Elucidating functions of mammalian SIRT7 deacetylase in aging and disease

Veterans Admin Palo Alto Health Care Sys, Palo Alto CA

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Abstract

Project Summary/Abstract Background and Innovation: The chromatin regulatory enzyme SIRT7 is implicated in many cellular processes associated with aging such as genomic instability, DNA damage, and cellular senescence. SIRT7- deficient mice exhibit shortened lifespan and many signs of premature aging; thus, studying the molecular mechanisms and physiologic functions of SIRT7 has potential to elucidate fundamental pathways that impact on the health of veterans. However, some studies have proposed that SIRT7 promotes, rather than prevents, aging-associated metabolic pathologies. This project aims to resolve this major controversy in the field, and directly test the hypothesis that increasing SIRT7 activity can protect against age-associated diseases in vivo. We will focus on elucidating roles and mechanisms of SIRT7 in adipose tissue function and aging, and their effects on systemic aging-associated metabolic pathologies. We will also characterize a novel histone substrate of SIRT7, H3K36ac about which little is understood. We will test the model that a key mechanistic function of SIRT7 is to remove acetylation at H3K36 to allow methylation of this chromatin mark, and that this H3K36 acetyl-methyl switch is crucial for maintaining adipose tissue function and gene expression programs. The project has multiple innovative features. It investigates innovative mechanistic paradigms, employs cutting edge epigenomic approaches, and leverages new cellular model systems and in vivo mouse models to study SIRT7. Notably, how SIRT7 activation affects whole body metabolism and aging has never been studied in vivo; this project fills this gap with the first analysis of SIRT7-overexpressing mouse systems. In addition, virtually nothing is known about H3K36ac in mammals due to a lack of experimental systems to selectively regulate H3K36ac levels; this project will overcome this barrier and provide new systems to elucidate the functions of this little understood chromatin mark. Significance and Impact to Veterans Healthcare: Aging is a major risk factor for many metabolic disorders that affect veterans including obesity, glucose intolerance, dyslipidemia, and T2D, and thus is a major contributor to morbidity in the VA population. Elucidation of molecular processes underlying such diseases is critical for development of therapeutic strategies to alleviate these disorders. The incidence of chronic metabolic diseases accelerates dramatically from age 65, and >90% of individuals over 65 years old have at least one chronic disease. With the growing numbers of aging veterans, the study of genes that regulate aging and age-associated metabolic disorders is highly relevant for medical advances to benefit veterans’ health. Indeed, according to the 2021 American Community Survey, of the 16.5 million veterans in the U.S., 4 million were 75 years or older. This project will reveal new functions of SIRT7 in protecting against diverse aging- associated metabolic disorders and provide the first direct evidence that increasing SIRT7 activity could be a promising therapeutic strategy for treating diseases that impact the health of aging veterans. Path to translation/implementation: SIRT7 has complex effects on pathways that impact on aging-related changes, possibly in opposing ways. Thus, elucidating the functions and biological contexts of new substrates, interacting partners, and downstream effectors of SIRT7 should provide important insights for the long-term goal of translating into strategies to selectively target specific SIRT7 regulated diseases pathways that impact veterans’ health. SIRT7 is a strong candidate for pharmacologic modulation, and our proposed work will be instrumental for defining the pathways that it regulates. Because SIRT7 is a highly selective enzyme, therapeutic modulation of SIRT7 or its downstream effectors might have fewer unwanted effects than modulating the activity of more promiscuous enzymes. This project sets the stage for studies to develop SIRT7 activator compounds and their translation into therapeutics to improve Veterans healthcare.