A research group at the Max Planck Institute for Biology of Aging in Cologne, Germany, has now shown in laboratory animals that brief exposure to rapamycin has the same positive effects as lifelong treatment opening new doors for a potential application in humans.
Rapamycin, known for its positive effects on life and health span in experimental studies with laboratory animals. To obtain the maximum beneficial effects of the drug, it is often given lifelong.
The scientists have tested different time windows of short-term drug administration in fruit flies and found that a brief window of 2 weeks of rapamycin treatment in young, adult flies protected them against age-related pathology in the intestine and extended their lives. A corresponding short time window, 3 months of treatment starting at 3 months of age in young, adult mice, had similar beneficial effects on the health of the intestine when they were middle-aged.
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Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.
The study is not without limitations. Aging phenotypes are often collected from very old mice (>18 months). However, aging phenotypes already appear in middle-aged mice39,40 and, indeed, evolutionary analysis indicates that aging is expected to commence with the onset of reproduction and adulthood41. In this study, we first assessed at what ages age-related gut phenotypes appear. Having found that they appear already at middle age (12 months old), we investigated the effects of short-term rapamycin treatment in early adulthood on middle-aged mice. Since these phenotypes are further exacerbated at older ages, it will be important to test in future the extent of protection that earlier-life, short-term rapamycin treatment confers in very old mice. Aging research is often limited by the need for long-term experiments, and the findings from our and other laboratories that age-related phenotypes appear and can be studied already at middle age, are of general utility for the field. Any importance of BCAT as a potential mediator of ‘rapamycin memory’ for gut dysplasia and lifespan in Drosophila should be assessed with a larger sample. A further challenge in this study was the measurement of autophagy in mice.
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