Fight Aging!

Rapamycin and some of the later rapalog derivatives such as everolimus, all of which function via inhibition of mTOR, are arguably the best of the present crop of geroprotective drugs capable of modestly slowing aging and extending life in animal studies. The effects of rapamycin in mice are robust and repeatable, though never as large as we'd all like them to be. Like many of the other interventions that modestly slow aging in animal models these small molecule drugs mimic some of the effects of calorie restriction, and likely produce benefits largely through increased efficiency of the cell maintenance processes of autophagy. Better recycling of damaged and unwanted proteins and structures leads to better cell function, fewer senescent cells, and better tissue function.

From what is known of the differences between mice and humans in the use of calorie restriction as an intervention, the effect on life span of any strategy based on upregulation of autophagy via pathways relevant to calorie restriction is likely smaller in humans than it is in mice. In the case of rapamycin, there is human data for short-term and mid-term effects on health, but nothing useful for life span. Rapamycin has been widely used for decades in various contexts, and a fair-sized population of self-experimenters is presently using rapamycin at the established anti-aging dosage, somewhere in the vicinity of 5mg taken orally once per week. One thing that is clear from the human data is that rapamycin use at this dose appears comparatively safe.

Targeting ageing with rapamycin and its derivatives in humans: a systematic review

Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18,400 unique articles, resulting in 19 included studies.

Rapamycin and its derivatives improved the immune, cardiovascular, and integumentary systems in healthy individuals or individuals with ageing-related diseases. Overall, these drugs had no significant effects on the endocrine, muscular, or neurological systems. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. There was no clear relationship between the dose of rapamycin or its derivatives and the effects of these drugs on different physiological systems. No serious adverse events were attributed to the interventions.

Although studies have reported that rapamycin and its derivatives can enhance learning and memory, and reduce neurodegeneration in animal models, these effects were not observed in the human studies assessed in this systematic review. Moreover, the reported effects on ageing-related macular changes were inconsistent. For instance, rapamycin reduced the need for anti-VEGF usage but also led to the loss of visual acuity in individuals with geographic atrophy in age-related macular degeneration. In addition, in preclinical studies, pharmacological mTOR inhibition reduced age-related cardiac inflammation, fibrosis, hypertrophy, and systolic dysfunction. Although improvements in the cardiac index and reductions in both pulmonary vascular resistance and pulmonary arterial pressure have been observed following intervention with everolimus, the effects of rapamycin and its derivatives on cardiovascular parameters in humans should be assessed more comprehensively in future studies.

As individuals age, their glucose tolerance declines. Overactivation of the mTOR pathway leads to the activation of S6K-1 and phosphorylated IRS-1, impairing the stimulation of PI3K by insulin and, subsequently, lowering insulin resistance in human muscle. The effects of rapamycin on glucose metabolism differed by study setting. Although rapamycin treatment increased glucose turnover under conditions of induced peripheral hyperinsulinaemia, it did not affect glucose turnover when there was low peripheral insulin, and did not affect post-exercise insulin concentrations, or post-amino acid infusion fasting insulin, C-peptide, glucose, or glucagon concentrations.

mTOR is hypothesised to be a crucial regulator responsible for maintaining skeletal muscle mass. Although animal studies investigating mTOR inhibition by rapamycin and its derivatives on the muscular system have reported inconsistent results, the human studies we assessed reported no significant effects. However, in these studies, rapamycin was administered in single doses. Further research with different dosing regimens might be necessary to better understand the potential effects of rapamycin and its derivatives on the muscular system.

Topical rapamycin significantly reduced the expression of markers of skin ageing. However, the effects of systemically administered rapamycin or its derivatives on the skin were not investigated and, therefore, require further research.

As individuals age, their capacity to mount a robust immune response diminishes, rendering them more vulnerable to infections and poor response to vaccinations. The mTOR pathway is a crucial signalling pathway within the immune system, controlling the activation, proliferation, differentiation, and function of immune cells. Although rapamycin is known to be immunosuppressive, there are several mechanisms that might explain the immunostimulatory effect of rapamycin in vitro and in animal studies, such as the improvement of immune memory, alteration of CD8+ cell response, and promotion of regulatory T-cell survival and function. In the studies analysed in this review, rapamycin and its derivatives improved immune function mainly by altering adaptive immunity.

There was no clear relationship between the dose of rapamycin or its derivatives and the efficacy of these drugs in ameliorating ageing-related outcomes in the assessed studies. This finding suggests that even though the pharmacokinetics of rapamycin are well known, pharmacodynamic studies that focus on target (ie, mTOR) engagement and the effects of rapamycin on ageing-related biomarkers are needed to establish an adequate dosing regimen for geroprotection.