Aging Reconsidered

Aging Reconsidered

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.

Club EvMed on Covid this week

Assessing SARS-CoV-2 susceptibility in 400 species with comparative genomics Tuesday, October 6th at 12pm EDT with Elinor Karlsson. Sign up here for the meeting link.

Join us for a conversation with Elinor Karlsson, Associate Professor inBioinformatics and Integrative Biology at the University of Massachusetts Medical School and the director of the Vertebrate Genomics Group at the Broad Institute of MIT and Harvard. SARS-CoV-2, the virus that causes COVID-19, is a zoonotic pathogen that readily infects some non-human species, posing a risk to humans, if viral reservoirs are established in other species, and to other species, particularly those already endangered. Data on susceptibility and pathology in non-human species is sparse, with natural infection documented in fewer than a dozen species, but genomic datasets are far more substantial. We compiled genomic data for over 400 species and used the sequence of ACE2, the host receptor protein, to make a prediction of SARS-CoV-2 susceptibility. We also show that the viral binding domain of ACE2 is enriched for signals of natural selection in bats, the proposed source of the progenitor virus. By leveraging existing data resources, we completed this work in just four weeks in the midst of a global pandemic. While the risk predictions are preliminary, this work demonstrates how open genomic resources can be leveraged to address questions never envisioned in their original design.
Sign up here for the meeting link.

ClubEvMed October, 2020

ClubEvMed October, 2020

ClubEvMed has a terrific line up of speakers for October. Sign up for each session on the website

Club EvMed: Student Spotlight

Thursday, September 24th at 11am EDT

Join us for a special Club EvMed where we’ll be highlighting some of the exciting graduate student research in the field of evolutionary medicine. We will hear 12-minute research talks from Lafi AldakakChenlu Di, and Iman Hamid (see abstracts below). There will be a brief Q&A period at the end of each talk, plus breakout rooms after all 3 talks to allow for more in depth conversations with the speakers. Sign up here for the meeting link.

The evolution of immune sensitivity and tolerance under multiple costs of immunity and ecological feedbacks” by Lafi Aldakak, University of Zurich Institute for Evolutionary Medicine. We explore how immune resistance and tolerance are affected by the pathogen’s characteristics and the host’s life-history traits. We examine a situation where the molecular signatures of parasites, used by the host for identification, have a normal distribution overlapping with the host’s own. Due to epidemiological feedbacks, the more hosts tolerate the parasite, the bigger its prevalence and hence the risk of infection. We determine the evolutionary stable strategies of the host’s immune sensitivity and find that hosts tolerate parasites with high mimicry and low virulence. Long lifespan selects for tolerance in the innate immunity but high resistance in the adaptive immunity. This contradicts previous findings and results from our inclusion of epidemiological feedbacks and immune memory.

“The causes of strongly depleted recent adaptation in human disease genes” by Chenlu Di, University of Arizona. Despite the fact that our knowledge of gene-disease associations has greatly expanded, it is currently unknown if human non-infectious disease genes have adapted more or less than genes not involved in diseases. By a conservative comparison between human non-infectious disease and non-disease genes, we found a strong depletion of recent adaptation in human disease genes. This supports our hypothesis that disease genes are more likely to be genes that are sensitive to changing environments and have not adapted to new environments yet.

“Rapid adaptation to malaria in under 20 generations in the admixed human population of Cape Verde” by Iman Hamid, Duke University. Malaria has played a major role in human evolution as one of the strongest selective pressures in human history. Recent large-scale migrations have exposed human populations to new environments and diseases, such as malaria. How quickly humans can adapt to such a strong selective pressure and how this rapid adaptation shapes genomic variation remain unclear. Here, we develop ancestry-based methods to test for evidence of and characterize rapid adaptation to the malaria parasite, Plasmodium vivax, during the last 20 generations in the admixed population of Cape Verde.

Everything You Ever Wanted to Know About Race: And Why That’s Important for Evolutionary Medicine

Thursday, October 1st at 12pm EDT

headshot of Joseph Graves

Join us for a conversation with Joseph L. Graves Jr., Professor of Biological Sciences at the Joint School for Nanoscience and Nanoengineering, administered by North Carolina A&T State University and UNC Greensboro. Ongoing confusion concerning the nature and significance of human biological variation exists within the lay public, medical practitioners, and biomedical researchers. This occurs despite the fact that a core principle of evolutionary science is the importance of variation. This talk addresses how evolutionary principles can be better applied to understand health disparities associated with socially defined race. Attendees are encouraged to read Graves 2019, “African Americans in evolutionary science: where we have been, and what’s next” and Graves 2018, “Biological Theories of Race Beyond the Millennium” (in Suzuki and Von Vacano, Reconsidering Race: Social Science Perspectives on Racial Categories in the Age of Genomics), which will be shared upon registration. Sign up here for the meeting link.

Assessing SARS-CoV-2 susceptibility in 400 species with comparative genomics

Tuesday, October 6th at 12pm EDT

Elinor Karlsson headshot

Join us for a conversation with Elinor Karlsson, Associate Professor in Bioinformatics and Integrative Biology at the University of Massachusetts Medical School and the director of the Vertebrate Genomics Group at the Broad Institute of MIT and Harvard. SARS-CoV-2, the virus that causes COVID-19, is a zoonotic pathogen that readily infects some non-human species, posing a risk to humans, if viral reservoirs are established in other species, and to other species, particularly those already endangered. Data on susceptibility and pathology in non-human species is sparse, with natural infection documented in fewer than a dozen species, but genomic datasets are far more substantial. We compiled genomic data for over 400 species and used the sequence of ACE2, the host receptor protein, to make a prediction of SARS-CoV-2 susceptibility. We also show that the viral binding domain of ACE2 is enriched for signals of natural selection in bats, the proposed source of the progenitor virus. By leveraging existing data resources, we completed this work in just four weeks in the midst of a global pandemic. While the risk predictions are preliminary, this work demonstrates how open genomic resources can be leveraged to address questions never envisioned in their original design. Sign up here for the meeting link.

Survival of the Friendliest

Tuesday, October 13th at 12pm EDT

cover of the book Survival of the Friendliest by Brian Hare and Vanessa Woods

Join us for a conversation with Brian Hare, Professor of Evolutionary Anthropology at Duke University. The only way to understand what it is to be human is to know what it is like to be not human. In this talk we will explore the minds of our closest relatives, bonobos and chimpanzees, and dogs — our closest friend. We will look at how these animals help us understand what makes us human, and how our minds came to be. We will arrive at the idea that it was friendliness that powerfully shaped both the bodies and minds of bonobos and dogs during their evolution. We will then consider if our own species evolved due to selection for friendliness. We will argue that comparing our friendly nature to other animals solves the paradox of human kindness and cruelty and points to the need for cross-group friendships to encourage a friendlier future. These ideas are explored in Hare’s new book, Survival of the Friendliest: Understanding Our Origins and Rediscovering Our Common Humanity. Sign up here for the meeting link.

How recent characterizations of somatic mutations in humans inform an evolutionary understanding of aging and cancer

Monday, October 19th at 1pm EDT

James DeGregori and his dog

Join us for a conversation with James DeGregori, Courtenay C. And Lucy Patten Davis Endowed Chair in Lung Cancer Research at the University of Colorado Anschutz Medical Campus. In the last five years, multiple studies have demonstrated that apparently healthy tissues in humans are patchworks of clones bearing somatic mutations, and the sizes and frequencies of these clones increases dramatically in old age. Often, there is clear evidence for positive selection for variants, which are frequently in genes frequently mutated in cancers, and yet the vast (VAST!) majority of these mutation-bearing clones will never develop into a cancer. We will discuss the implications of these findings for different evolutionary theories of aging and cancer. Sign up here for the meeting link.

Pathogen selection for HLA gene diversity and its consequences for autoimmunity and cancer immunotherapy

Tuesday, October 27th at 1pm EDT

headshot of Tobias Lenz

Join us for a conversation with Tobias L. Lenz of the Research Group for Evolutionary Immunogenomics at the Max Planck Institute for Evolutionary Biology in Ploen, Germany. Pathogen-mediated selection is a major driver of human evolution in general and of immune gene diversity specifically. A key component of the adaptive immune system are the human leukocyte antigen (HLA) genes, coding for molecules that present antigenic peptides to immune effector cells. The exceptional polymorphism at the HLA goes is assumed to reflect the need for diverse antigen presentation. However, an optimal immune response requires a delicate balance of maximizing recognition of pathogens while minimizing damage to self tissue by the immune machinery. As HLA molecules present both non-self and self antigens, depending on which antigens are presented by an individual’s HLA variants, this can trigger either pathogen resistance or autoimmunity. HLA-presentation of a broader antigen repertoire should thus be beneficial for pathogen recognition, but might also increase the risk for autoimmunity, leading to antagonistic selective pressures that shape the optimal antigen repertoire and thus HLA diversity in an individual.

Here Dr. Lenz will discuss this evolutionary trade-off for individual HLA diversity and present some examples from his work on the role of pathogens in the evolution of HLA diversity, but also on its consequences for autoimmunity and its role in immune checkpoint blockade therapy against cancer, a striking example for the success of evolutionary medicine. Attendees are encouraged to read Pierini and Lenz 2018, “Divergent allele advantage at human MHC genes: signatures of past and ongoing selection” and Chowell et al. 2019, “Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.” Sign up here for the meeting link.

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2020 Williams Prize awarded to article by Rosenberg, et al.

2020 Williams Prize awarded to article by Rosenberg, et al.

The $5,000 George C Williams Prize for the most significant article published in 2019 in Evolution, Medicine and Public Health is awarded to the paper: Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences by Noah Rosenberg, Michael Edge, Jonathan Pritchard and Marcus Feldman.

The paper focuses on potential misunderstandings of ongoing discoveries in human genomics. The Committee (David Houle, Neil Greenspan, Jenny Tung, Andrew Read (Chair)) agreed that the paper has important messages that will resonate across many fields of medicine and beyond. It is an outstanding example of how clarity of evolutionary thought is necessary to constructively advance discussions on sensitive and controversial topics involving humanity such as race and the causes of health disparities.

All articles published in Evolution, Medicine and Public Health in 2020 will be automatically considered for next year’s $5000 Williams Prize. The fully open access flagship journal of the International Society for Evolution, Medicine and Public Health, EMPH is published by Oxford University Press. It has an impact factor of 4.222 and is ranked 11th out of 50 journals in evolutionary biology. Author’s guidelines are here, or contact the Executive Editor Charles Nunn with your ideas for possible submissions.

ClubEvMed Events

See this webpage for upcoming ClubEvMed events and videos of past events. All are welcome but you must sign up ahead of time for these Zoom Webinars that provide a short talk followed by questions and discussion.

Thursday, June 11th at 11am ET Tacit creationism in emotions research Join us for a conversation with Randolph Nesse, Foundation Professor in the School of Life Sciences at Arizona State University. We will discuss his new article, “Tacit Creationism in Emotions Research,” published this week in Emotion Researcher. A pdf version is available here. Sign up here for the meeting link.

Monday, June 15th at 2pm ET Social determinants of health and survival in humans and other animals Join us for a conversation with Jenny Tung, Associate Professor of Evolutionary Anthropology and Biology at Duke, Noah Snyder-Mackler, Assistant Professor in the School of Life Sciences at Arizona State University, and Dan Belsky, Assistant Professor of Epidemiology at Columbia. They’ll be leading a discussion on their recent Science paper, “Social determinants of health and survival in humans and other animals.” Sign up here for the meeting link

ClubEvMed Friday with Joe Alcock on Cytokine Storm

A weekly Zoom meeting led by an expert in some evolutionary medicine-related topic centered around a paper, web resource, or dataset, with opportunities for brief presentation and then discussion. https://tricem.org/outreach-and-education/club-evmed 

Friday, May 15th at 1pm ET: Harmful or helpful? Cytokine storms examined in light of evolution with Joe Alcock

A variety of therapies for COVID-19 are aimed at inhibiting the harmful consequences of a cytokine storm, defined as an exaggerated and out-of-control immune response. Cytokine storms assume that immune responses are often dysregulated and maladaptive, causing more harm than good. Several drugs are proposed to inhibit the cytokine storm in COVID-19, but will these drugs work?

Join us for a conversation with Joe Alcock, emergency physician and professor in the University of New Mexico Department of Emergency Medicine. He will discuss the evidence for immunomodulatory drugs for infection (reviewed here: https://doi.org/10.3390/jcm7090247) and consider the concept of a cytokine storm in light of evolutionary medicine. Several evolutionary medicine concepts – the smoke detector principle, immune brinksmanship, mismatch, and cliff-edge effects may explain seemingly excessive immune responses. On the other hand, host-pathogen arms races may result in immune systems that are resistant to medical improvement. Sign up here for the meeting link: https://duke.zoom.us/meeting/register/tJIvceirrD8iGNyjreUITQ1ZTTz-6wyzmCA3.