Sirtuins are a family of NAD+-dependent deacetylases that are thought to have evolved to increase an organism's chances of surviving adversity. They are found in bacteria, fungi, plants and animals. In mammals, sirtuins are implicated in mediating many of the health benefits of calorie restriction (CR). There are seven mammalian sirtuins, SIRT1-7. SIRT1 is the best studied. Major processes controlled by SIRT1 include DNA repair, protein folding, fatty acid and glucose metabolism, hypoxic responses, autophagy, and anti-apoptotic mechanisms. Over expression of SIRT1 protects mice in a variety of common age-related disease models. Our cells contain two genomes, the nuclear and the mitochondrial. These must be tightly co-regulated to ensure normal tissue function. How this is achieved, and whether this has relevance to aging, is poorly understood. Our unpublished studies indicate that when SIRT1 is deleted in young adult mice, the normal transcriptional synchrony between the two genomes is disrupted, leading to loss of electron transport chain (ETC) stoichiometry, reduced respiration and ATP, increased reactive oxygen species (ROS) and lactate, and a failure of muscle mitochondria to adapt their metabolism to fasting. Strikingly, this same defect occurs in wild type mice as they age. Thus, loss of genome synchrony may be an underlying, and potentially reversible, cause of normal aging. We have traced the likely cause of the defect to a novel SIRT1-mediated pathway that does not involve the canonical factors PGC- 1?/? or NRF1/2.
Aim 1 of this proposal will investigate the mechanisms by which SIRT1 maintains genome synchrony and ETC stoichiometry in skeletal muscle, independent of the canonical PGC- 1?/? pathway. This will provide new and fundamental mechanistic insights into (i) how mitochondria are regulated in response to diet and (ii) how genome synchrony is lost over time.
Aim 2 uses novel genetic and pharmacological approaches to restore genome synchrony in aged mice to test whether any of the deleterious effects of aging in highly energetic organs and tissues can be reversed by assessing metabolism, motor function, and cognition. Recent evidence from C. elegans and Drosophila indicates that alterations in mitochondrial function in one cell type (e.g. disrupting the ETC) can extend lifespan by inducing the secretion of putative """"""""mitokines"""""""". Because so little is known about how mitochondria communicate within the cell or with other tissues, and its potential role in mammalian aging, Aim 3 will investigate these fundamental processes, in part, by taking advantage of our screen of the human genome that has identified 98 new mitochondrial regulators. Relevance Because of our evolutionary origins, our cells contains two genomes. We find that communication between them breaks down during aging. By understanding how the two genomes communicate -- between each other and potentially to other cells in the body -- the study could lead to new practical strategies for combating rare mitochondrial diseases and common diseases of aging.

Public Health Relevance

This study is aimed at understanding why highly metabolic organs lose their function over time. The SIRT1 gene is conserved from yeast to humans and plays important roles in protecting organs from the effects of aging. Our preliminary findings indicate that decline in SIRT1 activity during aging leads to a breakdown in communication between the nuclear and mitochondrial genomes, leading to mitochondrial dysfunction. This project will investigate how this process occurs and what deleterious effects it has on energy metabolism, physical strength, endurance, and memory. Then we test if the effects are reversible by raising SIRT1 activity in elderly mice. Finally we investigate novel factors that allw mitochondria to coordinate their activities, both within the cell and with other organs. These findings may lead to practical strategies for treating rare mitochondrial diseases and common age-related diseases such as Type II diabetes, heart failure, muscle wasting, and neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG028730-08
Application #
8723013
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Finkelstein, David B
Project Start
2006-08-15
Project End
2017-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Rajman, Luis; Chwalek, Karolina; Sinclair, David A (2018) Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab 27:529-547
Das, Abhirup; Huang, George X; Bonkowski, Michael S et al. (2018) Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell 173:74-89.e20
Schultz, Michael B; Lu, Yuancheng; Braidy, Nady et al. (2018) Assays for NAD+-Dependent Reactions and NAD+ Metabolites. Methods Mol Biol 1813:77-90
Wahl, Devin; Solon-Biet, Samantha M; Wang, Qiao-Ping et al. (2018) Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice. Cell Rep 25:2234-2243.e6
Costford, Sheila R; Brouwers, Bram; Hopf, Meghan E et al. (2018) Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance. Mol Metab 7:1-11
Latorre-Muro, Pedro; Baeza, Josue; Armstrong, Eric A et al. (2018) Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions. Mol Cell 71:718-732.e9
Longchamp, Alban; Mirabella, Teodelinda; Arduini, Alessandro et al. (2018) Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 173:117-129.e14
Dai, Han; Sinclair, David A; Ellis, James L et al. (2018) Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther 188:140-154
Cronise, Raymond J; Sinclair, David A; Bremer, Andrew A (2017) Oxidative Priority, Meal Frequency, and the Energy Economy of Food and Activity: Implications for Longevity, Obesity, and Cardiometabolic Disease. Metab Syndr Relat Disord 15:6-17
Uddin, Golam Mezbah; Youngson, Neil A; Doyle, Bronte M et al. (2017) Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Sci Rep 7:15063

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