Animal studies say rapamycin can slow aging – but does it work in humans? A new review finds the evidence for the off-label, low-dose use of the drug in healthy adults is thin, inconsistent, and far from conclusive.
Rapamycin, also known as sirolimus, is an immune-suppressing drug that’s been around since the 1970s. It was found to inhibit a cellular pathway called mTOR, which regulates cell growth, division, and autophagy, the process by which a cell “eats” its own damaged or unneeded components. For that reason, some clinicians have experimented with off-label, low-dose rapamycin to try to slow aging.
While animal studies suggest that using rapamycin to inhibit mTOR can extend both lifespan and healthspan, a new critical review of available human studies and clinical trials on the off-label use of low-dose rapamycin in healthy adults hasn’t quite maintained the hype.
The researchers found that taking low-dose rapamycin or related drugs (called rapalogs) produced effects across a range of body systems and diseases. Several trials suggested that low-dose rapamycin or rapalogs can enhance immune function in older adults, leading to increased vaccine responses and reduced biomarkers of immune aging. Results are mixed, however. The largest follow-up trials didn’t consistently replicate early immune-related findings, partly due to study design changes.
Evidence on muscle health was inconsistent. Some studies suggested rapamycin may reduce post-exercise protein synthesis, while others found no effect. The impact of the drug may depend on age or exercise status. A small trial in older adults found no significant metabolic benefits after eight weeks of 1 mg/day rapamycin. Although some potentially concerning metabolic changes were observed, such as increased triglycerides and decreased albumin (a possible marker of aging), insulin sensitivity and glucose tolerance remained unchanged. Mixed changes in blood biomarkers were seen, some of which are “youthful” and others potentially harmful.
The PhenoAge model is a validated biological aging assessment that uses routine blood biomarkers along with chronological age to estimate a person’s biological age. Using modeling data from one small study, the researchers estimated that rapamycin users reduced their biological age by around four years, compared to a slight increase in the placebo group. This result is suggestive but not conclusive, as it was based on modeling and not direct measurements. There are no completed human trials yet, but ongoing studies are exploring whether rapamycin can slow cognitive decline or Alzheimer’s disease progression.
There’s also limited human data on the effect rapamycin has on cardiovascular disease and cancer risk. Some evidence suggests a possible reduction in stroke risk and lower cancer incidence in organ transplant patients, where rapamycin is used to prevent rejection, but these findings cannot be generalized to healthy adults. One study hinted at a possible higher prostate cancer risk, though this might be due to testing interference. These findings were largely drawn from transplant patients receiving high-dose rapamycin, so they may not apply to healthy adults on low-dose regimens.
In brief, while rapamycin is one of the most promising anti-aging drugs we have based on animal research, the current body of research is insufficient to conclude that it slows aging in humans. Major limitations include small sample sizes and short study durations, a lack of long-term outcome data, mixed or contradictory findings, and a lack of consensus on the optimal dose and schedule, whether that is daily or weekly.
“This paper has reviewed trials of low-dose mTOR inhibition therapy in human subjects,” the researchers concluded. “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 [sic] yet to establish that rapamycin, or its analogues, is an effective seno-therapeutic to delay aging in healthy older adults.”
The researchers urged caution with the off-label use of rapamycin until further studies are conducted with larger cohorts to better establish whether, and how, rapamycin contributes to human aging.
The study was published in the journal Aging.
Source: Aging
