Biological Aging and the Cellular Pathogenesis of Huntington’s Disease

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life, suggesting that aging may play an active role in pathogenesis. Cellular aging is defined as the slow decline in stress resistance and accumulation of damage over time. While different cells and tissues can age at different rates, 9 hallmarks of aging have emerged to better define the cellular aging process. Strikingly, many of the hallmarks of aging are also hallmarks of HD pathology. Models of HD and HD patients possess markers of accelerated aging, and processes that decline during aging also decline at a more rapid rate in HD, further implicating the role of aging in HD pathogenesis. Furthermore, accelerating aging in HD mouse and patient-derived neurons unmasks HD-specific phenotypes, suggesting an active role for the aging process in the onset and progression of HD. Here, we review the overlap between the hallmarks of aging and HD and discuss how aging may contribute to pathogenesis in HD.