The SIR2/SIRT1 gene is an ancient gene that delays aging in diverse organisms, from yeast to flies, and potentially even mammals. Over 10 years ago, it was discovered that Sir2 extends lifespan of yeast cells by forming "silent" heterochromatin, a more compact protein-DNA structure that suppresses DNA instability, a cause of aging in that species. The discovery inspired the Heterochromatin Loss/Island Hypothesis of Aging, which proposes that a redistribution of heterochromatin factors (such as Sir2) across the genome over time causes the gene expression changes that are known to occur during aging and may even be a cause of aging itself. Recent work in C. elegans and the progeroid disorder Hutchinson-Guilford syndrome, have added additional support to this hypothesis. Despite the interest in yeast Sir2 and the growing interest in chromatin reorganization during aging, it is still not known whether the major function of yeast Sir2 is conserved in mammals. This proposal is a direct continuation of our studies of yeast Sir2. We have mapped where mouse SIRT1 binds to chromatin on a genome-wide scale, and discovered that it is an important component of silent heterochromatin, just like its yeast counterpart. We also find that SIRT1 binds and regulates key metabolic and DNA repair genes but that its association with these genes is dynamic. In response to DNA damage, the pattern of SIRT1 binding across the genome is greatly altered. Interestingly, this altered pattern of binding tightly correlates with gene expression patterns in old mice, indicating that stress-induced SIRT1 relocalization may underlie deleterious gene expression changes that occur as a part of aging. We seek continuation funds to characterize the changes that occur to heterochromatin in response to DNA damage and as yeast and mammals age. We wish to understand why these changes occur, and determine what consequences they have for the cell and the organism. Yeast will be used as a model in Aim 1 to elucidate fundamental aspects of the biology.
In Aim 2, we use cell culture models to understand its conservation in mammals.
In Aim 3, we analyze tissues from mice with normal or altered levels of SIRT1 expression to understand the consequences of chromatin reorganization in vivo and determine if this phenomenon is an important determinant of genomic stability and aging in mammals. PUBLIC HEATLH

Public Health Relevance

Over the past 20 years, it has become apparent that diverse laboratory organisms possess "longevity genes" that promote health and slow the pace of aging (2, 3). Sir2 is a key longevity gene that exists in all organisms, even humans (1, 5). The function of the Sir2 gene in yeast is to regulate genes and prevent DNA rearrangements. In mammals, it might have the same important function but no one has studied it. In this study, we will characterize the role of mouse Sir2 (a.k.a. SIRT1) in regulating genes and preventing DNA rearrangements that might be fundamental determinants of aging and cancer in humans. Understanding the function of SIRT1 is potentially of great importance to medicine. If a drug could be made that activated SIRT1, it would have the potential to prevent or treat age-related diseases such as diabetes, cancer, heart disease and even Alzheimer's disease, with greater efficacy and for a fraction of the cost of today's medicines (4).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019719-10
Application #
8293190
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2001-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$259,719
Indirect Cost
$103,659
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hubbard, Basil P; Sinclair, David A (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146-54
North, Brian J; Rosenberg, Michael A; Jeganathan, Karthik B et al. (2014) SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J 33:1438-53
Michan, Shaday; Juan, Aimee M; Hurst, Christian G et al. (2014) Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One 9:e85031
Sinclair, David A; Guarente, Leonard (2014) Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 54:363-80
Wu, Lindsay E; Gomes, Ana P; Sinclair, David A (2014) Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis. Cancer Cell 25:12-9
Lai, Lo; Yan, Lin; Gao, Shumin et al. (2013) Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation 127:1692-701
Armour, Sean M; Bennett, Eric J; Braun, Craig R et al. (2013) A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Mol Cell Biol 33:1487-502
Strong, Randy; Miller, Richard A; Astle, Clinton M et al. (2013) Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 68:6-16
Chen, Jing; Michan, Shaday; Juan, Aimee M et al. (2013) Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis 16:985-92
North, Brian J; Sinclair, David A (2012) The intersection between aging and cardiovascular disease. Circ Res 110:1097-108

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