The Evolution & Medicine Review

October 12, 2020

Research on aging has been foundational for evolutionary medicine. A recent article by Maklakov & Chapman in Proceedings B “Evolution of aging as a tangle of trade-offs: Energy versus function” reviews history and progress and offers a new idea.

The development of evolutionary medicine was spurred by George Williams’ 1957 article “Pleiotropy, Natural Selection, and the Evolution of Senescence.” His simple profound insight was that alleles with harmful effects late in life can be selected for and go to fixation if they give sufficient benefits early in life when selection is stronger. This is called the “Antagonistic Pleiotropy” (AP) theory because such alleles have opposite and multiple effects at different phases in the life span. The idea revolutionized our understanding of aging. A review of supporting evidence by Austad and Hoffman won last year’s $5000 Williams Prize for the best article published in the journal Evolution, Medicine and Public Health.

As soon as I heard about Williams’ theory I realized it offered a new kind of explanation for disease, and decided to test it. If aging results from the accumulation of mutations whose effects were deleterious only after the usual life span, then mortality rates should not increase with age in wild populations. Evidence for mortality rates that increase with age in wild populations would support antagonistic pleiotropy.  I spent a wonderful summer looking up mortality rates by age for wild populations and used them to calculate the force of selection resulting from aging. For many wild populations, aging had a devastating effect on fitness that could be explained by antagonistic pleiotropy but not by mutation accumulation. More sophisticated and extensive studies of wild populations have confirmed and extended the finding. Antagonistic pleiotropy is also supported by extensive experimental evolution studies showing that breeding for longer lifespan causes reduced early reproduction, and breeding for early reproduction results in shorter lifespan.

The Maklakov and Chapman article reviews this history and considers the mechanisms that account for aging. They note that attention has focused on how allocation of energy to survival limits investment in reproduction and vice versa with the Disposable Soma Theory (DST) being a prime example. They do not view DST an alternative to antagonistic pleiotropy (AP): “we agree with many researchers in the fields of evolutionary biology, ecology, and biogerontology that DST represents a physiological explanation of AP.”

They then suggest that energy allocation tradeoffs may not be the whole story. Instead, they argue that optimizing physiology for early-life “hyperfunction” may often result in problems later in life that selection can’t fix because it is weak at advanced ages. They call this the “Developmental Theory of Aging” (DTA), and they offer the optimistic suggestion that it might be possible to get full benefit from the hyperfunction of mechanisms early in life and then turn the expression of some genes down later in ways that extend the life span.

The study of aging offers a fine example of the importance and the challenge of considering evolutionary explanations at multiple levels simultaneously. Williams’ 1957 article set the bookends by framing the problem in genetic terms but offering a hypothetical example at a high phenotypic level: an allele that promotes fast bone healing in early life that also causes coronary artery calcification later in life. From the bottom up, progress has been steady in considering the evolutionary status of alleles that influence aging. From the top down, focus on tradeoffs between life history traits such as reproduction and survival have gradually expanded to look at physiological mechanisms.  Dramatic evidence that disruption of insulin signaling pathways can increase life spans of worms and flies is now central. A 2018 J Cell Biology article by Templeton and Murphy provides a recent overview.

I have wondered if these findings reflect a “Fundamental Metabolic Tradeoff” that maximizes metabolic efficiency and energy availability at the cost of limited ability to control the generation and disposal of reactive oxygen species and other tissue damaging products. But a moment’s thought reveals that while some tradeoffs are likely to be more fundamental than others, we should expect to find many tradeoffs at many levels. For instance, an aggressive immune system gives benefits throughout life, but it also causes chronic tissue damage. A cellular state of senescence has benefits including reducing cancer, but at the cost of inflammation. And the physiological and behavioral mechanisms that maximize success in reproductive competitions, benefiting an individual’s genes at great expense to the individual, have costs involved in tradeoffs, but also vulnerabilities resulting from the constraints associated with “hyperfunction.”

Maklakov and Chapman conclude, “We need to understand how trade-offs work in order to distinguish whether they are primarily energy-based or function-based.” I would go further and suggest we need to consider, for all traits and mechanisms, the many costs and risks that result from features that maximize a trait’s contributions to inclusive fitness. “Intrinsic vulnerability” is characteristic of many systems shaped to a pinnacle of performance.

The just-published Proceedings B Theme Issue “Evolution of the primate ageing process” compiled and edited by Melissa Emery Thompson, Alexandra G. Rosati and Noah Snyder-Mackler, will be of deep interest to many.