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Evolution of ageing as a tangle of trade-offs: energy versus function

ageing developmental theory of ageing life-history theory senescence disposable soma damage accumulation

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#1 Engadin

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Posted 04 October 2019 - 04:30 PM






F U L L   T E X T   S O U R C E :   Procedings of the Royal Society B_Biological Sciences







Despite tremendous progress in recent years, our understanding of the evolution of ageing is still incomplete. A dominant paradigm maintains that ageing evolves due to the competing energy demands of reproduction and somatic maintenance leading to slow accumulation of unrepaired cellular damage with age. However, the centrality of energy trade-offs in ageing has been increasingly challenged as studies in different organisms have uncoupled the trade-off between reproduction and longevity. An emerging theory is that ageing instead is caused by biological processes that are optimized for early-life function but become harmful when they continue to run-on unabated in late life. This idea builds on the realization that early-life regulation of gene expression can break down in late life because natural selection is too weak to optimize it. Empirical evidence increasingly supports the hypothesis that suboptimal gene expression in adulthood can result in physiological malfunction leading to organismal senescence. We argue that the current state of the art in the study of ageing contradicts the widely held view that energy trade-offs between growth, reproduction, and longevity are the universal underpinning of senescence. Future research should focus on understanding the relative contribution of energy and function trade-offs to the evolution and expression of ageing.



1. Introduction



It is indeed remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.

—George C. Williams



Ageing, or senescence, is a physiological deterioration of an organism with advancing age, which reduces reproductive performance and increases the probability of death [1,2]. Despite the fact that ageing reduces Darwinian fitness, it is ubiquitous and represents an integral part of the life course of most species on Earth [2,3]. It was originally believed that ageing is restricted only to humans, captive animals, and livestock because animals in nature die from predation, competition, and parasites before they senesce. Therefore, ageing was predicted to lie largely outside the realm of natural selection. However, this view has been overturned in recent years by a string of outstanding studies in natural populations that have definitively demonstrated that ageing also occurs in the wild and is very common (reviewed in [3]). Nevertheless, there is a remarkable diversity in the patterns of ageing across the tree of life, with some species showing negligible rates of senescence in either age-specific reproduction, mortality, or both [4]. To explain this variation, evolutionary biologists and biogerontologists have sought to understand why ageing evolves, what determines variation in lifespan and rates of ageing, what are the proximal causes of ageing, and are they evolutionarily conserved? Such an understanding requires an integrated approach in which evolutionary concepts are used to guide the research into the mechanisms of ageing, while knowledge of the mechanisms is then used to support or reject different evolutionary theories.



2. Why do organisms age?


This key and enduring question requires qualification: are we asking the precise reasons why you or I might be ageing, or alternatively why ageing evolved in the first place? The failure to clearly distinguish between these proximate and ultimate questions, and why it even matters has, arguably, resulted in a fair amount of confusion within the broader study of ageing. The aim of this review is to marry these approaches and to facilitate a more complete understanding of the biology of ageing by integrating the latest mechanistic advances with the evolutionary theory. Through this, we will promote the idea that these approaches are complementary, synergistic, and can help in the development of age-specific life-history theory.

Evolutionary theories of ageing have been extensively reviewed [1,2,5,6] and are only briefly summarized here. These theories rely on the axiom that selection maximizes fitness, not necessarily lifespan. Therefore, ageing is associated with selective processes to build vehicles for successful reproduction [7,8]. The key idea underpinning the evolutionary theory of ageing is that the strength of natural selection on a trait declines after sexual maturation and with advancing age [913] resulting in Haldane's [14] famous ‘selection shadow’ (figure 1). This is because non-ageing-related extrinsic mortality reduces the probability of late-life reproduction and old individuals in the population have already produced a large part of their lifetime reproduction and passed on their genes resulting in a decline in selection gradients on mortality and fertility [1113,17]. This single, fundamentally important insight led to the formulation of the major theories of ageing.

Figure 1. The strength of age-specific selection is maximized during pre-reproductive development but declines after sexual maturation with advancing adult age and reaches zero at the age of last reproduction [1113,15]. The colours along the selection gradient line represent the effect of an antagonistically pleiotropic (AP) allele on fitness across the life course, from positive green early in life to strongly negative red in late life. The shading of the background represents the effect of an AP allele on lifespan across the life course, from neutral white to strongly negative black. The classic AP allele, as envisioned by Williams [10], will have a positive effect on fitness during development but a negative effect on fitness in late life. However, the effects of such an AP allele on lifespan will vary across the life course depending on whether the trade-off between lifespan and other fitness-related traits is based on energy or function. The negative effect on lifespan can result from competitive energy allocation between development, growth, and reproduction on the one hand, and somatic maintenance on the other hand, resulting in energy trade-offs as suggested by the ‘disposable soma’ theory [16]. Under energy trade-offs, damage accumulation due to insufficient repair starts early in life and accumulates through the ages until the demise of an organism and lifespan extension is always costly. However, functional trade-offs result from suboptimal regulation of gene expression in late life resulting in suboptimal physiological function. Under functional trade-offs, optimizing gene expression in adulthood improves both fitness and lifespan, without developmental costs. (Online version in colour.)
Mutation accumulation: in this, mutations with late-life effects can accumulate and be transmitted through the germ line [9]. Ageing here occurs due to the summation of randomly acquired deleterious effects that are manifested only late in life [18]. Following from the premise of the ‘selection shadow’, ageing at late ages has relatively little impact upon an organism's overall fitness. Early formulations of MA assumed narrow ‘windows’ for mutational effects during the life course of the organism, and models based on such assumptions predicted a rapid increase in mortality after the end of reproduction, or ‘walls of death’ that are rarely seen in nature. Subsequent models considered the possibility for positive mutational effects across adjacent age-classes and explored the extent to which MA could occur even if genes ultimately responsible for ageing had mildly deleterious effects in early life [6,19,20]. These models allowed for post-reproductive lifespan, a more gradual increase in mortality rate with age and a decline in mortality rates at a very late age. MA theory makes no specific assumptions about which types of pathways should underpin ageing, as the accumulation of mutational effects could in theory occur across random loci. MA has some support (reviewed in [21]), though recent discussions have highlighted that it may not be consistent with the discovery of the molecular signalling pathways that potentially underpin ageing across many animal groups and appear to be evolutionarily conserved [2123].

Antagonistic pleiotropy: is the evolutionary theory of ageing which recognizes that genes often have multiple or pleiotropic effects and that a beneficial effect of a gene early in an organism's life can be strongly selected even if that gene causes a negative effect later in life [10]. Because selection gradients on survival and fertility decline with age, early-life beneficial effects are likely to be strongly positively selected, and deleterious late-life effects can persist because selection is weak and cannot eliminate them. Antagonistic pleiotropy (AP) emphasizes the importance and inevitability of trade-offs between different life-history traits across early and late life. To ascertain whether MA or AP was the dominant paradigm, many studies have examined whether enhanced success in reproduction early in life is inevitably associated with decreased lifespan or increased ageing. Laboratory evolution experiments have successfully selected for increased late-life fitness and observed decreased early-life fitness as a correlated response [24,25] in line with AP theory. Others selected directly for increased survival and observed decreased reproductive output [26]. The identification of individual alleles with AP effects has also strengthened support [2729]. As noted above, Williams originally suggested the types of loci that could show antagonistic effects and, while at first an abstract concept, the finding of genes with the appropriate profile of antagonistic effects provides intriguing support for AP. One example is found in the sword tail fish (Xiphophorus cortezi), in which individuals that carry the dominant Xmrk oncogene simultaneously have increased the risk of melanoma and a selective size advantage [30].



3. Energy trade-offs between growth, reproduction, and longevity


While the logic of the AP theory of ageing [10] is straightforward, supported by mathematical modelling [11] and quantitative and molecular genetics [2,27], it does not explain which physiological processes actually result in organismal senescence. Connecting evolutionary and mechanistic explanations for ageing is important because (i) this knowledge builds a general understanding of the ageing process, (ii) knowing which physiological processes contribute to organismal senescence could provide powerful tests of ultimate ageing theory. Perhaps the most accomplished physiological/mechanistic account of AP to date is the ‘disposable soma’ theory of ageing (DST) [7,16,31]. While this model was developed as an independent evolutionary theory of ageing, and is sometimes presented as such in the literature alongside MA and AP, we agree with many researchers in the fields of evolutionary biology, ecology, and biogerontology that DST represents a physiological explanation of AP.

The premise of DST is that most organisms develop in environments in which resources are limited at least during some part of their lives. Because growth, reproduction, and somatic maintenance require energy, it is reasonable to expect that limited resources will be allocated between these different traits to maximize fitness. These are the energy trade-offs that underlie the DST and more broadly life-history theory itself [32]. Cellular damage occurs constantly and can result from direct damage to the genome and from accumulation of insoluble protein compounds that interfere with cell function. While organisms possess many maintenance and repair mechanisms that can be deployed for genome repair as well as to re-fold or clear away misfolded proteins, it may ultimately be beneficial to invest in such maintenance and repair only to maximize the organismal function during the expected period of life, which will be determined by environmental mortality risk [31]. There is no benefit of investing in high fidelity and long-term maintenance and repair to produce an organism that shows negligible senescence, but which is highly likely to be quickly predated or killed by pathogens.








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Edited by Engadin, 04 October 2019 - 04:31 PM.

Also tagged with one or more of these keywords: ageing, developmental theory of ageing, life-history theory, senescence, disposable soma, damage accumulation

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