A team led by scientists at the Max Planck Institute for Biology of Ageing in Cologne claimed brief doses of the already licensed drug rapamycin, may have anti-aging effects, based on studies conducted on mice and flies.

The investigators showed that the negative side effects of life-long or long-term rapamycin dosing reported in earlier studies can be overcome through short-term treatments at the lowest effective dose in early adulthood, retaining the positive effects of the drug: increased lifespan, decreased age-related intestinal decline, and long-term increase in the degradation of damaged intestinal cells (autophagy).

The findings were published in the journal Nature Aging (“Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy”) and add to earlier work supporting rapamycin’s potential anti-aging role in laboratory model experimentations, opening new avenues for treating humans.

As the global population ages, scientists are redoubling their efforts in combatting age-related declines in physical and mental capacities. Optimal exercise and diet have positive effects on healthy aging, but alone are not enough in preventing age-related diseases. Geroprotective or senotherapeutics aim to target root causes of aging and age-related diseases, thereby prolonging healthy lifespan. This growing class of drugs includes melatonin, carnosine, metformin, nicotinamide mononucleotide (NMN), and delta sleep-inducing peptide.

Repurposing existing drugs for “geroprotection” is an additional weapon in the anti-aging arsenal—rapamycin being one of the most promising candidates.

Studies on mice have shown that rapamycin can delay several age-related diseases, such as cognitive decline, spontaneous tumors, cardiovascular disease, and immune dysfunction. The drug is a cell growth inhibitor and immunosuppressant, commonly used in cancer therapy and after organ transplantations.

Rapamycin inhibits the activity of TORC1—a protein complex that acts as a sensor for cellular nutrients and energy, and regulates protein synthesis. Increased autophagy—lysosome-mediated biologically conserved degradation and recycling of cellular components—is activated downstream of TORC1 activation and is essential for rapamycin’s role in extending lifespan.

However, until now it was unknown whether the effects of late-life treatment are the same as that of lifelong treatment, or whether brief treatment at younger ages is sufficient for long-term benefits.

Lead author of the study, Paula Juricic, PhD, an investigator in the department of Linda Partridge, PhD, professor and director at the Max Planck Institute for Biology of Ageing, said, “At the doses used clinically, rapamycin can have undesirable side-effects, but for the use of the drug in the prevention of age-related decline, these need to be absent or minimal. Therefore, we wanted to find out when and how long we need to give rapamycin in order to achieve the same effects as lifelong treatment.”

In the current study, the scientists tested different time windows of short-term drug administration in fruit flies and found that a brief window of two weeks of treatment in young adult flies protected them against age-related pathology in the intestine and extended their lives. In a similar study on mice, the authors found three months of treatment starting at three months of age had similar beneficial effects on the health of the intestine in middle-aged animals.

Co-author Thomas Leech, PhD, said, “These brief drug treatments in early adulthood produced just as strong protection as continuous treatment started at the same time. We also found that the rapamycin treatment had the strongest and best effects when given in early life as compared to middle age. When the flies were treated with rapamycin in late life, on the other hand, it had no effects at all. So, the rapamycin memory is activated primarily in early adulthood.”

“We have found a way to circumvent the need for chronic, long-term rapamycin intake, so it could be more practical to apply in humans”, said Yu-Xuan Lu, PhD, another co-author of the paper. These findings are of interest given the role of  autophagy in several age-related diseases, including cancer, immune system disorders, and neurodegenerative diseases.

Partridge points out questions that the current findings raise. “It will be important to discover whether it is possible to achieve the geroprotective effects of rapamycin in mice and in humans with treatment starting later in life, since ideally the period of treatment should be minimized. It may be possible also to use intermittent dosing,” she said. Further studies will be needed to answer these questions, in addition to determining any sex differences in the anti-aging benefits of rapamycin.

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