Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. Evolution has selected a complex network of genome maintenance systems to repair the tens of thousands of different types of lesions that occurs into the genome each day and maintain its integrity over time. Investigators have suggested that unrepaired lesions accumulate with aging because repair is erroneous; the rate of lesions is above the capacity of the repair system or occasional failure to correctly replicate the genome during cell division. The accumulation of such lesions may lead to the development of the phenotypes of aging through different still hypothetical mechanisms including inflammation, cell senescence, apoptosis, mitochondrial dysfunction among others. Indeed, while there is evidence that DNA mutations accumulate in various organs and tissues in flies and mammals, it has never been established whether detectable accumulation of DNA damage occurs in humans and whether the frequency of these random lesions correlate with phenotypic manifestation of aging. To address this issue, we plan to study genome damage accumulation in single monocytes collected in 25 healthy individuals distributed over a wide age range and correlate them with the major phenotypes of aging and with a global measure of DNA repair (COMET assay) performed in the same individuals. This study will be implemented in the ongoing GESTALT study, a longitudinal study performed at the NIA clinical research unit that is aimed at understanding the biological mechanisms of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000358-03
Application #
10012621
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Gonzalez-Freire, Marta; Moaddel, Ruin; Sun, Kai et al. (2018) Targeted Metabolomics Shows Low Plasma Lysophosphatidylcholine 18:2 Predicts Greater Decline of Gait Speed in Older Adults: The Baltimore Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci :
Atkins, Janice L; Delgado, João; Pilling, Luke C et al. (2018) Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts. J Gerontol A Biol Sci Med Sci :
Cohen, Alan A; Legault, Véronique; Fuellen, Georg et al. (2018) The risks of biomarker-based epidemiology: Associations of circulating calcium levels with age, mortality, and frailty vary substantially across populations. Exp Gerontol 107:11-17
Qian, Yong; Butler, Thomas J; Opsahl-Ong, Krista et al. (2017) fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences. Bioinformatics 33:1399-1401
Matteini, Amy M; Tanaka, Toshiko; Karasik, David et al. (2016) GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. Aging Cell 15:792-800
Travis, Ruth C; Appleby, Paul N; Martin, Richard M et al. (2016) A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk. Cancer Res 76:2288-2300