of the Research Plan Despite significant research effort to understand the aging process, we are still not able to confidently answer fundamental questions: Why do we age and can we delay it in humans? Recent studies suggest that various age-related pathophysiological conditions may have common underpinnings, the so-called hallmarks of aging that include mitochondrial defects, cellular senescence and inflammation. Our research group has worked for more than a decade on NAD+-dependent lysine deacetylases known as the Sirtuins (SIRT1-7). Thanks to this grant, we discovered a new cause of aging that explains why mitochondrial function declines with age, a process we call ?Genome Asynchrony?. Genome asynchrony manifests in heart and muscle tissue (and possibly other tissues) as a breakdown in nuclear-mitochondrial communication due to a decline the NAD+ levels and loss of SIRT1 activity. The result is the stabilization of the hypoxia factor HIF-1? in the absence of hypoxia (a phenomenon we call ?pseudohypoxia?) and a potent inhibitory effect on nuclear- mitochondrial communication. Importantly, by feeding old mice the NAD+ precursor, nicotinamide mononucleotide (NMN), for one week, thus restoring NAD+ to youthful levels, the mitochondrial defects of old muscle can be rapidly reversed, demonstrating that NAD+ is a key regulator of aspects of aging in mice and that aspects of aging are reversible. During the study we discovered that the NMN treatment was able to rapidly reverse key markers of aging in the muscle, suggesting declining NAD+ levels may underlie inflammation during aging. We find that NAD+ levels and HIF-1? specifically control the secretion of IL-18 and IL-1? by regulating the activity of the inflammasome, a key regulator of healthspan in mammals. In the next phase of the grant, we will determine the NAD+-dependent mechanisms that regulate inflammation along with its role in the secretory phenotype of senescent cells (SASP) and test interventions to counteract these pathways.
Aim 1 is to use primary macrophages from genetically modified mice (GEMMs), along with novel epigenetic manipulation technologies and clinic-ready small molecules to test our hypotheses.
In Aim 2, we will perform a comprehensive study of this pathway in vivo using young and old mice from colonies of both wildtype and GEMMs with altered levels of NAD+ and HIF-1? throughout the body or in specific tissues such as muscle and brain.
In Aim 3, we will evaluate the efficacy of the best NAD+ modulating compounds (from Aim 1) to prolong healthspan and lifespan in mice. We will also test the best compounds for their efficacy in a gold- standard model of acute gout (a common age-associated inflammatory disease for which there are no effective treatments) thereby paving the way for rapid human clinical trials. The work will have far-reaching implications by changing our understanding of why aging occurs and creating novel therapeutics to prolong human healthspan and longevity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG028730-12
Application #
9451219
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fridell, Yih-Woei
Project Start
2007-04-01
Project End
2022-02-28
Budget Start
2018-03-15
Budget End
2019-02-28
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Li, Jun; Bonkowski, Michael S; Moniot, S├ębastien et al. (2017) A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science 355:1312-1317
Pollack, Rena M; Barzilai, Nir; Anghel, Valentin et al. (2017) Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults. J Gerontol A Biol Sci Med Sci 72:1703-1709
Ferrer, C M; Lu, T Y; Bacigalupa, Z A et al. (2017) O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36:559-569
Schultz, Michael B; Sinclair, David A (2016) Why NAD(+) Declines during Aging: It's Destroyed. Cell Metab 23:965-966
Abdesselem, Houari; Madani, Aisha; Hani, Ahmad et al. (2016) SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition. J Biol Chem 291:2119-35
Wu, Lindsay E; Sinclair, David A (2016) Restoring stem cells - all you need is NAD(.). Cell Res 26:971-2
Schultz, Michael B; Sinclair, David A (2016) When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development 143:3-14
Dai, H; Ellis, J L; Sinclair, D A et al. (2016) Synthesis and Assay of SIRT1-Activating Compounds. Methods Enzymol 574:213-244
Mohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward et al. (2016) Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell 15:706-15

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