Aging and menopause

Spawn till you die by Ray Troll

Listen to this audio link by the Canadian born rapper Baba Brinkman: all the way to senescence (with lyrics):

http://music.bababrinkman.com/track/senescence

Understanding age-related risk of death and age-related disease are the result of tradeoffs and occur because of evolved life history traits.

We are going to cover evolutionary hypotheses of senescence for next week’s class. These hypotheses include antagonistic pleiotropy, declining power of selection, and mutation accumulation.

Antagonistic pleiotropy is the concept that a gene for survival or a gene that promotes
reproduction early can be selected for even if it kills you at a later
age. So selection favors juvenile survival at the expense of old age survival. This hypothesis recognizes that most traits have both costs and benefits, and are tradeoffs. The tradeoff in antagonistic pleiotropy is improved health and fertility in the young, but disease and premature death in older individuals.

Haldane and Medawar proposed the declining power of selection hypothesis of aging. This proposes that genes for maintenance and repair of the body are selected for more strongly at early ages (pre-reproduction) than after reproductive age. For this: imagine a hypothetical gene that prevents cancer at age 10 and another gene that prevents cancer at age 100. The gene that prevents cancer at age 100 will not have any effect most of the time because most people are dead by age 100 (this remains true even if you take senescence out of the equation – random accidents will claim many lives). The gene that affects 10 year olds is more likely to be expressed and have a benefit simply because most people are alive at age 10. Therefore the old-age gene will be invisible to natural selection, the gene that affects 10 year old will be subject to positive selection.

Medawar extended his idea to include mutation accumulation. This idea posits that the body accumulates deleterious mutations that take effect at older ages. Because of the declining power of selection, these mutations are not selected against, and contribute to declining function that we see with aging. In wild populations, not enough organisms reach advanced age, so these mutations are invisible. If allowed to achieve advanced chronological age, these mutations exert damaging effects, reducing fitness and contributing to senescence.

The disposable soma hypothesis is another idea to explain aging. This hypothesis recognizes that the nonreproductive part of the body (the soma) exists only to support the reproductive part of the body. At any moment in time an adult can devote energy to the maintenance of the body or to reproduction. Put simply, after successful reproduction, the soma is “disposable”, and genes are passed on. This tradeoff is vividly illustrated in adult salmon, also in octopus, which appear to do all their aging at once, immediately after a single reproductive effort. In many animals, bearing offspring shortens lifespan. There is some evidence of this in humans too.

Consider:

Menopause is a strange phenomenon, because it represents premature aging of the female reproductive organs, asynchronous with the rate of decline in function for the rest of the body. It is paradoxical because it would seem that natural selection would seem to favor maximal personal reproduction throughout a woman’s adult life. Given the fitness benefits of continued reproduction, why does the female reproductive organ – the ovary – quit working so early? Humans are nearly unique in having a menopause; although menopause is also reported in killer whales.

Some suggest that menopause evolved because grandmothers are more successful at passing on their genes by investing in grandchildren than in more babies of their own. Others argue that menopause is a consequence of modern medicine prolonging the lifespan. This artificial lifespan prolongation hypothesis proposes that most pre-historic women would be dead by 60 in the environment of evolutionary adaptedness (EEA). So for ancient women, reproductive aging might have been in sync with aging of the rest of the body. In this view menopause is a gene-environment mismatch.

Writing assignment: What best accounts for menopause in humans –  the grandmother hypothesis, the artificial lifespan prolongation hypothesis, something else?

Readings for next week:

1.  Still Pondering an Age-Old-Question. Flatt T and Promislow EL. 2007. Science (318) 1255-1256.

2. Fabian, D. & Flatt, T. (2011) The Evolution of Aging. Nature Education Knowledge 3(10):9

3. Why do we age? Kirkwood Austad Nature 2000  (focus on section on reproduction and menopause)

4. Hawkes K. Human longevity: the grandmother effect

5. Lemaitre 2015. Early-late life tradeoffs and the evolution of aging in the wild

This piece about the death habits of female octopus is also very cool and worth a read.

 

2016 Evolutionary Medicine Course

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The 2016 UNM Evolutionary Medicine course starts tomorrow, August 23rd, 2016!

Starting tomorrow, we will peel away conventional preconceptions about health and disease, using the lens of evolution to better understand our humanity and our well-being.

Students will learn:

  1. Amazing case studies that show why evolution matters to real patients.
  2. Cutting edge topics from expert guest lecturers in evolutionary medicine.
  3. Why evolution is indispensable for physicians and biomedical researchers.
  4. How we evolved with the human microbiome, with far-reaching consequences.
  5. And much more!

Check the syllabus here.

Students: please read the following before class tomorrow:

1. Alcock and Schwartz 2011 A clinical perspective in Evolutionary Medicine: What we wish we had learned in medical school. Evolution: Education and Outreach, 2011.

2. Stearns . Evolutionary Medicine: Its Scope, Interest, and Potential. Proceedings of the Royal Society B, 2013.

Optional, but please read if you have time:

  1. Rook.  2010. Clin Exp Immun 160: 70–79. (see emailed document)
  2. Stein et al. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children N Engl J Med 2016; 375:411-421.

The holobiont

Fitness InterestsAre we a mammal-microbial collective? Should we think of our interaction with our resident microbes as a harmonious, mutually helpful partnership, or a relationship gone sour?  In this podcast, I will lay out my case for why I think the (mutualistic) holobiont concept is often wrong headed and misleading.

Here is EvolutionMedicine ‘cast #6 for August 15th, ‘The Holobiont’:

 

Before proceeding further, let me first express my admiration for the point of view laid out in the recent paper “Getting the hologenome concept right, an eco-evolutionary framework for hosts and their microbiomes” (Theis et al. 2016).” My views align pretty well with the latter part of this paragraph:

“In The Hologenome Concept, some of us stated that “evolution of animals and plants was driven primarily by natural selection for cooperation between and with microorganisms” (Rosenberg and Zilber-Rosenberg  2013) while in other venues the concept “places as much emphasis on cooperation as on competition” (Rosenberg and Zilber-Rosenberg  2009) This latter statement is more precisely aligned with the pluralistic nature of the holobiont, namely that “natural selection…on holobiont phenotypes…can work to remove deleterious nuclear mutations or microbes while spreading advantageous nuclear mutations or microbes” (Bordenstein and Theis 2015). In fact, some of us argued that conflicts of interests resulting from the nature of the transmission of microbes to the next host could select for microbes that can manipulate the biology of their host to improve their own transmission (Dheilly et al. 2015)”

By contrast, Michael Shapira in a recent paper published in Trends in Ecology and Evolution argues that cooperation is the key to co-evolution of the host-microbiota collective. He writes: “overall, host–microbiota interactions describe a mutualistic symbiosis.”

I disagree.

It is this version of the holobiont point of view that I take issue with: natural selection for cooperation as a primary driver of the evolution of animals and plants. Instead my coauthors and I have argued that conflict is a more important driver.

Evidence for cooperation is exciting, fascinating, and necessary for the complete story of human-microbial association. But, these mutualistic interactions are not the most interesting or important, because they often fail to explain why diseases occur.

Mutualism is but one outcome of evolution acting on host and microbiome. Competition and conflict are equally likely, as we have argued here and here.

In diseases states,  our partnership with microbes is like a bad relationship:

Microbes consume you. They eat your lunch. And they invade your personal space.

Glossary:

Microbiome: collection of microbial genes in a host or other defined environment.

Microbiota: the collection of microorganisms resident in a host (or other environment).

Holobionts: the combined organism, made up of host & microbiota.

Hologenome: the combined host and microbial genes of a holobiont that may constitute a distinct and useful unit of selection that drives co-evolution.

References:

 

Copyright © Joe Alcock MD

Amish Asthma

This week a study by Stein and colleagues was published in the New England Journal of Medicine featuring differences in asthma risk between genetically similar Amish and Hutterite children living in the US. The main difference between these two farming groups is their exposure to farm animals. Amish have single family dairy farms  and live in close proximity to their animals. By comparison, the Hutterites farm on communal highly industrialized farms. That difference may be enough to protect Amish children from allergies. 1 in 20 Amish kids get asthma, while 1 in 5 Hutterite children have asthma.

I describe the study in the EvolutionMedicine ‘cast #5 Amish Asthma:

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Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. Stein et al. NEJM August 2016

What is the agent that protects Amish kids from asthma? Microbes. Amish farming lifestyle makes them have relatively greater exposure to farm animal microbes and antigens.

In this respect the Amish are like the Karelians, a Russian group of traditional farmers with a markedly lower allergy risk compared to genetically similar Finns.

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So these associations are not exactly new. What is different about this study is that they showed that the Amish children develop their immune systems differently, with more neutrophils and fewer eosinophils. Neutrophils are innate immune cells that chiefly fight bacterial infections, while eosinophils are immune cells responsible for defense against helminths and are the cells responsible for type 1 hypersensitivity reactions, like asthma. The gene expression patterns of white blood cells in Amish vs Hutterite were also markedly different:

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Circulating immune cells had different gene expression patterns in the Amish (blue) compared to the Hutterites (red). These differences are developmental and entirely driven by differences in microbial exposure. Remember, Amish and Hutterite have almost the same ancestors, and are thus remarkably genetically similar. So all these differences, in immune cells and in asthma phenotype, are essentially environmental. The dramatic differences in gene expression seen above is a good example of a human reaction norm (discussed in previous posts like this one). I propose that these changes in immune cell development, and the responses to microbial signals described in the Stein paper, evolved because they were adaptive in historic environments. This idea is similar to the hygiene hypothesis, which uses evolutionary principles, including gene environment mismatch to explain why more autoimmune diseases occur when microbes and pathogens are absent.The hygiene hypothesis was invoked to explain the inverse relationship between childhood infections and autoimmune disorders seen below:

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What we don’t know is what kind of microbial exposures, and which route, are most important in determining asthma and allergy risk. In the NEJM study, Stein et al. showed that protection from airway hypersensitivity could be achieved when dust from Amish homes was instilled into the noses of experimental mice. So maybe nasal inoculation of house dust is the most important route exposure. That makes sense since airway exposure would be expected to affect the risk of asthma, an airway disease. But other studies suggest the oral and gut route are important.  For instance, Hesselmar and colleagues have looked at pacifier cleaning methods in relation to allergy:

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Kids whose parents “clean” their pacifiers by sticking it in their mouth first had fewer allergies, even more so if the child was also born vaginally instead of by c-section. The same group has also shown that owning and using a mechanical dishwasher in the home increases the risk of allergy and asthma.

All of which is to suggest that childhood exposure to microbes, even some potentially dangerous ones, may do more good than harm. Perhaps your child really should “Eat Dirt” as the title of a recent book by Brett Finlay and Marie Claire Arrieta advises.

Here is some final food for thought: even though it horrifies parents, children may be well adapted to sample their microbial environment by putting anything and everything in their small mouths.

Link to New York Times article on the Amish asthma results.

 

 

 

Evolution meets evidence-based medicine


This is the EvolutionMedicine ‘cast #4, a bonus podcast for Saturday July 23th – evolution meets evidence-based medicine. This podcast is based on a presentation I gave at last month’s ISEMPH conference. A couple of weeks ago, we discussed how an evolutionary hypothesis regarding sepsis physiology was ultimately vindicated by evidence.  Xigris’ demise was the culmination of over 1000 publications, but a final well designed randomized controlled trial was the final nail in Xigris’ coffin.

Xigris’ failure was an example of the evidence-based medicine (EBM) dovetailing with predictions of evolutionary medicine. EBM is a movement in medical science that makes receommendations based on the best evidence provided by clinical trials. The hierarchy of EBM is shown here:

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Randomized controlled trials are the best quality evidence, especially when synthesized into systematic reviews.

If evolutionary medicine (EvMed) is a useful enterprise that produces better patient outcomes, then EBM and EvMed should overlap more often than not. Lets see if this proposition holds up, starting with evidenced-based opioid pain medication prescribing.

Here is our question: Should I prescribe an opioid pain medicine for patients with chronic musculoskeletal back pain?

Listen to the podcast:

Slides for this talk are available here

 

 

 

The New Normal – Podcast #3

This is the EvolutionMedicine ‘cast #3, entitled The New Normal, for Wednesday July 13th.

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Over half of all medical interventions are harmful or ineffective. Source: Clinical Evidence, BMJ.

This podcast is based on a presentation I gave at last year’s ISEMPH 2015 conference. I actually recorded this audio two weeks ago. That is why it is mis-identified  as podcast #1. It is indeed ‘cast #3! Careful listeners will also notice that this episode also mentions the need to cover Xigris in detail, and of course Xigris was the topic of last week’s podcast. Please forgive my lack of editing skills, which will come in time! But today is a good time to cover whether evolution can inform the question: “when to intervene, and when to leave alone.”

Enjoy:

More on Euboxia, a well-described physician bias favoring normal results, here.

 

 

The evolutionary lesson of Xigris

This is the EvolutionMedicine ‘cast #2, for July 4, 2016. This is a story worth telling.

Sepsis is an important cause of mortality, causing an estimated 60,000 deaths yearly. Sepsis is also expensive to treat, and is associated with expensive medical procedures, such as life support and intensive care. Despite advances in supportive care over the last 30 years, the mortality rates have remained stubbornly high, as much as 30-40%.

Sepsis MortalityPersistently high sepsis mortality prompted many researchers and funding organizations to seek anti-inflammatory treatment to decrease the apparently harmful immune effects of sepsis, which has been described as an out of control inflammatory response.

One thing that biomedical researchers noticed was that septic patients who die often had low levels of activated protein C.  A recombinant form of activated protein C, called  Xigris, has anti-inflammatory and anticoagulant properties. Since inflammation was thought to be out of control in the systemic inflammatory immune response, it stood to reason that an inhibitor of inflammation and clotting might reduce deaths in sepsis.

In 2001 the PROWESS study appeared to show just that.

10 years late, on October 25, 2011 the FDA recommended that Xigris be withdrawn from the market. Remarkably, the company selling Xigris, Eli Lilly, was able to profit from this ineffective drug for nearly the entirety of the time Xigris was under patent. The long road to arrive at this conclusion is an interesting story.

What if the immune and coagulation responses are adaptive in septic shock? If so, anti-clotting/inflammation treatments, like Xigris, will fail. Supporting that notion is the recent experimental experience with recombinant activated protein C:

Epitaph for Xigris – I never worked a day in my life!

What lesson from Xigris’s failure can we learn about the functioning of the immune system, about sepsis, and evolution? Notably, Xigris is not the only high-profile failure for sepsis immunomodulatory therapy. A more recent anti-inflammatory therapy, a toll-like receptor TLR-4 blocker known as Eritoran, also failed spectacularly in clinical trials.

Not be deterred, a new therapy for sepsis targeting the pro-inflammatory cytokine TNF-alpha, based on a compound called CytoFab, was recently tested. How do you suppose that one went? Shockingly, it too failed.

Why have clinical trials in sepsis failed?

Table 1 showing failed clinical trials of immune and other therapies in sepsis above, and the abstract below, is reproduced from Marshall Why have clinical trials in sepsis failed? Trends Mol Med 2014

“The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit.”

These examples suggest that continuing to search for elusive so-called “magic bullets” in sepsis is a losing strategy. As cited in a recent article about the failure of anti-TNF-α in sepsis:  “Success is the ability to go from one failure to another with no loss of enthusiasm,” a quotation attributed to Sir Winston Churchill. On the other hand, repeating same thing while expecting different results is also…well you know the cliché. Japanese investigators are at it again with a medication, ART-123, that works along similar lines at Xigris, at an earlier stage in the pathway leading to activated protein C. I predict the same fate for ART-123 as Xigris.

Hemostatic containment article is here

My previous post on why blood clotting is host defense and why bacteria dissolve clots

10 evolutionary mistakes physicians make

My post on underlying assumptions of sepsis treatment

Additional references from the podcast are in this file: Xigris epitaph

© Joe Alcock MD