Replicative cellular senescence is a phenomenon of irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. The great majority of normal cell types from all vertebrate species examined display this response. It is becoming increasingly evident that what has classically been described as cellular senescence is a collection of interrelated states that can be triggered by distinct intrinsic and extrinsic stimuli. The underlying cause of senescence due to replicative exhaustion is telomere shortening. In addition, it is now apparent that many types of stress, reactive oxygen species, pharmacological agents, and even nutrient imbalances can trigger a senescence response. Activation of some oncogenes also induces senescence in normal cells, and recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism. In contrast, the connections between cellular senescence and the aging of organisms are significantly more tenuous. The necessary first step is to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. We, and others, have recently developed a method based on the microscopic detection of DNA damage markers localized to telomeres, designated the `TIF'assay (for `telomere dysfunction-induced foci'). TIFs are a robust biomarker of telomere-initiated senescence, which we used to demonstrate a marked age-associated accumulation of senescent cells in normal primate tissues. This proposal is aimed to give us a better understanding of multiple cellular senescence processes, focusing on their roles in organismal aging.
Aim 1 will examine the in vivo occurrence of telomere-induced senescence in mouse, primate and human models, and probe the links between cellular senescence and pathways that functionally influence aging.
Aim 2 will extend recent studies linking genome-wide changes in chromatin structure with cellular senescence by developing new assays to assess in vivo states of heterochromatin in cells and tissues. These new biomarkers of cellular senescence will then be applied to the models developed in Aim 1.
Aim 3 will seek to discover what causes the age-dependent upregulation of the cyclin-dependent kinase inhibitor p16, an important effector implicated in regulating multiple senescent states.

Public Health Relevance

Replicative cellular senescence was discovered and first described as an irreversible growth arrest triggered by the accumulation of a discrete number of cell divisions. These findings generated two hypotheses regarding the significance of cellular senescence: that it contributes to aging, and that it suppresses cancer. Recent data have implicated cellular senescence as an important in vivo tumor suppression mechanism in a variety of human and mouse tissues. In contrast to tumor suppression, the connections between cellular senescence and the aging of organisms are significantly more tenuous. The necessary first step is to distinguish senescent cells from the majority of healthy but quiescent cells found in normal tissues. This proposal will develop new biomarkers of cellular senescence that will be applied in vivo investigate the occurrence of senescent cells in rodents, primates and humans. Mechanisms that lead to the generation of senescent cells will also be investigated, as well as the persistence of senescent cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG016694-12
Application #
7799694
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
1999-04-01
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
12
Fiscal Year
2010
Total Cost
$328,610
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Waaijer, Mariƫtte E C; Gunn, David A; van Heemst, Diana et al. (2018) Do senescence markers correlate in vitro and in situ within individual human donors? Aging (Albany NY) 10:278-289
Sarosiek, Kristopher A; Fraser, Cameron; Muthalagu, Nathiya et al. (2017) Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 31:142-156
Bacalini, Maria Giulia; Deelen, Joris; Pirazzini, Chiara et al. (2017) Systemic Age-Associated DNA Hypermethylation of ELOVL2 Gene: In Vivo and In Vitro Evidences of a Cell Replication Process. J Gerontol A Biol Sci Med Sci 72:1015-1023
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
Waaijer, Mariƫtte 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
Tatar, Marc; Sedivy, John M (2016) Mitochondria: Masters of Epigenetics. Cell 165:1052-1054
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
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
Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco et al. (2015) Reduced expression of MYC increases longevity and enhances healthspan. Cell 160:477-88

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