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Why do we age? · MicGyver Media

• 0:00
  SPEAKER_00: The Conundrum of Aging.
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  SPEAKER_00: The quest for immortality is both one of humanity's most ancient and most recent pursuits.
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  SPEAKER_00: From the ancient Sumerians and the Epic of Gilgamesh,
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  SPEAKER_00: our perhaps oldest known story,
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  SPEAKER_00: where the king searches for a plant that will restore his youth,
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  SPEAKER_00: via Pons de Leon and his search for the fountain of youth in the New World
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  SPEAKER_00: in the 1500s, to the current zeitgeist around longevity
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  SPEAKER_00: and biohacking your lifespan.
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  SPEAKER_00: The deep desire to postpone or even eradicate aging seems ever present in our civilization.
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  SPEAKER_00: But before anyone can seriously tackle this topic,
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  SPEAKER_00: there is an even more fundamental question that should be addressed.
• 0:36
  SPEAKER_00: Why do we age?
• 0:38
  SPEAKER_00: I'm Mads Mikkelsen, and this is an adapted audio version
• 0:41
  SPEAKER_00: of a scientific review I wrote on exactly that question.
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  SPEAKER_00: It's called The Conundrum of Aging, Exploring Senescence as an Evolutionary Puzzle.
• 0:49
  SPEAKER_00: Part 1.
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  SPEAKER_00: Introduction.
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  SPEAKER_00: Perhaps the simplest yet deepest question in relation to aging is why it exists
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  SPEAKER_00: as a phenomenon in the first place.
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  SPEAKER_00: The answer might seem obvious at first, a simple case of inevitable entropy or wear and tear.
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  SPEAKER_00: On further inspection, however, the question becomes far more intriguing.
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  SPEAKER_00: Firstly, a definition is in order.
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  SPEAKER_00: Many variants exist, but Kirkwood and Orstad defined aging, or senescence,
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  SPEAKER_00: as the progressive loss of function accompanied by decreasing fertility
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  SPEAKER_00: and increasing mortality with advancing age.
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  SPEAKER_00: To clarify, we are not talking about chronological aging here,
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  SPEAKER_00: but the associated biological process,
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  SPEAKER_00: the degradation of function over an organism's lifespan.
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  SPEAKER_00: Directly from the definition,
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  SPEAKER_00: we can see that such a process is clearly bad for the individual organism.
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  SPEAKER_00: This raises the question of how it has been able to arise and persist over evolutionary time.
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  SPEAKER_00: From an evolutionary perspective, aging presents somewhat of a paradox.
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  SPEAKER_00: Because it reduces an individual's fitness, all else held equal,
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  SPEAKER_00: it should theoretically be strongly opposed by natural selection,
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  SPEAKER_00: which favors traits that maximize survival and reproduction.
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  SPEAKER_00: And although aging shows a broad distribution across the tree of life,
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  SPEAKER_00: it is not universally present.
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  SPEAKER_00: There are groups of organisms that seemingly show little to no signs of senescence.
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  SPEAKER_00: Thus, the prevalence of aging cannot simply be explained away
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  SPEAKER_00: as the inevitable product of the Second law of thermodynamics.
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  SPEAKER_00: As Theodosius Dobzhansky famously said in 1973,
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  SPEAKER_00: nothing in biology makes sense except in the light of evolution.
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  SPEAKER_00: So that leaves us with the question how has aging evolved?
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  SPEAKER_00: One limitation before we start Explanations for senescence have been put forth
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  SPEAKER_00: on many different levels, from the cellular, biochemical, and physiological,
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  SPEAKER_00: to the genetic and evolutionary.
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  SPEAKER_00: This episode limits itself to mostly covering the evolutionary level.
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  SPEAKER_00: These levels of explanation are not exclusive.
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  SPEAKER_00: They are complementary, simply applying different lenses to the same question.
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  SPEAKER_00: And I'll focus on senescence as observed in the animal kingdom,
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  SPEAKER_00: although much of this applies to most multicellular organisms.
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  SPEAKER_00: Part two, why wear and tear is not enough.
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  SPEAKER_00: Before diving into the main evolutionary theories of aging,
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  SPEAKER_00: it might be expedient to dwell somewhat longer on why it is not satisfactory
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  SPEAKER_00: to simply see aging as inevitable.
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  SPEAKER_00: This view is sometimes referred to as the rate of living theory of aging.
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  SPEAKER_00: From this perspective, senescence is caused by the accumulation of inevitable,
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  SPEAKER_00: irreparable damage to cells and tissues.
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  SPEAKER_00: Damage caused by toxic byproducts from metabolism and by errors occurring
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  SPEAKER_00: during biological processes like DNA replication, transcription and translation.
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  SPEAKER_00: Furthermore, the theory posits that organisms have reached the maximum limit
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  SPEAKER_00: in their ability to resist and repair damage by means of natural selection.
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  SPEAKER_00: In other terms, populations lack the further genetic variation
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  SPEAKER_00: that would enable them to evolve more effective repair mechanisms than are already
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  SPEAKER_00: in place.
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  SPEAKER_00: Two key predictions follow from this.
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  SPEAKER_00: First, the rate of aging should strongly correlate with the metabolic rate.
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  SPEAKER_00: Second, species should not be able to extend their lifespans further regardless
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  SPEAKER_00: of being subjected to targeted selection pressure for this trait.
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  SPEAKER_00: However, different tests of the theory have largely contradicted these predictions.
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  SPEAKER_00: For instance, a comparative study of mammals by Ørstad
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  SPEAKER_00: and Fischer found wide variation in lifetime energy expenditure per unit
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  SPEAKER_00: of body mass, ranging from 39kcal per gram to 1100kcal per gram per lifetime.
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  SPEAKER_00: Most notably, bats have metabolic rates comparable to other mammals of their size
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  SPEAKER_00: but live nearly three times longer on average.
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  SPEAKER_00: Marsupials, on the other hand,
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  SPEAKER_00: have lower metabolic rates but significantly shorter than average lifespans.
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  SPEAKER_00: These patterns are inconsistent with the first prediction,
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  SPEAKER_00: the idea that aging is simply a function of metabolic rate.
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  SPEAKER_00: Furthermore, artificial selection experiments with fruit flies have demonstrated
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  SPEAKER_00: that populations can indeed evolve longer lifespans when selected for longevity.
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  SPEAKER_00: In 1984, Luckin, Bill and colleagues ran four lab populations of fruit flies for 13 generations.
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  SPEAKER_00: In two of them, only eggs from late reproducing females were carried on to the next generation.
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  SPEAKER_00: In the other two, only eggs from early reproducers.
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  SPEAKER_00: At the start, all four populations lived around 35 days on average.
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  SPEAKER_00: Thirteen generations later, the early reproducing
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  SPEAKER_00: The late reproducing populations still lived around 35 days.
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  SPEAKER_00: The late reproducing populations lived around 60.
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  SPEAKER_00: Similar studies have later given support to this.
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  SPEAKER_00: These findings indicate that populations do indeed harbour genetic variation
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  SPEAKER_00: for increased longevity, and that ageing is not simply an unavoidable consequence
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  SPEAKER_00: of intrinsic physiological limits.
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  SPEAKER_00: So, if senescence can't be explained simply as the fated result of biological wear
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  SPEAKER_00: and tear, why does it happen?
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  SPEAKER_00: To follow Dobzhansky's quote, we now must turn to the evolutionary theories of aging.
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  SPEAKER_00: Part 3.
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  SPEAKER_00: The Declining Force of Selection A common thread through all evolutionary theories
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  SPEAKER_00: of aging is that senescence results not so much from the wear and tear itself,
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  SPEAKER_00: which does occur, but rather from organisms' failure to completely repair
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  SPEAKER_00: the accumulated damage.
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  SPEAKER_00: In the end, this is caused either by the quiet accumulation of deleterious mutations
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  SPEAKER_00: in the genome or through trade-offs between reproductive success
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  SPEAKER_00: and somatic maintenance.
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  SPEAKER_00: The core insight driving all three main theories to be covered here is
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  SPEAKER_00: that the power of natural selection declines later in life due
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  SPEAKER_00: to decreasing survival rates driven by extrinsic mortality factors such
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  SPEAKER_00: as predation, infection and starvation.
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  SPEAKER_00: As a general rule, wild animals simply don't survive long enough to become old.
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  SPEAKER_00: Picture a survival curve.
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  SPEAKER_00: Age runs from left to right and the share of a population still alive runs from top to bottom.
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  SPEAKER_00: For a protected population, say in a lab or a zoo,
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  SPEAKER_00: the curve stays high for a long time and then drops steeply late in life.
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  SPEAKER_00: For a wild population, the curve plunges almost immediately,
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  SPEAKER_00: and only a thin sliver of the population ever reaches the ages
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  SPEAKER_00: where the protected animals start to decline.
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  SPEAKER_00: Keep that picture in mind, because all three theories live in it.
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  SPEAKER_00: Part 4.
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  SPEAKER_00: Mutation Accumulation In his 1952 paper, An Unsolved Problem of Biology,
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  SPEAKER_00: Peter Medawar put forth his seminal evolutionary theory of aging,
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  SPEAKER_00: later coined the mutation accumulation hypothesis.
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  SPEAKER_00: The rarity of old animals in the wild served as his starting point.
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  SPEAKER_00: As a result of extrinsic mortality,
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  SPEAKER_00: selection progressively weakens with advancing age,
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  SPEAKER_00: and by the time survival has reached very low levels with old age,
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  SPEAKER_00: selection pressure is too weak to oppose the accumulation
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  SPEAKER_00: of late acting deleterious mutations in the genome.
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  SPEAKER_00: A selection shadow emerges in later life.
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  SPEAKER_00: In the survival curve, that's the region on the far right,
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  SPEAKER_00: where the wild curve has all but hit the floor.
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  SPEAKER_00: In that shadow, a broad array
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  SPEAKER_00: of late acting harmful genes can heap up throughout generations
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  SPEAKER_00: without being weeded out by natural selection.
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  SPEAKER_00: The hypothesis is logically sound and has experimental support,
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  SPEAKER_00: while valid question marks have also been raised,
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  SPEAKER_00: so the evidence for mutation accumulation remains contested.
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  SPEAKER_00: Part 5.
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  SPEAKER_00: Antagonistic Pleiotropy Building on Medawar,
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  SPEAKER_00: George Williams suggested in 1957 that it is not only selection shadows
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  SPEAKER_00: and weak selection pressure that can make late-acting,
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  SPEAKER_00: senescence-promoting genes propagate.
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  SPEAKER_00: They can also be actively selected for.
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  SPEAKER_00: His view, named the antagonistic pleiotropy hypothesis,
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  SPEAKER_00: notes that mutations in pleiotropic genes, that is,
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  SPEAKER_00: genes involved in several traits,
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  SPEAKER_00: giving fitness benefits early in life and costs late in life,
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  SPEAKER_00: can be beneficial on balance.
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  SPEAKER_00: Of the individuals carrying such a gene,
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  SPEAKER_00: more will reap the early benefit than will suffer the late cost.
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  SPEAKER_00: As a result, the gene can improve the fitness of the average carrier,
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  SPEAKER_00: even if the upside seems limited and the downside seems high.
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  SPEAKER_00: In Williams' own words, the rate of senescence shown by any species will reflect
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  SPEAKER_00: the balance between the direct,
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  SPEAKER_00: adverse selection of senescence as an unfavorable character and the indirect,
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  SPEAKER_00: favorable selection through the age-related bias in the selection
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  SPEAKER_00: of pleiotropic genes.
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  SPEAKER_00: The age-related bias refers to the outsized importance of early life
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  SPEAKER_00: because a gene's contribution to fitness is a combination of the size of its effect
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  SPEAKER_00: and the probability of surviving to be impacted by it.
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  SPEAKER_00: Thus, antagonistic pleiotropy suggests that senescence is a group
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  SPEAKER_00: of adaptively unfavorable changes that are side effects
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  SPEAKER_00: of otherwise favorable genes, which selection has only partly mitigated.
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  SPEAKER_00: The observed rate of senescence is a balance between these forces,
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  SPEAKER_00: a life history trade-off between fitness late in life
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  SPEAKER_00: and increased reproductive success and survival early in life.
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  SPEAKER_00: As for empirical support, Williams himself provided examples of genes in fruit flies
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  SPEAKER_00: which increase longevity in laboratory conditions but are rare in nature,
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  SPEAKER_00: suggesting their normal variants confer some offsetting early advantage.
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  SPEAKER_00: Stronger evidence comes from studies on a gene called Age 1 in the nematode worm C. elegans.
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  SPEAKER_00: Mutations in Age 1 can significantly extend lifespan.
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  SPEAKER_00: While mutation carriers appear normal under standard lab conditions,
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  SPEAKER_00: experiments simulating more natural environments showed
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  SPEAKER_00: that the normal Age 1 variant increased reproductive success early in life
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  SPEAKER_00: for the price of a shortened lifespan, exactly as antagonistic pleiotropy predicts.
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  SPEAKER_00: Similarly, the Methuselah gene in fruit flies shows a trade-off.
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  SPEAKER_00: A mutant variant increases lifespan and stress resistance,
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  SPEAKER_00: but normal flies have higher early reproductive success,
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  SPEAKER_00: implying that the normal variant trades longevity for early fecundity.
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  SPEAKER_00: There is strong support for the antagonistic pleiotropy hypothesis.
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  SPEAKER_00: One critique that has been raised, however,
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  SPEAKER_00: is that the argument can be considered somewhat circular.
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  SPEAKER_00: The concept of late expression of genes itself seems to imply detectable differences
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  SPEAKER_00: in the physiological state of older versus younger individuals,
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  SPEAKER_00: whereas organisms that do not age should essentially be in a steady state,
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  SPEAKER_00: in which chronologically young and old individuals are physiologically the same.
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  SPEAKER_00: Part 6.
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  SPEAKER_00: Disposable Soma The third theory is the disposable SOMA hypothesis proposed
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  SPEAKER_00: by Tom Kirkwood in 1977.
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  SPEAKER_00: SOMA simply means the body as opposed to the germline that carries the genes onward.
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  SPEAKER_00: The theory centers around fundamental life history trade-offs,
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  SPEAKER_00: positing that organisms optimally allocate metabolic resources
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  SPEAKER_00: between somatic maintenance and reproduction.
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  SPEAKER_00: It is closely related to antagonistic pleiotropy,
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  SPEAKER_00: picking up on its life history trade-off theme,
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  SPEAKER_00: but provides a specific framework for understanding the trade-offs involved
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  SPEAKER_00: by focusing on resource allocation.
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  SPEAKER_00: To prevent senescence, the assembly and repair of the body's molecules
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  SPEAKER_00: and signaling pathways must be accurate enough to prevent the damaging accumulation
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  SPEAKER_00: of errors, and that is metabolically costly.
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  SPEAKER_00: This presents an energetic dilemma.
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  SPEAKER_00: Is it optimal to allocate any marginal resource to growth and reproduction,
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  SPEAKER_00: maximizing early fitness, or to maintaining and repairing the body
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  SPEAKER_00: to ensure long-term survival and future reproduction?
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  SPEAKER_00: An investment in somatic repair only makes sense
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  SPEAKER_00: if it confers increased survival probability in the wild environment.
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  SPEAKER_00: Kirkwood and Ostad illustrate this balance with the example of wild mice,
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  SPEAKER_00: where over 90% perish within the first year of life.
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  SPEAKER_00: Therefore, any investment in repair mechanisms beyond the first year benefits
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  SPEAKER_00: at most 10% of the population.
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  SPEAKER_00: Metabolic resources are scarce,
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  SPEAKER_00: underlined by the fact that the main cause of death for wild mice is freezing
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  SPEAKER_00: to death.
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  SPEAKER_00: So a wild mouse's fitness will likely benefit from investing any spare resources
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  SPEAKER_00: into traits with immediate benefits, such as generating heat,
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  SPEAKER_00: at the cost of somatic maintenance.
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  SPEAKER_00: Empirical support for the disposable soma theory comes
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  SPEAKER_00: from comparative studies showing that species with higher potential longevity tend
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  SPEAKER_00: to exhibit more effective maintenance and repair.
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  SPEAKER_00: Long-lived mammals and birds show lower production of reactive oxygen species,
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  SPEAKER_00: higher levels of antioxidant enzymes, less oxidative damage to proteins,
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  SPEAKER_00: and better DNA repair capacity compared to shorter-lived species.
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  SPEAKER_00: This suggests that species evolve different levels of investment
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  SPEAKER_00: in cellular maintenance depending on their expected lifespan in the wild.
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  SPEAKER_00: Part 7 Synthesis The three main evolutionary theories, mutation accumulation,
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  SPEAKER_00: antagonistic pleiotropy and disposable soma are not really mutually exclusive
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  SPEAKER_00: but rather complementary explanations building on each other.
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  SPEAKER_00: They all rest on the fundamental principle that the power of selection decreases
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  SPEAKER_00: with advancing age.
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  SPEAKER_00: Mutation accumulation explains how harmful mutations can accumulate in the shadow
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  SPEAKER_00: of weak selection late in life.
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  SPEAKER_00: Antagonistic pleiotropy explains how certain genes are actively favored early
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  SPEAKER_00: in life despite late acting harmful effects.
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  SPEAKER_00: And disposable soma theory offers a mechanism for antagonistic pleiotropy,
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  SPEAKER_00: namely the trade-off between reproduction and early survival on the one hand
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  SPEAKER_00: and costly somatic maintenance on the other.
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  SPEAKER_00: For all three theories, the key predictor of longevity is the level
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  SPEAKER_00: of extrinsic mortality experienced by the species or population.
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  SPEAKER_00: If life expectancy in the natural environment is short,
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  SPEAKER_00: the selection shadow is large,
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  SPEAKER_00: the reward for investing in somatic maintenance is low,
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  SPEAKER_00: and deleterious late-acting genes have a higher probability of accumulating.
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  SPEAKER_00: The opposite is also true.
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  SPEAKER_00: If life expectancy is long due to weaker extrinsic mortality, the prediction is
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  SPEAKER_00: that selection will more strongly counteract senescence-promoting genes
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  SPEAKER_00: and promote somatic maintenance.
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  SPEAKER_00: This prediction has solid support in the literature,
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  SPEAKER_00: from comparative studies within and between species experiencing different levels
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  SPEAKER_00: of extrinsic mortality in nature.
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  SPEAKER_00: For example, a natural experiment by Stephen Austad compared a mainland
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  SPEAKER_00: and an island population of opossums.
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  SPEAKER_00: The mainland population was subject to considerable predation by mammals,
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  SPEAKER_00: while the island population faced no such predation.
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  SPEAKER_00: Austad found that the island population experienced delayed senescence,
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  SPEAKER_00: perfectly in line with the prediction of the evolutionary theories.
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  SPEAKER_00: Bottom line, investing in the future only pays off if you are likely to still be around.
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  SPEAKER_00: Part 8. Conclusion So, if natural selection favors traits that maximize survival
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  SPEAKER_00: and reproduction, why do we age and die?
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  SPEAKER_00: The solution to this evolutionary puzzle lies in the declining force
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  SPEAKER_00: of natural selection with increasing age.
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  SPEAKER_00: This age-dependent selection allows for the accumulation
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  SPEAKER_00: of late-acting deleterious mutations and favours genes
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  SPEAKER_00: with antagonistic pleiotropic effects, where early benefits outweigh late costs.
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  SPEAKER_00: The disposable soma theory further explains this latter mechanism by highlighting
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  SPEAKER_00: the trade-off in resource allocation between somatic maintenance and reproduction.
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  SPEAKER_00: These mechanisms lead to the evolved rate of senescence being tightly linked
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  SPEAKER_00: to an organism's life history, and particularly to its rate of extrinsic mortality.
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  SPEAKER_00: Senescence is thus not a malfunction or a programmed death,
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  SPEAKER_00: but an evolved outcome of optimizing fitness across a lifespan constrained
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  SPEAKER_00: by extrinsic mortality.
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  SPEAKER_00: Understanding these evolutionary forces better should guide further research
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  SPEAKER_00: into the mechanisms and molecular basis of aging
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  SPEAKER_00: and might help identify potential interventions and, perhaps most importantly,
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  SPEAKER_00: their trade-offs.
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  SPEAKER_00: The quest for immortality continues.
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  SPEAKER_00: Thanks for listening.
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  [music]