Genetic and epigenetic regulation of human aging and longevity.


Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, University of Sydney, New South Wales 2006, Australia; Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, HI 96817, United States; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Kuakini Medical Center Campus, Honolulu, HI 96813, United States. Electronic address: [Email]


Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive "leak". There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.


APOE,Aging,Epigenetics,FOXO3,Genome-wide association studies,Histones,Longevity,Network analysis,Transcription,