Fight Aging!

Rapamycin is increasingly prescribed off-label by anti-aging physicians based on animal studies and very limited human data (even including the relatively recent crowdfunded PEARL trial) for it to improve late-life metabolism. Rapamycin and other mTOR inhibitors are calorie restriction mimetics, provoking a greater level of autophagy to improve cell maintenance. In mice, rapamycin results in a ~20-25% increase in life span, a sizable fraction of the ~40% that is possible via calorie restriction. We know that human calorie restriction is beneficial to health in many ways, but doesn't add more than a few years to life span - while no actual assessment has been carried out, it would be hard for an effect of more than five years or so to remain hidden from interested epidemiologists and scientists across the course of history.

Rapamcyin can be prescribed off-label because it has long been used as an immunosuppressant drug at much higher doses than the anti-aging use, and the safety profile for that use is well mapped. The drug has existed for long enough that it is now generic, outlasted its patent protection. Generic drugs tend to see little further formal clinical trial activity because they cannot produce enough income to sustain the high costs imposed by regulatory authorities. That doesn't stop academics from sometimes managing to obtain enough funding to explore unanswered questions, however.

While enough people are presently using rapamycin off-label at anti-aging doses for a recent study to find more than 300 individuals who were willing to provide information on their rapamycin use, in general this sort of use generates next to no actually useful, robust data. To obtain that data clinical trials of some sort, at the very least run by a reputable organization, remain needed. At present, there is no great consensus that any of the present range of anti-aging doses used in the community are in fact the optimal dose for humans. There are also remaining questions as to the dose at which undesirable immunosuppressive or hyperglycemic effects begin to emerge, and how prevalent they are. So it is good to see that an academic group has found the funds needed to run an initial set of trials aimed at answering these questions.

Large rapamycin clinical trial launches

Researchers are launching a multi-phase clinical study to better understand the biological effects of rapamycin in older adults. The study reflects a shift toward evidence-based dosing, safety, and long-term outcomes rather than off-label and speculative use of rapamycin. "Rapamycin is widely discussed in popular culture as a longevity drug. But there's a difference between something that is biologically plausible and something that has been rigorously tested in people."

The current study is structured as a series of interconnected sub-studies, each designed to answer a specific question. The translational pipeline will move from biological benchmarks to long-term clinical observation. The first sub-study establishes a reference point by examining immune and metabolic markers in younger adults. These measurements help define what "optimal" function looks like before aging-related changes begin.

The second sub-study will determine the optimal rapamycin dosage for older adults that will safely bring them back to the optimal functioning seen in the younger population. The dosage used for transplant patients may be too high for safe use in generally healthy older adults, so the scientists are testing different dosing schedules to determine how much rapamycin is needed to reach biological targets without negative side effects. "This phase is about precision. We're asking how much drug it actually takes to achieve a desired biological effect, not more than that."

The third sub-study is the largest cohort and will run the longest. It is a randomized, placebo-controlled clinical trial involving approximately 84 older adults who will receive either daily rapamycin, intermittent dosing, or a placebo. Participants will be treated for six months and followed for an additional six months to assess both short-term effects and sustained effects after treatment ends.

Muscle tissue is metabolically active to a degree perhaps not fully appreciated in past years. An only partially explored class of signals known as exerkines are generated by muscle tissue in response to physical activity and produce beneficial outcomes to cell behavior and tissue function throughout the body. Much of the signaling that passes between cells is carried by extracellular vesicles, membrane-wrapped packages of molecules of various sorts. As we enter an era in which extracellular vesicles are harvested from donors and cell cultures to be used as a basis for therapies, in much the same way as stem cells have been used, there is an increasing interest in muscle cells as a source of potentially therapeutic extracellular vesicles.

In recent years, a paradigm shift has occurred in the understanding of intercellular communication, moving beyond soluble factors (e.g., myokines) to embrace the critical role of extracellular vesicles (EVs). Among these, exosomes, small lipid-bilayer vesicles (30-150 nm) derived from the endosomal pathway, have emerged as powerful mediators of both localized and long-distance cellular crosstalk. These nanovesicles, which contain a diverse and specific cargo of proteins, lipids, and nucleic acids, are increasingly recognized as "fingerprints" of their originating cells, reflecting their metabolic and physiological state. The confluence of these fields - exercise physiology, exosome biology, and muscle pathology - has given rise to the "exerkine" hypothesis, which posits that the systemic benefits of exercise are, in part, mediated by the modulation of exosomal cargo.

This review will integrates the current evidence supporting this hypothesis, exploring the mechanisms by which exercise-induced exosomes influence muscle health, detailing their role in inter-tissue communication, and critically evaluating their potential as therapeutic tools and biomarkers. Importantly, the circulating EV pool induced by exercise is heterogeneous and originates from multiple tissues and cell types (e.g., skeletal muscle, adipose tissue, endothelium, immune cells, platelets), each contributing distinct cargo signatures and biological effects. Moreover, the physiological impact of a given exosome is not determined solely by its source cargo, but also by the recipient tissue's state (e.g., aging, inflammation, insulin resistance), which shapes uptake, signaling competence, and downstream transcriptional responses.

In this review we detail how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks.

Link: https://doi.org/10.3389/fcell.2026.1706977

Epidemiological studies consistently show a sizable difference in mortality rates between those who exercise regularly and those who do not. Clearly at some point aging forces a reduction in activity, and those more impacted by aging will tend to have a greater mortality risk. But animal studies show that exercise does in fact slow aging; it doesn't have much of an effect on maximum life span in mice, but it does reduce mortality and postpone frailty and mortality to lengthen median life span. How much of the observed correlation in humans is due to causation in one direction versus the other is up for debate, but the consensus is that physical activity is beneficial.

Long-term causal evidence comparing different physical activity patterns and mortality outcomes is needed. Using observational data to emulate a randomized controlled trial, this study compared different physical activity patterns over 15 years in relation to mortality from all causes, cardiovascular disease (CVD) and cancer in 11,169 mid-aged women in the Australian Longitudinal Study on Women's Health.

Two emulated interventions were compared against consistent non-adherence (control) to World Health Organization moderate-to-vigorous physical activity (MVPA) recommendations during the 15-year 'exposure period': (1) consistent adherence to recommendations (at least 150 min/week) over 15 years (2001-2016; women were 50-55-65-70 years); and (2) starting to meet the recommendations at age 55, 60, or 65 years.

Mortality outcomes that occurred between surveys (women were 53-58 at the first survey and 68-73 years at the last survey), were ascertained from Australian death registries. Comparing consistent adherence to MVPA recommendations with consistent non-adherence, there was evidence (Bayes factor [BF] = 5.71) for a protective effect for all-cause mortality (risk ratio [RR]: 0.50; risk difference [RD]: -5.2%). Findings for cardiovascular disease (BF = 2.05; RR: 0.50; RD: -2.1%) and cancer mortality (BF = 2.26; RR: 0.35; RD: -3.3%) were more uncertain and less conclusive, as were those for an effect of starting to meet MVPA recommendations in the mid-fifties on mortality outcomes.

Link: https://doi.org/10.1371/journal.pmed.1004976