A brief history of the hyperfunction theory of aging and future directions.

Aging remains a mystery of biology, and debate regarding why we age has been ongoing for centuries. Many theories of aging have been proposed, most of which focus on errors and the gradual accumulation of molecular damage. By contrast, aging may be primarily a programmatic process, arising from developmental programs that continue to run later in life and, as a form of antagonistic pleiotropy, become detrimental. Here, I review the history of programmatic theories of aging, from early caloric restriction experiments to more recent conceptual frameworks to which Mikhail Blagosklonny made key contributions, particularly the hyperfunction theory. The discovery that single-gene manipulations can modulate aging in animal models, together with evidence that rapamycin extends lifespan, provides empirical support for the hyperfunction theory. Finally, I discuss the prospects of the hyperfunction theory and its implications for the future of aging biology.