A new paper from the PEARL study:
As an FDA-approved small molecule drug, rapamycin is an evolutionary conserved inhibitor of the mammalian target of rapamycin serine/threonine kinase complex 1 (mTORC1), though it is known to also impact mTORC2 in certain contexts. mTORC1 is a known regulator of aging processes, and its hyperactivity has been linked to multiple chronic disease processes [10, 11]. Conversely, partial inhibition of mTORC1 induced by caloric restriction and rapamycin is hypothesized to be a major mediator of their lifespan and healthspan-enhancing effects across organisms from yeast to non-human primates [12–21]. Rapamycin has demonstrated particular efficacy as a geroprotective intervention in mice, extending lifespan in heterogeneous genetic backgrounds in both males and females across multiple studies from independent labs at multiple dosages, dosing periods, and regimens, even in elderly animals [14, 16, 21–25]. Similar effects have been reported to be conserved in companion dogs and marmosets, however, clinical data on rapamycin’s gerotherapeutic effects in humans remains limited [9, 12, 17, 26].
Given the substantial promise of preclinical data, it is essential to obtain a deeper understanding of the clinical benefits of rapamycin use for improving aging in healthy human adults. While biomarkers for evaluating rapamycin’s longevity effects are not yet well defined, body composition metrics provide a more tangible measure of factors known to be associated with age-related disease and mortality risk. Specifically, salient measures such as visceral adipose tissue (VAT) accumulation, a loss of lean muscle tissue, and loss of bone mass are all associated with reductions in quality of life (QoL), increased pain, and limited mobility, particularly for post-menopausal women [27–34]. While available evidence suggests use of low-dose rapamycin may mitigate these features of the aging process to enhance healthspan, many open questions remain [25, 35, 36].
Conclusions: Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.
Full Open Access Paper:
