The long-term goal of Project 1 is to identify mechanisms responsible for more efficient DNA repair in long-lived species. Accumulation of somatic mutations and genomic rearrangements is believed to be a contributing cause of aging. Genomic rearrangements, arising from errors during repair of DNA breaks are a characteristic feature of aged tissues. DNA double-stranded breaks (DSBs) are repaired by two pathways homologous recombination and non-homologous end joining. Our preliminary data indicate that the efficiency of both NHEJ and HR pathways strongly correlates with maximum lifespan. We have also demonstrated that SIRT6 protein is an upstream regulator of both NHEJ and HR pathways and is the only factor capable of stimulating both pathways of repair, and of rescuing the declining NHEJ and HR in senescent human cells. We hypothesize that variations in SIRT6 function contribute to the differences in DSB repair across species. Our objectives are to characterize the differences in SIRT6 function between short- and long-species, as well as to identify novel factors responsible for more efficient DSB repair in long-lived species. We propose to: (1) perform detailed biochemical analysis of SIRT6 from 18 rodent species and identify the properties that distinguish SIRT6 in long-lived species;test, in collaboration with Project 3, whether more efficient SIRT6 function in long-lived species leads to lower mutation loads;(2) Identify the differences in upstream regulation of SIRT6 and its downstream targets between the short- and long-lived rodents;(3) Characterize, in collaboration with Project 4, novel DSB repair genes that contribute to more efficient DSB repair in long-lived species. Gore B will provide access to primary cell collections and Core C will assist with statistical analysis and sequence analysis of newly cloned genes. The results of Project 1 will determine the mechanisms responsible for more efficient DNA DSB repair in long-lived species. Furthermore, Project 1 in collaboration with the other three Projects of this PPG will identify potential targets for intervention aimed at extending lifespan and preventing cancer.

Public Health Relevance

Understanding the mechanisms responsible for the vast differences in lifespan between animal species has the tremendous potential to advance our understanding of the aging process. We found that long-lived species have more efficient DNA repair. The Project 1 of this proposal seeks to identify the mechanisms responsible for more efficient repair and to test whether improving DNA repair will extend lifespan. The information obtained in this study will help develop strategies to prevent cancer and extend lifespan in humans.

National Institute of Health (NIH)
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Special Emphasis Panel (ZAG1)
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University of Rochester
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Ma, Siming; Upneja, Akhil; Galecki, Andrzej et al. (2016) Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. Elife 5:
Quispe-Tintaya, Wilber; Gorbacheva, Tatyana; Lee, Moonsook et al. (2016) Quantitative detection of low-abundance somatic structural variants in normal cells by high-throughput sequencing. Nat Methods 13:584-6
Dokukin, Maxim; Ablaeva, Yulija; Kalaparthi, Vivekanand et al. (2016) Pericellular Brush and Mechanics of Guinea Pig Fibroblast Cells Studied with AFM. Biophys J 111:236-46
Gorbunova, Vera; Seluanov, Andrei (2016) DNA double strand break repair, aging and the chromatin connection. Mutat Res 788:2-6
Patrick, Alison; Seluanov, Michael; Hwang, Chaewon et al. (2016) Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan. Aging (Albany NY) 8:841-7
White, Ryan R; Vijg, Jan (2016) Do DNA Double-Strand Breaks Drive Aging? Mol Cell 63:729-38
Tian, Xiao; Azpurua, Jorge; Ke, Zhonghe et al. (2015) INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc Natl Acad Sci U S A 112:1053-8
Ma, Siming; Yim, Sun Hee; Lee, Sang-Goo et al. (2015) Organization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity. Cell Metab 22:332-43
Ma, Siming; Lee, Sang-Goo; Kim, Eun Bae et al. (2015) Organization of the Mammalian Ionome According to Organ Origin, Lineage Specialization, and Longevity. Cell Rep 13:1319-26
MacRae, Sheila L; Zhang, Quanwei; Lemetre, Christophe et al. (2015) Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human. Aging Cell 14:288-91

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