Sex and Aging

Female advantage in longevity has been observed across years and countries. In addition to sex hormones, sex differences in the physiology of adipose tissue and immune system have been recognized as responsible for the phenomena suggesting both cell signaling and metabolism are involved. Understanding the mechanism behind sex differences in lifespan can provide new insights and novel therapies for aging. Our recent finding that mTORC1 signaling is differentially activated in male and female aging and diabetic tissues. Now we are focus on the upstream of mTORC1 to investigate the interplay between intrinsic cellular signaling and sex, and discover how these two factors may be converged to aging. These studies will specifically trace the dynamic signaling changes of metabolic reprogramming during normal health aging, and provide sex-specific metabolic profiles. This study will shed light in the mechanism underlie sex differences that drive the divergent in male or female aging process. Understanding the biology of sex differences in aging will make it possible to test for a sex-specific medicine on extending health lifespan.

Sarcopenia and protein Homeostasis in Aging

The temporal activity of mTORC1 is tightly regulated in skeletal muscle. Upon exercise and injury, muscle growth and repair are heavily relied on muscle cells’ capability of acutely activating mTORC1 activity. Yet chronic activation of mTORC1 has been documented to be associated with aging-related sarcopenia, suggesting both the timing and duration control of mTORC1 expression are subject to the strict regulation in muscle cells, to achieve the maximum benefit for injury-induced repair responses and long-term tissue health. To explore how mTORC1 expression in skeletal cells may contribute to the muscle homeostasis and related metabolic adaptation, we utilized genomic approach to specifically modulate mTORC1 activity in mouse skeletal cells, in order to analyze those involved metabolic parameters. Given 4E-BP1 and S6K1 are two mTORC1 effectors equally important yet functionally divergent, we examined which downstream mTORC1 effector may have better therapeutic potential to maintain muscle health. Data show that activation of 4E-BP1 rescued the muscle pathology associated within aging or upon TSC1-deficient defects, which causes chronic mTORC1 activation. Whereas S6K1 did not gain the protection against sarcopenia from the chronic mTORC1 activation. Our studies suggested the two mTORC1 effectors, 4EBP1 and S6K1, contributed differently to regulate skeletal muscle homeostasis and metabolism. A better understanding of mTORC1 pathway would lead to the development of more effective and safe therapies to treat aging-related metabolic diseases, and limiting potential off-target side effects while targeting mTORC1.