The OYerarching goal of this Program Project Grant (PPG), entitled Comparative Genomics of Longevity, is to identify molecular mechanisms responsible for more efficient DNA repair and high cancer resistance in long-lived rodent species, with implications for human health. Rodents are an Ideal group for comparative aging studies because they are phylogenetically related, even though their lifespans are extremely diverse, ranging from 2-4 years in mice and rats to over 20 years in naked mole rats, beavers, porcupines, and squirrels. The mechanisms responsible for these vast differences in aging rates between species are largely unknown. Characterization of the processes responsible for this disparity in lifespan may enable the development of interventions to extend the human lifespan and prevention of age-related diseases. Preliminary studies show that long-lived rodents have more efficient DNA double-strand break (DSB) repair and that some ofthe long-lived species are highly resistant to cancer. The central hypothesis of this PPG, therefore, is that long-lived species have evolved more efficient mechanisms to maintain genome stability and prevent cancer. Efforts will focus on testing this hypothesis and understanding the exact moiecuiar mechanisms responsible for more efficient DNA repair and cancer resistance in long-lived rodents. This PPG is comprised of four highly integrated projects. Project 1 (Vera Gorbunova) will identify mechanisms responsible for more efficient DSB repair in long-lived species. Project 2 (Andrei Seluanov) will examine mechanisms responsible for anticancer properties of high molecular weight hyaluronan found in long-lived rodents. Project 3 (Jan Vijg) will test whether more efficient DSB repair and hyaluronan prevent accumulation of mutations in long-lived species using novel high throughput approaches. Project 4 (Vadim Gladyshev) will use genomic and transcriptomic approaches to identify genes and pathways involved in DSB repair and hyaluronan biosynthesis that are differentially regulated in long-lived species. Thus, the research team consists of five investigators dedicated to longevity research who are experts in comparative biology and DNA repair (Gorbunova), cancer-resistance and long-lived rodents (Seluanov), mutagenesis and high throughput approaches (Vijg), comparative genomics (Gladyshev), and bioinformatics (Zhang, Core C). Moreover, the team has developed a collection of primary rodent cells and tissues specifically to facilitate comparative studies of longevity (Seluanov, Core B). This joining of expertise will allow unprecedented insight into the biology of longevity; In summary, this team of investigators is uniquely positioned to pursue integrated studies of longevity across rodent species using a combination of cell, molecular, and genomic approaches.
; Mammalian species differ dramatically in their aging rates, but mechanisms responsible for these differences are unknown. This program project will identify mechanisms responsible for more efficient DNA repair and higher cancer resistance in long-lived rodents. This knowledge will enable the development of interventions to extend the human lifespan and delay the onset of age-related diseases.
| Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441 |
| Meer, Margarita V; Podolskiy, Dmitriy I; Tyshkovskiy, Alexander et al. (2018) A whole lifespan mouse multi-tissue DNA methylation clock. Elife 7: |
| Tian, Xiao; Doerig, Katherine; Park, Rosa et al. (2018) Evolution of telomere maintenance and tumour suppressor mechanisms across mammals. Philos Trans R Soc Lond B Biol Sci 373: |
| Zhou, Xuming; Sun, Di; Guang, Xuanmin et al. (2018) Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans. Genome Biol Evol 10:967-975 |
| Piscitello, D; Varshney, D; Lilla, S et al. (2018) AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene 37:427-438 |
| Swovick, Kyle; Welle, Kevin A; Hryhorenko, Jennifer R et al. (2018) Cross-species Comparison of Proteome Turnover Kinetics. Mol Cell Proteomics 17:580-591 |
| Sziráki, András; Tyshkovskiy, Alexander; Gladyshev, Vadim N (2018) Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17:e12738 |
| Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279 |
| Tan, Li; Ke, Zhonghe; Tombline, Gregory et al. (2017) Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming. Stem Cell Reports 9:1721-1734 |
| Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406 |
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