The Hyperfunction Theory: An Emerging Paradigm for the Biology of Aging

Abstract

The process of senescence (aging) is largely determined by the action of wild-type genes. For most organisms, this does not reflect any adaptive function of senescence, but rather evolutionary effects of declining selection against genes with deleterious effects later in life. To understand aging requires an account of how evolutionary mechanisms give rise to pathogenic gene action and late-life disease, that integrates evolutionary (ultimate) and mechanistic (proximate) causes into a single explanation. A well-supported evolutionary explanation by G.C. Williams argues that senescence can evolve due to pleiotropic effects of alleles with antagonistic effects on fitness and late-life health (antagonistic pleiotropy, AP). What has remained unclear is how gene action gives rise to late-life disease pathophysiology. One ultimate-proximate account is T.B.L. Kirkwood’s disposable soma theory. Based on the hypothesis that stochastic molecular damage causes senescence, this reasons that aging is coupled to reproductive fitness due to preferential investment of resources into reproduction, rather than somatic maintenance. An alternative and more recent ultimate-proximate theory argues that aging is largely caused by programmatic, developmental-type mechanisms. Here ideas about AP and programmatic aging are reviewed, particularly those of M.V. Blagosklonny (the hyperfunction theory) and J.P. de Magalhães (the developmental theory), and their capacity to make sense of diverse experimental findings is described.

DNA methylation meta-analysis confirms the division of the genome into two functional groups

“…When discussing the role of IntG genes, which represent the basis for organismal functions, we should mention the hyperfunction theory [38], according to which the metabolism and energy consumption of the organism must constantly increase. In contrast to this theory, for us the leading role in aging processes is played not by a direct and continuous gain of functions in the organism, but by the increase in their resource consumption, which increases after the organism reaches fertility.…”

“…The currently available data on the relationship between methylation level and gene biosynthesis magnitude are inconsistent [33,34,35,36,37] and do not allow us to draw an unequivocal conclusion about an increase in IntG gene expression due to a decrease in their methylation level with age. When discussing the role of IntG genes, which represent the basis for organismal functions, we should mention the hyperfunction theory [38], according to which the metabolism and energy consumption of the organism must constantly increase. In contrast to this theory, for us the leading role in aging processes is played not by a direct and continuous gain of functions in the organism, but by the increase in their resource consumption, which increases after the organism reaches fertility.…”

Is “Cellular Senescence” a Misnomer?

“…Drawing on diverse experimental findings, the programmatic (or hyperfunction) theory argues that mechanisms of aging are to a large extent driven by wild-type developmental processes that cause pathogenic changes in the composition and properties of tissues and organs (Blagosklonny, 2006;de Magalhães and Church, 2005;Gems, 2022;Gems and de Magalhães, 2021;Maklakov and Chapman, 2019). Although specified by the wild-type genome, such deteriorative changes are not adaptive: though programmed in the mechanistic sense they are not programmed in the adaptive sense (Galimov et al, 2019), and may therefore be described as quasi-programmed (Blagosklonny, 2006) or programmatic (Gems, 2022). Here senescence results not from loss of function resulting from damage, but rather the opposite: hyper-function (Blagosklonny, 2006).…”

“…Here senescence results not from loss of function resulting from damage, but rather the opposite: hyper-function (Blagosklonny, 2006). How such programmatic changes might arise from the evolutionary process, including the role of antagonistic pleiotropy, is discussed further elsewhere (Gems, 2022;Gems and Kern, 2022a;Williams, 1957).…”

“…How, then, might "cellular senescence" be redefined to avoid such confusion? One possible way is to draw a distinction between two forms of cellular senescence: adaptive (as in fibroblasts aiding in wound healing) and non-adaptive (such as that resulting from DNA damage) (Gems, 2022). Arguably though, this does not cut deep enough.…”