Identifying genetic mechanisms that are protective or detrimental to age-dependent events would have profound consequences for preventing or delaying age-related functional declines. Studies on rare heritable human disorders and targeted gene mutations in rodents demonstrate that both the rate of age-related changes and longevity can be modulated through genetic mutation in single genes. In particular, there is a critical role of longevity genes that modulate hormonal, metabolic, and cellular insult repair pathways for the rate of aging in model organisms and potentially also in humans. While the genetics of aging has been predominantly studied in dividing peripheral tissues in relation to senescence, or in the context of neurodegenerative disorders, here we propose to explore a less studied area, """"""""normal"""""""" human brain aging. We present a concise approach to defining age in the human central nervous system (CNS) using postmortem DNA microarray. This approach is based on the observation that gene expression correlates of aging are progressive and continuous throughout the adult life. This observation allows for evaluation of """"""""age-trajectory"""""""", which we define as the deviation of molecular brain age from chronological age (a measure of rate of aging). We employ this approach to test our hypothesis that each of five single nucleotide polymorphisms in three putative human longevity genes will alter human """"""""age-trajectory"""""""" and will have partially overlapping mechanisms. These candidate genes (snps), the serotonin 1B receptor (G861C), sirtuin 5 (prom1,2,3), and klotho (KL-VS) were selected for their potential relevance to modulation of human CNS aging and for the translational extension of our work on accelerated CNS aging in serotonin receptor 1B knock-out mice. We use human postmortem DNA microarray datasets to characterize age sensitive transcripts in two brain areas relevant to our specific interest in the intersection of aging and affect, Amygdala and Anterior Cingulate Cortex. We then propose to evaluate by genotypic two-group comparison, our five candidate snps effects on the transcriptome, age-trajectory, and specific age-sensitive transcripts in these .two brain areas. This study provides useful previously uncharacterized information on transcriptional changes with age. It then harnesses this basic information to investigate the mechanistic relationship between putative longevity genes and molecular brain age-related correlates. This will provide insight into CNS aging mechanisms and entry points into the potential interaction of genetics of """"""""normal"""""""" aging with vulnerability to age-related CNS disorders.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F01-Z (20))
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Wise, Bradley C
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University of Pittsburgh
Schools of Medicine
United States
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Glorioso, Christin; Sibille, Etienne (2011) Between destiny and disease: genetics and molecular pathways of human central nervous system aging. Prog Neurobiol 93:165-81
Glorioso, Christin; Oh, Sunghee; Douillard, Gaelle Guilloux et al. (2011) Brain molecular aging, promotion of neurological disease and modulation by sirtuin 5 longevity gene polymorphism. Neurobiol Dis 41:279-90