A Snapshot of One Portion of the Ongoing Debate over Causes and Processes of Aging
A person dies, and there is the irresistible urge to draw a line under their life and summarize. So to the late Mikhail Blagosklonny and his contributions to the modern debate over the causes of aging. Hyperfunction theory doesn't end with the originator, any more than any thread of scientific thought on the matter of aging - Robert Bradbury would no doubt be most interested to see where thought on the role of double stranded breaks in DNA as a mechanism of aging has ended up these days, were he still alive. Still, here we are, a chance to look back at one portion of the ongoing debate over programmed aging versus antagonistic pleiotropy, and the primacy versus secondary nature of molecular damage.
Blagosklonny directly engaged with Aubrey de Grey, a proponent of damage-based theories, in a 2021 exchange. Blagosklonny emphasized that hyperfunction, not damage accumulation, underpins aging, arguing that Hyperfunction Theory explains why damage accumulates - not from aging but as a downstream byproduct of hyperactive signaling: "Hyperfunction of signaling pathways can occur without progressive changes of their activity. For example, when the same activity of growth-promoting pathways remains unchanged in postdevelopment, it is a hyperfunction. By analogy, a car driving 65 mph on highway is not speeding (hyperfunction) but driving 65 mph on the driveway is. In the latter case, the car certainly will be damaged, but not by rusting (molecular damage), but by damage of its macroparts. Similarly, hyperfunction does not cause molecular damage, but causes organ damage. Thus, the brain is damaged by stroke, which can be a result of hypertension, which, in turn, is developed by hyperfunctional cells of multiple tissues. There is no place for molecular damage in this sequence of events..."
In his rebuttal, de Grey argued that while the Hyperfunction Theory offers valuable insights, damage repair remains essential for addressing aging: "While hyperfunction undoubtedly contributes to aging, it cannot fully explain the accumulation of oxidative and genetic damage that impairs cellular function." Blagosklonny further posited that while molecular damage accumulates, it does not necessarily constrain lifespan under typical conditions; however, if interventions extend lifespan significantly, such damage may become more limiting. This dialogue highlights the contrasting paradigms while reinforcing Blagosklonny's central assertion that aging interventions should prioritize targeting hyperfunction at its source.
Building on the Hyperfunction Theory, Blagosklonny proposed that targeting overactive growth pathways could mitigate aging and its associated diseases. This theoretical framework directly informs the exploration of rapamycin, an mTOR inhibitor, as a potential therapeutic agent. The Hyperfunction Theory, together with João Pedro de Magalhães' related developmental model has inspired the emergence of an expanding suite of programmatic theories, encompassing hypofunction, costly programs, constraint theory, and adaptive death.