From a starting point of the small list of options to treat aging that are presently accessible to the average individual, if pushed to list the interventions with the most useful human evidence for safety, the most robust and replicated animal data for efficacy, and with relatively well-explored mechanisms of action, then one might start with (a) calorie restriction, (b) exercise, © rapamycin, and then (d) the senolytic combination of dasatinib and quercetin. Note that I say nothing of effect sizes when arranging that list. Rapamycin appears better than exercise in mice, but is not as good as calorie restriction when it comes to extending life span. None of those three produce anywhere near the rapid, impressive reversal of measures of aging and age-related disease in mice as have resulted from the use of first generation senolytic treatments, such as dasatinib and quercetin.
Today's open access paper might be read as a companion piece to a recent conservative review of the merits of rapamycin as a treatment to slow aging. When it comes to moving from data obtained in animal studies to data obtained from human clinical trials, well, there is very little human data for the use of rapamycin at the relatively low doses thought to be optimal for slowing aging. The long history of rapamycin use in humans is largely focused on high dose immunosuppression, and we can learn little from that.
This absence of a robust body of evidence was the point made in the above mentioned review, and it is the point made in today's open access paper. We might reasonably expect a calorie restriction mimetic like rapamycin, a drug that upregulates the operation of autophagy, to be capable of producing some degree of benefit in humans. The data to make a compelling case in humans remains absent. We should probably not hold our collective breath awaiting for that human data to arrive, unfortunately. Rapamycin is a generic drug, cheap, hard to monopolize in the way that pharmaceutical companies must in order to justify the vast investment of funds needed for regulators to grant clinical approval. So clinical trials for an age-slowing application of rapamycin are not a priority for the industry, and few other groups have deep enough pockets.
What is the clinical evidence to support off-label rapamycin therapy in healthy adults?
Rapamycin therapy is considered a promising approach for lifespan extension and the delay of age-related disease, with numerous preclinical studies documenting benefit. These benefits have inspired some patients to seek rapamycin therapy from specialty practitioners. Yet, the clinical evidence of benefit associated with low-dose rapamycin use in healthy human adults has not been established, and there may exist signals indicating caution with off-label use at non-immunosuppressive doses.
While the benefit of rapamycin therapy has been demonstrated in non-human models, nonetheless, the clinical evidence for low-dose mTOR inhibitors such rapamycin as a therapy for extending lifespan or delaying the onset of age-related disease in healthy adults remains unestablished. Here, we provide a critical appraisal of studies evaluating low-dose rapamycin therapy in healthy adults and offer considerations for its potential use as an off-label longevity drug in humans.
Longevity data in humans is difficult to acquire. Any well-designed trial that attempts to assess the longevity impact for any drug in people will be time consuming, expensive, and complicated by uncertainties in clinically valid endpoints. Since rapamycin is a generic medication, there is little incentive for any private group to fund such a study, which further complicates acquisition of high quality evidence with regard to low-dose rapamycin therapy. Accordingly, the clinical evidence evaluating low-dose rapamycin, or its analogues, in healthy participants is scant, with less than a dozen known trials exploring a variety of biomarkers, including immune function, protein synthesis, and hematologic parameters.
What emerges is a complex picture that remains insufficient to affirm or negate the longevity and healthspan extending benefits attributed to rapamycin. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans has yet to establish that rapamycin, or its analogues, is an effective senotherapeutic to delay aging in healthy older adults.
View the full article at FightAging
