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.

The Boeing 737 Max and Evolutionary Medicine

The Boeing 737 Max and Evolutionary Medicine

The recent Boeing 737 Max crashes provide a tragic illustration of how the core principle of evolutionary medicine can be useful for understanding failures of machines as well as bodies.

On October 29, 2019 Lion Air flight 610 crashed into the Java Sea 13 minutes after takeoff, killing all 189 aboard. Initials explanations focused on what was different about that individual plane and its pilots. This is a mechanic’s approach, much like most medical research. It asks what part of the mechanism failed in this individual instance.

On March 10, 2019 Ethiopian Airlines flight 302, another Boeing 737 Max, crashed six minutes after take-off. The similarities to the previous crash turned attention to shared traits of Boeing 737 Max planes. This is an engineer’s approach. It poses the question asked by evolutionary medicine: why did the forces that shaped the design leave it vulnerable to failure?

The course of events that led to the tragedy began a decade ago when airplane manufacturers were in a desperate competition to reduce fuel costs and increase range. Airbus had the advantage. The competition created strong pressure on Boeing to create a new model fast, in much the same way that pathogens can induce strong selection pressures.

Planes, like bodies, have path dependent designs that make starting from scratch nearly impossible.  So, Boeing decided to adapt an older 737 model.

Longer-range and better fuel efficiency required larger engines that could not be mounted on the older 737 models, so the wings were shifted forward on the fuselage to accommodate the larger engines. The trade-off gave fuel cost and range benefits that increased linearly with larger engine size, but risks that increased exponentially, especially stalling during the climb after take-off. A cliff-edged fitness function resulted.

In recognition of the risks, engineers added a defense system to monitor angle and airspeed and automatically push the nose down when a stall is imminent. As is the case for bodily defenses, dire risks were manifest only in unusual circumstances. Sensor failure activated the automatic stall prevention mechanism and pushed the nose down even as the plane plummeted.

Engineers who recognized the risk suggested adding redundant sensors and controls, but the changes were rejected because they would add cost and delay.  If a sensor failed, pilots could turn off the automated system.

However, the rapid change in design was not fully coordinated with pilot training so some did not know about the automatic stall prevention system and how to turn it off. Catastrophic failure required failure of only one component combined with inability of the pilot to respond quickly and accurately in an emergency situation.

Test pilots reported related problems two years ago, but their experiences were never analyzed in a way that revealed the inherent vulnerability of the Boeing 737 Max.  Today’s news suggests that their concerns may have been concealed to avoid costly delays in production.

Could the principles of evolutionary medicine have helped to prevent the tragedy of Flights 610 and 302?  We can’t know, but system failures, whether bodily or mechanical, make more sense in light of careful attention to the forces shaping the design, the historical sequence and path dependent constraints, trade offs, fitness functions, and the vulnerabilities imposed by defense systems.

Articles in The Economist, The Atlantic and other media sources provided background for this essay; it is intended to be illustrative, not definitive.

Why NIH needs evolution expertise–The amyloid beta case study

Why NIH needs evolution expertise–The amyloid beta case study

Sharon Begley has written a lovely article on Tanzi and Moir’s research on the antimicrobial properties of amyloid beta and the outrageous difficulty they have had getting NIH to fund their work. They noted that study after study has found no benefit from treatments that disrupt amyloid synthesis, and that there must be some reason why amyloid beta exists.

The crucial paragraphs are in italics below

“For years in the 1990s, Moir, too, researched beta-amyloid, especially its penchant for gunking up into plaques and “a whole bunch of things all viewed as abnormal and causing disease,” he said. “The traditional view is that amyloid-beta is a freak, that it has a propensity to form fibrils that are toxic to the brain — that it’s irredeemably bad. In the 1980s, that was a reasonable assumption.”

But something had long bothered him about the “evil amyloid” dogma. The peptide is made by all vertebrates, including frogs and lizards and snakes and fish. In most species, it’s identical to humans’, suggesting that beta-amyloid evolved at least 400 million years ago. “Anything so extensively conserved over that immense span of time must play an important physiological role,” Moir said.  What, he wondered, could that be?

Their subsequent work has demonstrated beyond doubt that amyloid beta is a powerful antimicrobial [1] and has strongly suggested a role for herpes viruses[2]. But despite these findings, they still are having difficulty getting their work published and getting NIH funding. I predict this will lead to a Nobel prize, and go into the history books as an especially egregious example of how pure reductionism obstructs progress.  Evolutionary thinking about the reasons why we are vulnerable to Alzheimer’s disease adds the missing perspective. We can hope that it will also inspire new approaches to prevention and treatment.

  1.  Kumar, D. K. V., Choi, S. H., Washicosky, K. J., Eimer, W. A., Tucker, S., Ghofrani, J., … others. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine, 8(340), 340ra72–340ra72
  2. Eimer, W. A., Vijaya Kumar, D. K., Navalpur Shanmugam, N. K., Rodriguez, A. S., Mitchell, T., Washicosky, K. J., … Moir, R. D. (2018). Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron, 99(1), 56-63.e3.

Photo credit: Creator:Jon ChaseInformation extracted from IPTC Photo Metadata

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How EvMed Misled Me—The ASA saga

How EvMed Misled Me—The ASA saga

The history of medicine is replete with examples of the disasters that result when clinical practice is guided by theory alone. For instance, in the early 20th century sudden infant death was attributed to suffocation caused by an enlarged thymus.1 Thousands of infants received radiation treatment that created an epidemic of thyroid cancer, with new cases still emerging 45 years after exposure.2 

Such examples make most of us in evolutionary medicine extremely wary of basing clinical advice on theory. However, recommending aspirin to prevent strokes and heart attacks seemed like a sure thing. In modern environments, bleeding is less of a risk, and clots in coronary or cerebral arteries are a much more of a risk, than in ancestral environments. Taking a baby aspirin every day should adjust the tradeoffs to help our ancient bodies cope better with modern environments.  Also, studies showing that a baby aspirin a day reduced heart attacks by more than 25% led medical organizations to endorse aspirin for prevention.3

The data supported the evolutionary theory, so I started taking a daily aspirin, and I recommended that my patients over 50 years old do the same. Millions of people took an aspirin every day for years. But it is becoming clear that even solid theory and supporting data are not enough.

The first warnings came from new studies showing that even small doses of aspirin caused more gastrointestinal bleeds than expected. Then, late in 2017, the results of a double-blind long-term study were published. The ARRIVE trial enrolled over 12,000 subjects averaging 55-60 years of age with an average risk for a heart attack; half got aspirin half got placebo. At the end of five years, cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack had occurred in 4.29% of the aspirin group, and 4.48% of the placebo group.4 The rate of gastrointestinal bleeding was twice as high for the aspirin group. I stopped taking aspirin and decided to write this article.

This will not be the last word on the issue; compliance was inconsistent, and the results may not generalize to people with higher risk. Patients who have had a cardiac event should not stop their aspirin. But the trial offers yet more evidence that there is no substitute for a controlled trial with random assignment…and that clinical recommendations based on apparently solid evolutionary thinking may not be justified, even when apparently supported by data.

  1. Symmers D. The Cause of Sudden Death in Status Lymphaticus. Am J Dis Child. 1917 Dec 1;14(6):463–9.
  2. Adams (Michael) Jacob, Shore RE, Dozier A, Lipshultz SE, Schwartz RG, Constine LS, et al. Thyroid Cancer Risk 40+ Years after Irradiation for an Enlarged Thymus: An Update of the Hempelmann Cohort. Radiat Res. 2010 Dec;174(6):753–62.
  3. Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-Dose Aspirin for the Prevention of Atherothrombosis. N Engl J Med. 2005 Dec 1;353(22):2373–83.
  4. Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. The Lancet. 2018 Sep 22;392(10152):1036–46.
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After 60 years, the seminal Williams paper on aging is aging well

After 60 years, the seminal Williams paper on aging is aging well

The paper George Williams published in 1957 about senescence has inspired much of the field of evolutionary medicine.  I never heard about it in medical school, but the evolutionary biologists I was talking with at the University of Michigan in the 1980’s said I should get a copy. Reading it changed my life. If aging has an evolutionary explanation, what about everything else in medicine?  I spent a summer in the library finding and analyzing data on survival curves for animals in the wild.  They showed that senescence greatly decreases fitness for many species in the wild, contradicting the the mutation accumulation theory, and supporting Williams’ idea of antagonistic pleiotropy. That led to publications and a wonderful collaboration with George for the next two decades. 
Now 60 years after its publication, Williams’ article remains fresh. In a new article in Evolution, Laillard and Lemaître offer a review of the paper, and the status of the hypotheses it proposed. I hope it inspires many people to read the original paper that inspired much of the progress in evolutionary medicine. 
Gaillard, J.-M., & Lemaître, J.-F. (2017). The Williams’ legacy: A critical reappraisal of his nine predictions about the evolution of senescence. Evolution.
Abstract:  Williams’ evolutionary theory of senescence based on antagonistic pleiotropy has become a landmark in evolutionary biology, and more recently in biogerontology and evolutionary medicine. In his original article, Williams launched a set of nine “testable deductions” from his theory. Although some of these predictions have been repeatedly discussed, most have been overlooked and no systematic evaluation of the whole set of Williams’ original predictions has been performed. For the sixtieth anniversary of the publication of the Williams’ article, we provide an updated evaluation of all these predictions. We present the pros and cons of each prediction based on recent accumulation of both theoretical and empirical studies performed in the laboratory and in the wild. From our viewpoint, six predictions are mostly supported by our current knowledge at least under some conditions (although Williams’ theory cannot thoroughly explain why for some of them). Three predictions, all involving the timing of senescence, are not supported. Our critical review of Williams’ predictions highlights the importance of William’s contribution and clearly demonstrates that, 60 years after its publication, his article does not show any sign of senescence.
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