RESEARKA

Despite the growing number of clinical investigations, several critical unresolved questions surround rapamycin effects as a potential geroprotector. The translation of robust preclinical lifespan extension to human healthspan benefit is not guaranteed, and the tension between mechanistic promise and clinical reality is evident across the evidence base. For example, preclinical studies have shown that rapamycin treatment increases survival and expression of the anti-aging klotho protein in elderly mice (Szoke 2023), yet the direct human RCT evidence for functional benefit in older adults remains sparse and inconclusive (Stanfield 2026). Dose-response relationships are poorly characterized in the aging context: the PEARL trial used 5 mg and 10 mg weekly doses (Moel 2025), while the RAPA-EX-01 trial used 6 mg weekly (Stanfield 2026), and the ERAP protocol uses 7 mg weekly (Svensson 2024), yet whether these doses are optimal for geroprotection — or whether they carry meaningful immunological or metabolic risks — has not been established. The duration of treatment required for benefit is also unclear: preclinical evidence suggests that even transient treatment can produce lasting effects (Bitto 2016), but human trials have typically been limited to weeks or months rather than years. Population specificity adds further complexity: rapamycin effects may differ between healthy older adults, patients with neurodegenerative disease, transplant recipients, and cancer survivors, yet most trials enroll narrow populations that limit generalizability. The question of whether rapamycin effects on immune function, metabolism, and tissue homeostasis represent a net benefit or a net risk in aging populations — and under what dosing and scheduling conditions — remains the central unresolved issue in the field.

Citation Support

• source_1 Mandrioli 2023
• source_2 Lin 2022
• source_3 Moel 2025
• source_4 Gkioni 2025
• source_5 Zhou 2024