Human ageing, longevity and evolution: can ageing be programmed?

Abstract

Understanding the proximate and ultimate causes of ageing is one of the key challenges in current biology and medicine. These problems are so important that they are sometimes referred to as the Holy Grail of biology and the Great Conundrum in biogerontology. From an evolutionary perspective, ageing is due to a failure of selection that is caused either by declining strength of selection after the onset of sexual reproduction (Medawar’s theory and Charlesworth’s model) or pleiotropic constraints (Williams’ theory). According to the disposable soma theory, which was proposed by Kirkwood and Holliday, ageing is driven by the accumulation of damage during life and failures of defensive and repair mechanisms as the more an animal expends on sexual reproduction, the less it can expend on bodily maintenance, and vice versa. Although these standard models rule out the possibility that ageing is programmed, there is no consensus about the nature of ageing within the life history in current biogerontology. Interestingly, empirical studies show that there are molecular instructions for ageing and evolutionarily conserved mechanisms for ageing, which seems inconsistent with the idea that ageing is a matter of neglect or a consequence of a failure of selection due to pleiotropic constraints. Here, selected arguments for programmed (i.e. either determined and adaptive or prearranged but non-adaptive) and non-programmed ageing are discussed. Recent advances in biogerontology that cast new light on these problems are outlined here in the context of the idea that the pace of ageing can act as an adaptation in nature, even though ageing is non-programmed and non-adaptive.

The dynamic nature of ageing: novel findings, therapeutic avenues and medical interventions

“…Kenyon (2010) argues that ageing could have evolved as an adaptation to nutrient conditions, and the biology of insulin/IGF-1 provides a particularly interesting context for understanding the evolutionary aspects of senescence in model organisms. Whilst this interpretation might explain, at least to some extent, the malleability of ageing in model organisms, it is still not clear what is 'programmed': ageing, longevity or both because it depends on arbitrary definitions (Chmielewski et al 2016a;Chmielewski 2017Chmielewski , 2019aChmielewski , 2019b.…”

“…Ageing is arguably one of the most complex and difficult problems for humans to face and for science to solve (Kirkwood and Franceschi 1992; Kaczmarek and Szwed 1997;Chmielewski et al 2016a;Cohen 2016;Muntané et al 2018;Chmielewski 2019aChmielewski , 2019b. At the same time, ageing is a fascinating phenomenon that has captivated philosophers and researchers for centuries (da Costa et al 2016).…”

“…It has been established that there are specific molecular signatures and 'instructions' for ageing at the molecular level, and a better understanding of the molecular biology of ageing will open new possibilities regarding rational strategies and interventions (López-Otín et al 2013;Kennedy et al 2014;DiLoreto and Murphy 2015;McHugh and Gil 2018;Campisi et al 2019;Dönertaş et al 2019). Nevertheless, the complexity of ageing diminishes the possibility that the problem of ageing can be solved using reductionist and disease-oriented approaches (Chmielewski 2017(Chmielewski , 2019a(Chmielewski , 2019bRattan 2019). To understand the nature of ageing, we must first understand life.…”

If ageing is a disease, then life is also a disease

“…Unlike any disease or pathology, age changes: (1) are universal and occur in every individual that lives longer than the essential lifespan (ELS), (2) can be observed in all sexually reproducing animals, (3) have the same molecular basis or aetiology, i.e. the accumulation of molecular and cellular damage that results from the gradual failure of maintenance mechanisms that are unwarranted in the long run (Rattan 2014;Hayflick 2016;Chmielewski 2017Chmielewski , 2018Chmielewski , 2019Chmielewski , 2020a The fundamental cause of ageing is a failure of natural selection that is caused either by declining strength of natural selection or pleiotropic constraints (Chmielewski 2019, 2020b), whereas the fundamental cause of any pathological process is a disruption of the normal structure and/or function or 'any abnormality of bodily structure or function' (Bulterijs et al 2015). From an evolutionary perspective, ageing has nothing to do with the molecular biology of the eukaryotic cell, as this dynamic and emergent metaphenomenon originates in the difficulty in maintaining homeostasis in complex biological systems (Kirkwood 2005;Cohen 2016).…”

“…If normal, not to mention healthy or successful, ageing is a fact, then this traditional distinction should be pursued. From a biological standpoint, ageing is prima facie quite different from a disease, and it is definitely too broad to be understood as any type of pathology that is easily treatable with pharmaceuticals (Hayflick 2003(Hayflick , 2004(Hayflick , 2007(Hayflick , 2016Carnes et al 2008Carnes et al , 2013Rattan 2014Rattan , 2018Rattan , 2019Gavrilov and Gavrilova 2017;Chmielewski 2017Chmielewski , 2018Chmielewski , 2019Chmielewski , 2020aChmielewski , 2020b.…”