{"publication_id":"9cc65260-bc75-401b-be49-205b11c0f464","screening":{"identified":55,"screened":55,"excluded":0,"included":55,"included_or_retained":55,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"55 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."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["Zone 2 training, characterized by sustained sub-lactate-threshold aerobic work, has attracted interest as a longevity-oriented modality, yet the comparative evidence base against moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) spans cardiometabolic, muscle-function, and contextual outcomes across more than 50 curated studies.","Across the corpus, the curated evidence does not yet support a uniform superiority claim for any single intensity zone: HIIT outperforms MICT for selected cardiometabolic and body-composition endpoints in adolescents, cancer survivors, and CAD patients, but the same trials show no advantage, or reversal, in prediabetes, chronic low back pain, and select elderly cohorts.","Because most context-specific signals rest on indirect or observational evidence and the few direct RCTs disagree on directional effect, the clinical case for Zone 2 training as an anti-aging intervention remains incomplete; mechanistic plausibility coexists with mixed human data, and population-specific boundary conditions still need to be defined in adequately powered head-to-head trials.","Population aging is reshaping the priorities of clinical medicine, and the question of whether healthspan can be meaningfully extended through scalable, low-burden interventions has moved to the center of the geroscience agenda. The clinical stakes are concrete: multi-morbidity accrues with age, polypharmacy is the rule rather than the exception in those over 65, and the marginal cost-effectiveness of adding yet another disease-specific drug diminishes as the count of accumulated conditions grows. Against this backdrop, attention has turned toward interventions that target aging biology itself rather than any single chronic disease. The premise is straightforward — if the rate of biological aging can be slowed, multiple downstream conditions might be postponed together, and the cumulative disability burden across a lifetime compressed. This synthesis takes that question seriously for one specific candidate intervention, Zone2, defined here as moderate-intensity continuous aerobic exercise delivered within a defined, ecologically accessible training band. The motivating concern is that the public-health case for any anti-aging therapy rests on evidence that is both mechanistically credible and translationally robust, and evidence suggests that for Zone2 the two halves of that equation have not yet been independently settled. The Zone2 question is therefore not whether exercise is healthful — that has been demonstrated across many populations — but whether this specific intensity-domain prescription, applied over realistic durations in heterogeneous adults, performs as an aging-targeted intervention with reproducible clinical benefits. The answer matters because Zone2 is one of the few candidate interventions that is essentially free, has no regulatory gatekeeping burden, and could plausibly be deployed at population scale if the evidence supports it.","The geroscience hypothesis underlying the present synthesis rests on the proposition that the major chronic diseases of late life share a finite set of upstream biological drivers — mitochondrial dysfunction, chronic low-grade inflammation, cellular senescence, dysregulated nutrient sensing, and altered intercellular communication — and that modulating these drivers could in principle delay the onset of multiple age-related conditions simultaneously. Within this framework, exercise modalities such as Zone2 are positioned as candidate geroprotectors, alongside pharmacological candidates and dietary restriction mimetics, because they engage several of the same upstream pathways, including mitochondrial biogenesis, insulin sensitivity, and inflammatory tone. The methodological question this raises is whether such mechanistic plausibility is sufficient evidence on which to base a public-health recommendation, or whether Zone2 must instead be evaluated on its own terms, against the same hard-outcome standards applied to any candidate anti-aging drug. The repurposing-versus-novel-development distinction is particularly sharp here: unlike newly developed geroprotectors that require de novo safety profiling and dose-finding, Zone2 draws on a substantial pre-existing behavioral and clinical safety base, but it also lacks the standardized dosing, quality-controlled delivery, and outcome standardization that a pharmaceutical development program would impose. Whether the lack of standardization constitutes an obstacle or a feature remains an open question, and one that the present evidence base for Zone2 is poorly positioned to resolve on its own. Importantly, the geroscience framing does not require that Zone2 reverse aging — only that it slow one or more measurable axes of biological or functional decline, and that this slowing be observable in human cohorts under realistic deployment conditions.","Zone2 belongs to the broader drug class — using the term loosely for an intervention category — of exercise-based modalities, which in clinical research have historically been operationalized as moderate-intensity continuous training (MICT) defined by a target heart-rate or oxygen-uptake band, typically delivered across 30-60 minute sessions and repeated two to four times per week. The mechanism most often invoked for Zone2 is enhancement of mitochondrial oxidative capacity, substrate oxidation efficiency, and capillary density in working skeletal muscle, with downstream effects on systemic cardiometabolic risk markers such as blood pressure, lipid profile, glycemic control, and cardiorespiratory fitness expressed as peak oxygen uptake. Regulatory and clinical history matter for the question at hand: exercise interventions sit outside the formal drug-approval pathway and have instead accumulated evidence through decades of small-to-medium physiological and rehabilitation studies, supplemented in recent years by larger trials in cardiac rehabilitation, type 2 diabetes management, cancer survivorship, and post-stroke recovery. Access is essentially universal, in the sense that no prescription is required, but adherence is notoriously variable and dose-response is poorly defined compared with pharmacological agents. The source-grounded reality is that the Zone2 literature is dominated by comparisons against higher-intensity alternatives such as high-intensity interval training and sprint interval training, not by dose-finding studies of Zone2 against a true no-intervention control or against lower-intensity comparators — a structural feature of the evidence base that complicates any clean estimate of Zone2's independent effect on aging biology. The question of whether Zone2 is the active therapeutic ingredient, or merely the convenient comparator arm against which more novel modalities are tested, has been proposed as a central interpretive challenge for the field.","The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.","The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.","Contextual Adjacent Evidence: n=34; claims=3091; mixed signal in 15/34 sources | directness: 7 direct; 15 indirect; 11 review; 1 protocol; main limitation: directionally heterogeneous.","Quantitative findings across the indirect cohort and review evidence are catalogued in detail in the evidence synthesis, which preserves every study × p-value tuple. B 2024, a systematic review of HIIT versus MICT on vascular function in 346 individuals with overweight and obesity, contributed no individual p-values but framed the indirect mechanistic substrate.","Further cardiometabolic contrasts appear in Guo 2023, Li 2022b, Liang 2026, Li 2026, and the sedentary-blood-pressure-reactivity review (Effects of High-Intensity Interval 2025). Li 2026, focused on adults with prediabetes, contributed no p-values but concluded that MICT showed a small but statistically significant advantage over HIIT on cardiometabolic risk factors.","Mechanistically, the contextual other evidence base spans clinical RCT, mechanistic human, and indirect observational streams that converge on aerobic, metabolic, and substrate-utilization pathways without producing a uniform direction. Across mechanistic human and indirect observational streams the picture is therefore one of overlapping but non-identical physiological signatures, with substrate oxidation, lactate handling, and lipidomic remodeling differentiating modalities while whole-body aerobic endpoints frequently converge.","Within-corpus tensions on 'contextual other' are dense and must be read against effect direction and directness rather than collapsed to a single verdict. Neuendorf 2023 (positive review) and Peng 2025 (positive meta-analysis) agree with Rohmansyah 2023, while Chu 2026 (positive in healthy elderly) adds a third positive review-level signal; these three positive reviews sit against Gu 2023 (null in heart failure), Luo 2024 (null in overweight/obese), Feng 2025 (null in endurance runners), Ahmad 2025 (null protocol in prehabilitation), and Zhao 2025 (null in polycystic ovary syndrome), producing a high-severity null vs positive pattern across review-level evidence. By contrast, Neuendorf 2023 (positive) is in direct conflict with Gao 2025 (negative), and Peng 2025 (positive) conflicts with Gao 2025 (negative); Chu 2026 (positive) likewise conflicts with Li 2022a (negative), and Gao 2025 plus Li 2022a agree on a negative reading. Direct RCTs (Nikoletou 2023, Yu 2023b, Goncalves 2023, Goncalves 2025, Chen 2025, Liu 2026, Lapointe 2023) repeatedly diverge in effect direction from indirect or review-level signals on the same outcome class, so the 'contextual other' verdict cannot be resolved without stratifying by population, modality fidelity, and directness of endpoint.","Eight curated references populate the muscle function outcome class, spanning one direct clinical RCT, several systematic reviews and meta-analyses, and a mechanistic mitochondrial-dynamics study. Jung 2020, a randomized trial in adults, examined one year of free-living HIIT versus MICT on cardiorespiratory fitness (CRF) and accelerometer-measured physical activity and reported a key between-group comparison at P = 0.018, providing the only direct-exercise-trial anchor for this outcome class. The remaining evidence base is dominated by pooled syntheses: Yu 2023a (NCT02916225), Zheng 2025, Li 2025b, Effects of High-intensity Interval 2023, B Compare the Effects 2025, Effectiveness of High-intensity Interval 2024, and Impact of Low-Volume High-Intensity 2024, each contributing indirect or review-level estimates of how interval versus continuous training modifies functional endpoints."]}