In this proposal, I seek an extension of my MERIT award.
The aims of the current funding period were: 1) To assess telomere-initiated cellular senescence in vivo;2) To investigate heterochromatin-associated senescence states. 3) To study the upregulation of p16. In the 3 years and 8 months since the start of this funding cycle, our projects have evolved from a predominant focus on cellular senescence to a much stronger connection with in vivo organismal aging. We do not wish to imply that cellular senescence is not relevant for aging, but rather that our research has led us in directions that include significant components of chronological aging. Our work has coalesced along 2 predominant themes: 1) Physiological changes that accompany a lifespan extension elicited by a hypomorphic allele of the ubiquitous c-Myc transcription factor;2) Age-associated epigenetic changes that lead to chromatin remodeling, and other genome-wide changes. The first project is based on the remarkable discovery that mice heterozygous for a knockout of the c-myc gene have an extended lifespan. We have completed an extensive demographic analysis showing that both median and maximum lifespans are increased in both sexes: 10-11% in males, and 17% in females. In studying these animals we have taken unbiased approaches, assessed known mouse age- associated phenotypes, and investigated specific pathways targeted by c-Myc. Our studies have identified inflammation and lipid metabolism as the major targets of future investigation. Going forward we propose to investigate a large number of physiological phenotypes in the Myc-het mice, how they change with age, and which ones may explain the observed lifespan extension. The second project has revolved mostly around replicative senescence of human fibroblasts in cell culture. We performed high throughput studies of epigenetic changes during senescence, and discovered extensive genome-wide rearrangements of chromatin that culminate in the heterochromatinization of active genes and expression and activation of retrotransposable elements. Interestingly, we have also found that retrotransposable elements and satellite sequences become expressed with age in several mouse tissues. We propose to apply these approaches to study the aging epigenome in the mouse.

Public Health Relevance

First, we have found a novel genetic intervention that significantly extends lifespan in the mouse. Our data indicate that the mechanisms responsible for this effect are likely to be quite different from those studied in other models of longevity. Second, we have discovered that the fundamental architecture of the genome undergoes widespread alterations during cellular senescence. These degenerative changes that profoundly affect genome integrity are likely to be the consequence cellular aging processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AG016694-16
Application #
8656500
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Velazquez, Jose M
Project Start
1999-04-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brown University
Department
Type
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02912
Criscione, Steven W; De Cecco, Marco; Siranosian, Benjamin et al. (2016) Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2:e1500882
Gravina, Silvia; Sedivy, John M; Vijg, Jan (2016) The dark side of circulating nucleic acids. Aging Cell 15:398-9
Waaijer, Mariëtte E C; Croco, Eleonora; Westendorp, Rudi G J et al. (2016) DNA damage markers in dermal fibroblasts in vitro reflect chronological donor age. Aging (Albany NY) 8:147-57
Borghesan, Michela; Fusilli, Caterina; Rappa, Francesca et al. (2016) DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. Cancer Res 76:594-606
Longo, Valter D; Antebi, Adam; Bartke, Andrzej et al. (2015) Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14:497-510
Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco et al. (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160:477-88
Giampieri, Enrico; De Cecco, Marco; Remondini, Daniel et al. (2015) Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence. PLoS One 10:e0118442
Nelson, David M; McBryan, Tony; Jeyapalan, Jessie C et al. (2014) A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging. Age (Dordr) 36:9637
Hofmann, Jeffrey W; McBryan, Tony; Adams, Peter D et al. (2014) The effects of aging on the expression of Wnt pathway genes in mouse tissues. Age (Dordr) 36:9618
Gorbunova, Vera; Boeke, Jef D; Helfand, Stephen L et al. (2014) Human Genomics. Sleeping dogs of the genome. Science 346:1187-8

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