David Sabatini - MD, PhD
Member/Principal Investigator - Whitehead Institute for Biomedical Research
Massachusetts, United States
Glenn/AFAR Breakthroughs in Gerontology Award - 2015
Reversing age-associated deterioration in intestinal stem and niche cells by targeting the mTORC1 and PPARδ signaling pathways
Higher organisms have evolved specialized organs that can absorb, metabolize and distribute key nutrients necessary for survival. The mammalian intestine is one of the first sites of nutrient sensing and is maintained by long-lived intestinal stem cells.
In many tissues, metabolic sensors integrate nutrient signals and can become deregulated with aging. The mTOR pathway regulates metabolism and growth in response to nutrient availability and becomes deregulated in age-related diseases like cancer and diabetes. The PPARδ pathway regulates fat absorption and burning and is also implicated in age-associated diseases. Interestingly, caloric restriction, which has been long known to delay and reverse some metabolic disorders, can both inhibit mTORC1 and increase PPARδ activity in a number of tissues.
Dr. Sabatini’s group is working to understand how an organism’s nutrient state regulates these key metabolic pathways in the aged intestine, and in turn how they regulate intestinal stem cell function and intestinal regeneration. In addition, the team will test whether these pathways may integrate to renew mitochondria, the cell’s power plants, which may be damaged upon aging.
In the future, Dr. Sabatini’s group will further explore the function of these nutrient sensing pathways in other mammalian organs and test how diet and therapeutic interventions affect them. Their ultimate goal is to develop methods to improve stem cell function and prevent debilitating, chronic diseases.