The development of lifespan-extending drugs to reduce the burden of both normal aging and age-related diseases is appealing – especially considering population trends in the US, where growth of the population aged 65 and over is expected to jump from 43 million in 2012 to 84 million in 2050.
Rapamycin (also known as sirolimus), an FDA-approved drug currently used to prevent organ rejection in transplant recipients, is known to extend lifespan in model organisms including mice, yeast, flies, and nematodes. In mice, research suggests that rapamycin – which inhibits a key metabolic protein called mTOR – slows both normal aging processes and the progression of age-related maladies such as Alzheimer’s disease, cancer, and cardiovascular disease. In humans, rapamycin is currently in several clinical trials for cancer. However, investigation of rapamycin as an anti-aging pill has been hampered by undesirable metabolic and physiological side effects such as impaired glucose metabolism and an increased risk of infection.
A research team at the University of Wisconsin School of Medicine and Public Health has now shown in a mouse study that intermittent dosing every five days with rapamycin or daily dosing with the rapamycin-related drugs everolimus or temsirolimus reduces these undesirable side effects, suggesting a strategy to “rescue” anti-aging uses for this class of compounds.
“Conventional rapamycin treatment has many side effects, including causing high blood sugar levels and diabetes. In this study, we have shown that we can get many of the same benefits of rapamycin at the molecular level with reduced side effects by changing the dosing regimen or by using a related FDA-approved analog,” says Dr. Dudley Lamming, assistant professor of medicine, University of Wisconsin School of Medicine and Public Health.
To assess the function of insulin-producing pancreatic beta cells in mice treated with altered rapamycin dosing regimens, Lamming and colleagues collaborated with Dr. Michelle Kimple, also a UW assistant professor of medicine. “Daily treatment with rapamycin has a severe impact on the production of insulin by beta cells in response to glucose, and the altered dosing regimen decreases this effect,” says Kimple.
The results suggest that a carefully designed dosing strategy may enable the clinical use of rapamycin or related molecules for diseases of aging, but further study is needed. “Many important unanswered questions remain, including examination of other side effects of rapamycin and efficacy,” says Lamming. The scientists are continuing to investigate optimal therapeutic approaches.
The research was published in Aging Celland will be presented as scientific poster #340 at the Gerontological Society of America meeting. It was supported by funding from the National Institutes of Health, the American Diabetes Association, the UW-Madison Department of Medicine, the UW School of Medicine and Public Health, and the UW Carbone Cancer Center, as well as facilities and resources at the William S. Middleton Memorial Veterans Hospital.
University of Wisconsin-Madison