI/STEMI 68.6 / 31.4 (205 / 94) 3-vessel disease 2 61 (21.3) Maximum Troponin T (ng/L) 700 (153, 2500) NT-proBNP (ng/L) 634 (279, 1374) LVEF < 50% 3 52 (32.1) Taking n-3 FA supplement 135 (45.2) BMI Body Mass Index; NSTEMI Non-ST-segment elevation myocardial infarction; STEMI ST-segment elevation myocardial infarction; NT-proBNP N-terminal pro-Brain natriuretic peptide; LVEF Left ventricle ejection fraction; FA fatty acids 1 creatinine > 150 μmol/L 2 of n = 286 with angiography 3 of n = 162 with echocardiography The findings in this study of telomere lengths in elderly patients with a recent MI were predominantly neutral. A weak, but significant correlation between serum levels of linoleic acid and LTL, and a borderline relationship between LTL and dietary habits were found, whereas no significant relation to conventional cardiovascular risk factors or features of MI could be demonstrated. Previous studies investigating the associations between LCPUFAs and LTL have shown that these fatty acids affect telomere attrition rate. However, in accordance with our findings no associations on a cross-sectional level have been demonstrated. Farzaneh-Far et al. found that the higher quartiles of serum EPA+ DHA were associated with reduced telomere shortening over 6 years in patients with coronary heart disease [ 21 ]. A decreasing n-6/n-3 ratio was associated with reduced shortening in a 4 months intervention study on healthy, sedentary overweight middle-aged and older individuals [ 22 ]."},{"id":"source_37","type":"source","study":"Association of Short-term Change in Leukocyte Telomere Length With Cortical Thickness and Outcomes of Mental Training Among Healthy Adults","year":2019,"doi":"10.1001/jamanetworkopen.2019.9687","url":"https://doi.org/10.1001/jamanetworkopen.2019.9687","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Puhlmann 2019","evidence_span":"Leukocyte telomere lengthening, for example, has been observed after 6 months of physical training programs, 19 , 20 as well as after an intensive 1-month mental training intervention. 21 Because telomere lengthening implies a reversal of biological aging processes, these observations have received much attention. However, the biological plausibility of short-term telomere change, herein defined as less than 2 years, remains controversial, particularly for lengthening. 22 , 23 , 24 Relating change in LTL with brain structure may provide insight into the biological implications of short-term","excerpt":"Leukocyte telomere lengthening, for example, has been observed after 6 months of physical training programs, 19 , 20 as well as after an intensive 1-month mental training intervention. 21 Because telomere lengthening implies a reversal of biological aging processes, these observations have received much attention. However, the biological plausibility of short-term telomere change, herein defined as less than 2 years, remains controversial, particularly for lengthening. 22 , 23 , 24 Relating change in LTL with brain structure may provide insight into the biological implications of short-term LTL change. If short-term LTL change reflects biological processes that are generally meaningful for an individual’s aging trajectory, such change is unlikely to happen in isolation. Rather, LTL change should be associated with changes in other aging- and health-related markers. Structural brain indices are biomarkers of individual differences in aging and health. 25 The first aim of the present study was therefore to investigate whether naturally occurring aging- or lifestyle-related change in LTL over 9 months was related to structural changes in the brain. Cortical thickness (CT) was selected as our measure of brain structure as a more anatomically specific modality than, for example, volumetric measures, 26 , 27 and was accordingly expected to be more sensitive to structural changes, including aging-related gray-matter decline. 27 , 28 The second aim of this study was to assess whether training in different mental practices over the same 9-month period could systematically influence LTL, potentially buffering against aging-related shortening or facilitating lengthening. Mental training protocols, such as the mindfulness-based stress reduction program, 29 have been found to reduce several psychological strains that are associated with shorter telomeres, including rumination, loneliness, and stress. 30 , 31 However, of the 9 studies 21 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 that have investigated LTL in association with mindfulness or meditation, as discussed in a review, 40 only 2 found evidence for a change in LTL. One study observed LTL after a 1-month retreat (N = 28), 21 and the other after a 5-year lifestyle intervention (N = 10). 32 The remaining 7 studies used less-intensive or shorter interventions, which may in part explain the absence of LTL change. 33 , 34 , 35 , 36 , 37 , 38 , 39 Evidence for an effect of mental training on LTL therefore appears preliminary and requires replication on a larger scale, which was possible in the present study. The present investigation was conducted as part of the ReSource Project, 41 a longitudinal mental training study that included training cohorts (TCs) and a retest control cohort (RCC). The RCC was used to address our first aim: to assess potential dynamic associations between LTL and CT. We expected associations with CT change in brain regions previously linked cross-sectionally to LTL. 7 Nonetheless, we conducted analyses on a whole brain level to be able to detect potential aging- or lifestyle-related CT changes more broadly. The main effects of the ReSource Project training on CT have been reported elsewhere. 42 Our second aim focused on a nonoverlapping sample, namely, participants trained in 3 distinct types of mental practices (TCs). These practices were designed to cultivate attention, interoception, and focus on the present moment (Presence); socioaffective capacities, such as compassion (Affect); and sociocognitive skills, such as meta-cognition (Perspective) ( Figure 1 ). 43 , 44 All 3 training modules had the potential to influence LTL by buffering the experience of acute or chronic stress. 31 , 45 The Presence module could additionally have influenced LTL by reducing rumination, 46 whereas the Affect and Perspective modules may have had an effect through reduced loneliness or social isolation. 42 , 47 We thus predicted leukocyte telomere lengthening or relative maintenance in the TCs compared with the RCC, which, on average, was expected to show aging-related attrition or no change in LTL. In the case of significant training-induced differences in LTL change, we had planned to subsequently analyze how this systematically induced change relates to structural plasticity of regions associated with LTL in the first aim and exploratively at the whole-brain level. A, Key concepts and core exercises taught during the modules Presence (yellow), Affect (red), and Perspective (green). B, Timeline of the ReSource Project and training sequence per cohort. Retest control participants were recruited in 2 cohorts for logistic reasons but were analyzed jointly. We therefore refer to a single retest control cohort in the text. The displayed study timeline was adapted to most accurately reflect the time points of blood sampling. Test phases for other variables may differ slightly. Samples of retest control cohort I were collected after approximately 2 months of no training before T1 and T2; however, given the smaller sample size of this cohort compared with"},{"id":"source_38","type":"source","study":"Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study","year":2018,"doi":"10.1093/eurheartj/ehy585","url":"https://doi.org/10.1093/eurheartj/ehy585","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Werner 2018","evidence_span":"In a primary prevention cohort of untrained healthy middle-aged subjects, aerobic endurance training, or intensive interval training for 6 months increased telomerase activity and telomere length, indicating vascular anti-aging effects. No changes were observed in the control and resistance training groups. Telomeres cap the ends of all eukaryotic chromosomes and are a prerequisite of genomic stability. 6 During the process of natural aging of somatic cells, TL is one of the major determinants of the cells’ capability to divide and function. The process of telomere attrition plays both a","excerpt":"In a primary prevention cohort of untrained healthy middle-aged subjects, aerobic endurance training, or intensive interval training for 6 months increased telomerase activity and telomere length, indicating vascular anti-aging effects. No changes were observed in the control and resistance training groups. Telomeres cap the ends of all eukaryotic chromosomes and are a prerequisite of genomic stability. 6 During the process of natural aging of somatic cells, TL is one of the major determinants of the cells’ capability to divide and function. The process of telomere attrition plays both a causal as well as a potentiating role in human disease processes and is susceptible to life style factors. 7 , 10 , 28 Telomere length in circulating leucocytes has been linked to cardiovascular risk factors and diseases. 6 , 8–11 , 29 Physical exercise is a regulator of cellular senescence and TL. 10 , 12 , 13 , 16 , 18 , 19 However, previous training studies in humans did not provide a conclusive answer with regard to telomere biology because of lack of prospective randomization, a control group, methodological homogeneity, and sufficient duration. 12 To our knowledge, no randomized controlled prospective studies comparing different exercise modalities with respect to cellular senescence have been performed to date. Data on the acute effects of exercise on TL and telomere-associated proteins after a single or a few bouts of exercise are scarce, especially with regard to RT. 30 , 31 Here, we present the first data of a cross-over study in healthy young volunteers directly comparing endurance and resistance exercise. A single bout of AET (running) acutely up-regulated MNC telomerase activity. The novel and unexpected finding is that circle training on eight strength devices did not induce these cellular effects in the same individuals. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed increased telomerase activity in CD34+ and in CD14+ cells that was observed immediately after endurance exercise and persisted after 24 h. Similarly, up-regulation of telomerase activity was specific for the endurance protocol. The participants in the training groups exercised three times per week for 26 weeks. The blood draw was performed between 48 h and 7 days after the last training bout. In addition to the comparison of traditional endurance training and RT, high-intensity IT was included. Low-volume high-intensity interval exercise may induce more potent effects on fitness and metabolism, both in healthy individuals as well as patients with heart failure. 5 The IT led to comparable changes in physical fitness compared with AET. These data confirm the recent SAINTEX-CAD study. 32 While acute endurance exercise-induced up-regulation of leucocytes, 33 the cell numbers of leucocytes, monocytes, lymphocytes, CD3+, CD4+, CD8+, CD19+, CD19+, CD16+/56+, CD3+, and HLA-DR+CD3+ did not differ in the chronic exercise study between the four study groups and did not differ between the start and the end of the training period. CD34+ haematopoietic progenitor cells were up-regulated by endurance training and IT as expected, 15 , 34 but not in the control or the endurance groups. Assessment of stress hormones confirmed marked up-regulation of cortisol after the extreme physical stress of marathon running. 35 However, the chronic levels of cortisol did not differ between the four groups before and after the training period in the chronic exercise study. To test whether the increased telomerase activity will persist long term with endurance training, a prospective randomized training study including a control group was conducted. The main finding of our training study is the differential effects of the three training modalities on TL. In order to account for the methodological challenges of TL measurements in humans, especially with regard to PCR, 36 two established independent methods were used. 8 , 12 , 13 , 22 , 23 Both assays were carefully controlled (details described in Supplementary material online, Methods ). In addition, the findings are supported by the measurements of telomerase activity. While the two endurance-based training protocols markedly increased telomerase activity and TL after 6 months, the strength-based protocol did not. 37 So far, only one prospective study addressed the effects of training on TL. 38 Melk et al. trained n = 59 men for 210 minutes per week for 6 months. Consistent with our findings they found an increase in TL and telomerase activity. However, that study was not controlled or randomized, did not test IT or RT and did not report which methodology was used for TL measurement. We would like to highlight the importance of a prospective randomized design, a control group and a sufficient follow-up for the interpretation of a training study. Endurance training and RT induce a number of differential haemodynamic, metabolic, and/or neurohumoral responses, both acute and chronic. 4 , 39 , 40 Precise comparisons between endurance and a resistance exercise protocols are scarce. Our intra-individual comparisons of heart rate during acute AET, intensive IT, and resistance exercise ( Supplementary material online , Figure S8 ) showed that the mean and the maximum heart rate are higher in the endurance training modalities. This may suggest that, compared with resistance exercise, endurance training may induce a higher rate of (laminar) vascular shear stress, which may, e.g. via NO, potentially contribute to the observed cellular effects. 17 Endothelial NO synthase and telomerase activity have shown to be linked in a signalling pathway mediating exercise-induced vascular protection. 13 In agreement with this hypothesis, we observed a differential regulation of iNOS which was only up-regulated by the endurance training protocols. From an evolutionary perspective, endurance training and high-intensity IT may mimic advantageous travelling and fight and fly behaviour better than strength training. 19 Our data set the stage for future studies to elucidate the details of these regulatory processes. While acute physical stress leads to up-regulation of stress hormones and leucocytes, these alterations are not observed chronically in the basal state after long-term regular exercising. However, we believe that it is likely that the repeated bouts of stress-induced changes induced by the endurance protocols three times a week lead to a shift towards increased baseline telomerase activity when applied long term. This hypothesis represents a possible explanation for the increase of TL with endurance, but not resistance exercise. Telomere length has become a widely accepted molecular/cellular biomarker of aging. 6 We and others have demonstrated that changes in blood cell telomeres and their associated factors reflect changes in the vessel wall and the myocardium. 13 , 14 This may be important for the mechanism of cardiovascular prevention by exercise, because increased telomere erosion is associated with disease incidence and severity. 8 , 11 , 41 Importantly, telomere dysfunction by chronic inflammation, as in cardiovascular disease, can induce cellular senescence without telomere shortening. 42 Training responses are characterized by an inter-individual variability. Our study shows that changes in telomerase activity correlate not only with the training modality but also with the changes of the individual performance. Measurements of TL could therefore be a useful indicator of ‘biological age’ in future intervention studies. The sample size is smaller than other cardiovascular studies, however, this trial is the largest prospective randomized controlled training study performed to date regarding the cellular effects of exercise that includes randomization to well-defined and supervised 6 months training protocols."},{"id":"source_39","type":"source","study":"Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial","year":2017,"doi":"10.3233/JAD-170123","url":"https://doi.org/10.3233/JAD-170123","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Sindi 2017","evidence_span":"The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60–77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning,","excerpt":"The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60–77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL ( p -value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals. Leukocyte telomere length (LTL) is a biomarker of aging and aging-related diseases, representing cells’ ‘biological age’, as opposed to ‘chronological age’ [ 1 ]. Telomeres are nucleoprotein structures at the end of eukaryotic chromosomes that protect chromosomes from end-to-end fusion and damage [ 2 ]. While LTL shortens during aging, there is inter-individual variability in the rate of LTL change over time, and determinants of LTL include both genetic and non-genetic factors [ 1, 2 ]. A broad range of non-genetic factors have been linked to shorter LTL, including chronic psychological stress and related psychiatric conditions, unhealthy dietary habits and altered nutrition-related biomarkers, physical inactivity, smoking, and obesity [ 1, 2 ]. Because of the variety of such non-genetic factors, LTL shortening may represent a proxy for the overall exposure to risk factors promoting disease [ 2 ]. As these risk factors are often shared by several chronic late-life conditions, it is perhaps not surprising that LTL shortening has been related to the increased risk of, for example, cardiovascular conditions, diabetes, various cancers, poor immune function, and mortality [ 2 ]. Neurodegenerative conditions and dementia have also been associated with LTL [ 1 ]. A recent meta-analysis reported that patients with Alzheimer’s disease (AD) had shorter telomere length (measured in leukocytes or other tissue) compared to controls [ 3 ]. In addition, links between genetic determinants of shorter telomere length and AD have been reported [37, 38]. However, the significance of LTL across the cognitive continuum between normal aging and dementia is less clear. Dementia-related diseases such as AD have a long preclinical phase, and brain pathology can start decades before dementia onset. Differentiating between normal aging and high-risk states or preclinical disease stages is still challenging, and studies focusing on mild cognitive impairment (MCI) have had conflicting results. Shorter LTL was reported among patients with MCI [ 4 ], but both shorter and longer LTL have been linked to increased risk of subsequent MCI [ 5 ]. Other studies showed that the progression from MCI to dementia was not associated with LTL [ 4, 6 ]. Concerning cognition, some studies have reported that longer LTL was associated with better performance on various cognitive domains including executive functioning, attention, psychomotor speed, working memory, episodic memory, and general mental ability [ 7–10 ]. Also, LTL attrition was inversely related to global cognition and specific cognitive sub-domains [ 11 ]. However, other studies showed modest or no associations of LTL with various cognitive domains [ 12–16 ]. Such discrepancies may be due to varying age ranges and timing, and differing methods for LTL and cognitive assessments [ 5, 11 ]. Cognitive impairment and dementia have become a major public health challenge [ 17 ], and it is essential to find effective preventive interventions, as well as identify individuals who are most likely to benefit from them. Given that LTL may be regarded as a proxy for overall exposure to risk factors for cognitive impairment and dementia, determining if and how pre-intervention LTL might modify intervention effects is particularly important. Few studies have so far investigated LTL in the context of clinical trials, and none have focused on cognitive outcomes. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a 2-year randomized controlled trial, investigated the effects of a multidomain lifestyle intervention versus regular health advice among at-risk older adults from the general population [ 18 ]. Significant intervention benefits were reported on overall cognitive performance (primary outcome), executive functioning and processing speed (secondary outcomes), and an abbreviated memory score including more complex memory tasks ( post-hoc analyses). The aim of the present study is to assess whether baseline LTL modifies these cognitive benefits. The initial trial protocol did not specifically include LTL, and thus analyses are exploratory. Based on previous literature, we hypothesized that individuals with the shortest LTL would benefit most from the intervention. This study is the first to assess whether baseline LTL modified the effects of a multidomain lifestyle intervention on cognition among older adults who are at risk for cognitive decline. Results showed that the beneficial intervention effects on cognition [ 18 ] were more pronounced with shorter baseline LTL, particularly for executive functioning. The impact of shorter baseline LTL on intervention effects on other cognitive domains was less pronounced in the present study, with some trends observed for NTB total score. Lifestyle factors such as unhealthy dietary habits, physical inactivity, or smoking have been related to shorter LTL [ 1 ], and they have also been related to increased risk of cognitive decline and dementia [ 33 ]. In the present study, shorter LTL was indeed associated with less healthy lifestyle at baseline, suggesting that FINGER participants with shorter LTL may have had more ‘room for improvement’ at the start of the lifestyle intervention. However, this did not seem to fully explain the findings, which were still present after adjustment for baseline lifestyle factors. While shorter LTL has been suggested to represent a proxy for elevated risk due to, for example, exposure to unhealthy lifestyle [ 2 ], it may also be a direct risk predictor via genetic pathways. Previous studies have suggested direct links between genetic determinants of telomere length and AD [37, 38] or cognition [ 34 ]. Such genetic pathways and their associated vulnerabilities may be independent of, or interactive with, lifestyle factors. The multidomain FINGER intervention targeted simultaneously multiple lifestyle-related, vascular, and metabolic risk factors, thus potentially mitigating several of these pathways. However, the present study cannot pinpoint the exact mechanisms behind the increased cognitive benefits among participants with shorter baseline LTL. Interestingly, LTL was not associated with cognition, vascular factors, or history of cardio/cerebrovascular conditions at baseline in this study. A key reason may be the FINGER target population, and the trial context. The intervention was targeted towards at-risk individuals who were most likely to need it, and thus FINGER participants do not reflect the entire risk continuum (from low to high) observed in an unselected general population. In addition, individuals with dementia, substantial cognitive impairment, or serious health conditions affecting safe engagement in the intervention were excluded. This may have limited the ability to identify associations of LTL with cognition and other baseline population characteristics. However, this lack of associations also suggests that the significance of LTL is more complex than a mere proxy for exposure to risk factors promoting disease. Relations between LTL and various diseases seem to be bidirectional [ 2 ]. Telomere dysfunctions may be promoters of disease (in a highly interactive manner with other health-related factors), but they may also result from ongoing disease processes [ 2 ]. Potential activation of LTL-lengthening mechanisms has been hypothesized to be triggered by decline of LTL below a critical threshold [ 16 ]. While the present study found that individuals with shorter LTL had more intervention benefits on executive functioning, we cannot fully exclude that such benefits may have been present in other cognitive domains as well. The study was not powered to detect intervention effects by baseline LTL, and some of the 3-way interactions may have failed to reach significance due to limited statistical power. It is not yet clear if LTL-cognition associations are domain-specific. Previous observational studies have reported different findings, and conclusions are difficult to reach due to variability in cognitive tests, populations, and study designs (cognition often assessed only once, without assessment of change over time) [ 5, 7–16 ]. The strengths of the present study include the large sample of older adults at risk for cognitive impairment, the multidomain intervention with a long duration, and comprehensive cognitive assessment including multiple cognitive domains (NTB, previously used in AD clinical trials), and carefully controlled LTL measurement. However, the FINGER LTL subpopulation had better baseline cognition compared to the rest of the FINGER participants, thus limiting the generalizability of the results (i.e., whether the potential for improvement with shorter baseline LTL would still be present at somewhat lower cognition levels). Also, the FINGER trial included a 2-year intervention in an at-risk general population aged 60–77 years, and without substantial impairment at baseline [ 18 ]. We do not know if there is a time-, age-, and/or stage-limited window of opportunity for more intervention benefits with shorter baseline LTL, i.e., if this effect persists beyond two years, and if it is also present in individuals aged above 80 years and/or with clinically manifest cognitive impairment at baseline."},{"id":"source_40","type":"source","study":"Frailty is associated with the epigenetic clock but not with telomere length in a German cohort","year":2016,"doi":"10.1186/s13148-016-0186-5","url":"https://doi.org/10.1186/s13148-016-0186-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Breitling 2016","quote":"No correlation of epigenetic age acceleration with telomere length was found in our study ( p = 0.63).","evidence_span":"No correlation of epigenetic age acceleration with telomere length was found in our study ( p = 0.63).","excerpt":"No correlation of epigenetic age acceleration with telomere length was found in our study ( p = 0.63)."}],"edges":[{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_1","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_2","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_3","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_4","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_5","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_6","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_7","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_8","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_9","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_10","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_11","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_12","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_13","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_14","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_15","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_16","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_17","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_18","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_19","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_20","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_21","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_22","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_23","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_24","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_25","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_26","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_27","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_28","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_29","type":"contains_claim"},{"from":"28e44ab0-b228-4dba-8e70-b25bbc6c7ac8","to":"claim_30","type":"contains_claim"}],"screening":{"identified":40,"screened":40,"excluded":0,"included":40,"included_or_retained":40,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"40 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}