A study published in Nature Aging has shown that short-term rapamycin treatment in early adulthood extends lifespan in flies and improves gut health in both flies and mice .
A well-studied drug
Rapamycin, an inhibitor of mTOR signaling, is capable of extending the lifespan of several organisms and is thus believed to be one of the most promising anti-aging drugs. Researchers are actively studying the longevity-promoting effects of rapamycin when taken by itself and in combinations with other drugs.
Within the last few months, several studies demonstrating a synergetic rejuvenation effect of drug cocktails containing rapamycin have been published. Moreover, when taken with metformin, rapamycin seems less toxic, at least in pre-diabetic mice.
It was previously shown that chronic rapamycin treatment can have a detrimental effect. Therefore, in this study, the researchers sought to explore if a brief treatment of rapamycin alone would attenuate age-related decline in two model organisms without the unwanted toxicity.
One of the co-authors of the paper, Dr. Xu-Xuan Lu, a scientist at Max Planck Institute for Biology of Aging, was interviewed by one of our writers, Arkadi Mazin, during Ending Age-Related Diseases 2022. Dr. Lu shared his insights about the therapeutic potential of rapamycin as a geroprotector. We are excited to share the latest research results coming from his lab.
Rapamycin and flies
In the first set of experiments, the researchers treated female fruit flies with rapamycin at different ages. They show that 30-day rapamycin treatment (~⅓ of these flies’ lifespan) in early adulthood, but not later, extends the lifespan of flies as much as lifelong exposure. Moreover, flies treated with rapamycin in only the first 15 days of their adult lives enjoyed similarly extended lifespans.
In addition to the increased lifespan, these flies demonstrated preserved intestinal function. This was evidenced by the reduced turnover of the intestinal epithelium and apoptotic enterocyte cells along with fewer lesions and a more intact gut barrier. Age-related increased intestinal permeability (leaky gut) is a well-described phenomenon in flies and other organisms, and ways to fix it are actively being explored.
Next, the researchers confirmed that the beneficial effect of short rapamycin treatment early in life was achieved via the inhibition of TORC1 and prolonged upregulated autophagy. Indeed, blocking the increase of rapamycin-induced autophagy canceled out both the lifespan extension and the improved intestinal health of rapamycin-treated flies.
The researchers also showed that unlike chronic rapamycin treatment, short rapamycin exposure does not act through the increased expression of histones, structural proteins that DNA is wrapped around. Instead, rapamycin increases the levels of proteins involved in branched-chain amino acid (valine, leucine, isoleucine) and carbohydrate metabolism. It also seems that one of rapamycin’s key beneficial effects is to increase the expression of a gene involved in lysosomal activity, lysosomal alpha-mannosidase V (LManV).
Rapamycin and mice
In the next set of experiments, the researchers compared chronic and short-term rapamycin treatment in female mice. Both groups of mice were exposed to rapamycin starting from the age of 3 months, but the second group was only treated for 3 months. The tissues of all the mice were collected at the age of 12 months and evaluated.
Similarly to flies, gut integrity was preserved in short-term rapamycin-treated mice on par with the chronically treated mice. The researchers show that short-term rapamycin treatment improves the health of Paneth cells, specialized epithelial cells in the gut, by increasing autophagy, leading to improved regenerative capacity of the intestine.
Importantly, treating 15-month-old mice with rapamycin for 3 months resulted in improved regenerative capacity of the intestine, suggesting a beneficial effect of the drug even when taken later in life. Rapamycin seems to act in mice as it does in flies, by increasing lysosomal activity via LManV.
The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.
This enlightening study demonstrates that short-term rapamycin treatment in early adulthood has the same beneficial long-lasting effects as chronic rapamycin exposure without the adverse effects that the latter might bring. The researchers call this phenomenon “rapamycin memory”, which is achieved via upregulated autophagy. Unfortunately, the effect of short-term rapamycin treatment on murine lifespans was not assessed. In addition, only females of both flies and mice were used in this study.
Finally, the effect of this treatment on organs other than the intestine warrants further investigation. Therefore, there are still many questions regarding the effect of various rapamycin regimens even in animals, let alone in humans. Nevertheless, time and time again rapamycin shows its geroprotective effects conserved across species.
 Juricic, P. et al. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nature Aging 1–13 (2022)