Reduced calorie intake without malnutrition delays aging and extends lifespan in diverse species including yeast, worms, flies and mice (Anderson & Weindruch Trends Endocrinol. Metab. 2010 21,134-141). CR also has a beneficial effect in rhesus monkeys (Colman et al. Science 325:201-204. 2009), improving survival and lowering the incidence of diseases including diabetes, cancer and cardiovascular disease. The critical question that arises now is -“how does CR work?” Finding the answer to this question is the goal of my research. Key regulatory pathways identified as playing a role in the mechanisms of CR may be exploited to reveal novel targets for disease treatment.
The decline in mitochondrial function is a hallmark of aging in multiple species, and in mammals, in multiple tissues. The inverse linear relationship between calorie intake and lifespan in mice suggests a role for factors involved in the regulation of energy metabolism in the mechanisms of CR. Alterations in energy metabolism are observed in multiple species on CR including mammals. Our work tests the hypothesis that CR-induced reprogramming of mitochondrial energy metabolism is important in promoting longevity pathways. PGC-1α is a transcriptional co-activator and a critical regulator of mitochondria. There is a complex interplay between PGC-1α and other nutrient sensitive metabolic regulators including SIRT1, mTOR and GSK3β. These factors have been associated with longevity and are also regulated by CR in mammals.
There are three linked project areas ongoing in my research lab that focus on the role of metabolic regulators in the mechanisms of CR. The first area investigates the impact of age and CR on metabolism in rhesus monkeys. This highly translational project is part of an interdisciplinary program exploring mechanisms of aging and CR through high resolution molecular profiling. The second area investigates the tissue specific impact of CR on cellular energy metabolism in mice with complementary mechanistic studies conducted in cultured cells. A linking theme in these studies is the potential role of adipose tissue-derived adipokines and lipokines in aging and CR, and their contribution to differences in metabolic homeostasis and systemic inflammation. This research is relevant not just for aging but also for diseases of obesity where mitochondrial dysfunction is thought to play a causative role, including diabetes and metabolic syndrome. The third project area explores the role of metabolic regulators in brain aging. This research, in cultured cells, mice, and monkeys, aims to understand the role that metabolism plays in cognitive decline and brain atrophy as a function of age.