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Description
SUMMARY: DNA damage has long been implicated as a driver of aging. DNA damage is very frequent, with
estimates of about 100,000 lesions per cell per day in mammals. Such lesions can impact transcription directly,
elicit cellular responses, such as apoptosis and cellular senescence, or result in mutations due to errors during
repair or replication of a damaged DNA template. Project 3 has been focused on somatic DNA mutations, which
can vary from base substitutions to large chromosomal aberrations. This is commonly termed "genomic
instability", now considered a hallmark of the aging process. Because DNA mutations cannot be repaired (except
through cell or organismal death) they accumulate in cells and tissues during aging, which has been empirically
confirmed in multiple species, including humans and mouse. Accurate detection and quantitative analysis of
DNA mutations in cells and tissues is a challenge due to the very low abundance of de novo mutations in normal
somatic cells. We developed methods that allow for the accurate quantitative detection of de novo somatic
mutations in normal cells and tissues. In the previous, still ongoing project period, we used one of these methods
to compare mutation frequency and spectra in cells from different rodent species after DNA damage (see
Progress Report). Genome maintenance capacity has long been implicated in the evolution of species-specific
maximum life span. Hence, Project 3 is testing the hypothesis that cells from short-lived species, such as mice,
would show more mutations after DNA damage than the same cell type from long-lived species. In this renewal
project period, we will specifically test the hypothesis that genome structural variation (Aim 1) and DNA
methylation changes (Aim 2) induced by gamma radiation correlate with species-specific life span in rodents. In
Aim 3 we will then test if interventions developed by our collaborators in Project 1 and Project 2, based on the
longevity mechanisms discovered in long-lived rodents, promote genome and/or epigenome integrity when
applied to mice.
Status | Active |
---|---|
Effective start/end date | 5/1/19 → 4/30/23 |
Funding
- National Institute on Aging: $332,391.00
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Projects
- 1 Active
-
Comparative Genomics of Longevity
Gorbunova, V. V., Seluanov, A. A., Gladyshev, V. N., Gorbunova, V., Vijg, J., Seluanov, A., Vijg, J., Gladyshev, V. V. N., Zhang, Z. D. & Zhang, Z.
5/1/14 → 4/30/23
Project: Research project