With today's aging society comes an increased prevalence of age-related disorders including cancer, diabetes and heart disease. Aging was once thought to be the unregulated decay of the genome over time. It is now known, however, that there are carefully regulated genetic and environmental influences on aging. For instance, mutations in the IGF-1 and TOR signaling pathways are known to affect longevity. Also, the environment, such as cigarette smoking, affects aging. While several recent studies have focused on the effects of single nucleotide DNA damage on aging, the role of other forms of DNA damage has gone largely unstudied. Copy number aberrations (CNAs) are somatic events, marked by the gain and loss of genomic material during one's lifetime. The potential consequences of CNAs on gene expression and aging have not been addressed on a genome-wide scale. The proposed research plan will use the most current genomics technology to assess copy number changes that occur over time. The study includes both monozygotic twin DNA from multiple time points and mouse DNA from multiple time points. Using array comparative genomic hybridization (aCGH), the copy number changes that occur in monozygotic twins and mice as they age will be determined. Both the mouse and human studies will allow us to directly assess the question: Do CNAs accumulate over time? Furthermore, the mouse samples in this study have either been subjected to a caloric restriction or ad libitum diet. Caloric restriction has been shown to increase the lifespan of mice and humans, but the molecular mechanisms of this phenomenon are still largely unknown. By determining the number of copy number changes in these two mouse cohorts as they age, the potential protective effects of caloric restriction on the genome will be exposed. In addition, by combining aCGH with sequencing data, duplicated sequence will be precisely mapped in order to better understand the consequences of CNAs. RNA from the mice will be subjected to RNA-seq to study gene expression. Therefore, aging and diet can be associated with gene expression patterns. Notably, studying both mouse and human will provide an evolutionary perspective on aging, answering the question: Does aging result from the apparent random accumulation of DNA damage or is aging driven by copy number changes at evolutionarily conserved loci? Such a comprehensive, genome- wide study may find novel genes, pathways, and mechanisms involved in the process of aging. Furthermore, a better understanding of the mechanisms of aging could potentially lead to the use of novel therapeutics in age- related disorders.

Public Health Relevance

In today's aging society, age-related disorders are pervasive, however, the molecular mechanisms of aging remain largely unknown. In the proposed research, the role of genomic duplications and deletions in the process of aging will be studied. In addition, caloric restriction (a potential treatment to slow aging) will be assessed for its ability to slow the accumulation of DNA damage by altering the expression of specific genes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-E (20))
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Guo, Max
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Brigham and Women's Hospital
United States
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Gokcumen, Omer; Tischler, Verena; Tica, Jelena et al. (2013) Primate genome architecture influences structural variation mechanisms and functional consequences. Proc Natl Acad Sci U S A 110:15764-9
Iskow, Rebecca C; Gokcumen, Omer; Lee, Charles (2012) Exploring the role of copy number variants in human adaptation. Trends Genet 28:245-57