Understanding the molecular mechanism of aging and longevity in mammals
My laboratory focuses on the molecular mechanisms of aging and longevity in mammals. Recent studies in worms and flies have suggested that systemic interplay between multiple tissues regulates aging and longevity. In mammals, however, the complexity of tissue interplay is multiplied, and a systemic network that regulates aging and longevity has still been poorly understood. To dissect such a complex network for the systemic control of aging and longevity in mammals, our lab has addressed the following three questions: 1) Are there any dominant organs/tissues that regulate the process of aging and longevity in mammals? 2) How do these “control centers” communicate with other organs/tissues to control aging and longevity in mammals? 3) What signaling pathways or molecules regulate such communications at a systemic level? We are particularly focusing on the tissue-specific functions of the mammalian NAD-dependent deacetylase Sirt1, a key mediator that coordinates various metabolic responses in multiple tissues, and NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT), a critical pacemaker that comprises a novel circadian regulatory feedback loop through the regulation of Sirt1 activity in peripheral tissues.
Most recently, we have obtained critical clues to these three questions from our study on brain-specific Sirt1-overexpressing (BRASTO) transgenic mice. We have clearly demonstrated that BRASTO mice exhibit a significant delay in the aging process and extension of life span in both males and females. SIRT1-dependent neural activation in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively) protects against age-related declines in skeletal muscle mitochondrial function, physical activity, body temperature, oxygen consumption, and quality of sleep. SIRT1 and its novel partner Nk2 homeobox 1 (Nkx2-1) regulate these physiological functions through the upregulation of orexin type 2 receptor (Ox2r) expression in the DMH and LH, and their colocalization identifies a specific subset of neurons in these hypothalamic regions. These findings provide critical insight into the importance of hypothalamic SIRT1 and also suggest a fundamental role of the hypothalamus as a high-order “control center of aging” in the systemic regulation of mammalian aging and longevity.