Cautionary introduction

I am a biomedical engineer with an interest in the science of aging. The Handbook of the Biology of Aging, 9th ed, is a great 400-page introductory resource, looking at aging on every level from evolutionary and conceptual, to public health, to specific molecular and organ systems, to genetics, to immortal organisms.

My goal is to teach readers key concepts and facts about aging research in short posts with accessible language. I follow the substance of the handbook chapters, though I sometimes reorganize them. I'm also presenting the chapters out of order, because I think it creates a better narrative. I encourage readers to take the facts and concepts tentatively - they are just pointers to a rich and sometimes controversial underpinning literature. My hope is that some readers will go on to read the handbook and explore the literature it cites.

Chapters will be presented out of order in order to improve the overall narrative flow. This post is for chapter 4:

Hornsby, P. J. (2021). The nature of aging and the geroscience hypothesis. In Handbook of the Biology of Aging (pp. 69-76). Academic Press.

Next: Compression of morbidity (available 7/12/2023)

The nature of aging and the geroscience hypothesis

This chapter is about making sense of a seemingly paradoxical thesis:

The fact that aging and injury are inevitable should encourage us about the possibility of advanced medicine that makes frailty and death preventable.

Your body is made of physical stuff - DNA, proteins, sugars, fats, cells, tissues, and organs - and physical stuff, left alone, inevitably breaks down and becomes disordered. The longer you live, the more chances you take with car crashes, disease, and other external causes of death. Aging is entropy - the inevitable process by which the laws of physics guarantee that a system will become disordered over time.

Yet the entropy of aging and injury is something we fight every time we heal a wound (or for that matter, repair a car or clean the house). Physics also tells us that we can repair the damage of aging and injury as long as we have the skill and energy to do so.

The fact that physics guarantees we'll experience aging and injury means we can reject the idea that aging is somehow directly beneficial to us or to our species. By Occam's Razor[1], there's no need to suppose some evolutionary benefit from aging and injury, since they're already explained perfectly well by entropy.

Yet as we'll see, not all evolutionary pressures tend in the direction of longer, healthier lives, so we can't expect that evolution has already taken every opportunity to preserve our health for as long as possible.

Together, these facts are encouraging. They mean that we can reject the pessimistic notions that evolution has already endowed us with the longest, healthiest lives possible, or that frailty and death are the inevitable results of entropy[2]. Therefore, modern medicine has plenty of scope to add new maintenance and repair abilities to those our bodies already possess.

Point #1: There is no need to speculate that evolution is making you age “on purpose” or that it's already endowed us with the longest, healthiest lives possible.

Of course, you can die from a disease, predator, car accident or gunshot wound, not only by aging. Aging can make you more vulnerable. But there’s a meaningful difference between being eaten by a shark, succumbing to pneumonia after years of declining health, and dying peacefully in your sleep at age 102.

Point #2: There’s a difference between aging and extrinsic causes of death, but they interact.

We can overcome the extrinsic damage and gradual aging of our houses, cars and clothing with cleaning, maintenance and repair. The bodies of living things largely clean, maintain and repair themselves: old stained proteins are broken down and new ones are built, our kidneys constantly filter the toxins and byproducts that build up in our blood, and our cells regrow to heal wounds. Yet repair typically means that we remove some broken, worn-out part and replace it with fresh material, whether we’re talking about replacing the roof on our house or replacing the outermost layer of our skin cells.

Unfortunately, most, if perhaps not quite all, living things can only repair themselves for only so long. Who will repair the repairers? Stem cells split into two new cells: a fresh stem cell and a copy that matures into a replacement skin cell, for example. But that “fresh” stem cell isn’t perfectly fresh. It has aged a bit. Eventually, your body is full of old stem cells, trying to replace still more aged mature skin, kidney, eyeball and brain cells.

Point #3: Our bodies can repair themselves, but in almost all organisms, that self-repair ability is limited and declines with age.

The whole succession of your ancestors and descendents, including you, is an immortal germ line. Your individual physical body is merely a way of perpetuating it, and that makes you a disposable soma. The genes encoded by your DNA are using your body as a tool to perpetuate themselves, and they have been doing so successfully for billions of years. They’ve realized that the key thing is to get their host to make children. They have no loyalty to their host, and will gladly sacrifice their host’s health if it helps with the reproduction and survival of children. 

Point #4: Your genes only care about your survival insofar as it helps you to reproduce.

The worst thing that can possibly happen to your genes is that you fail to reproduce. The best way to ensure you’ll survive to childrearing age is to build you sturdy enough to survive well past it, into middle and old age. Almost as bad as failure to reproduce would be a decline of the germ line over the generations. Every budded bacterial or fertilized egg has to be equally fresh, perfectly restored, despite being made from the deteriorating cells of the soma, your aging body.

Point #5: Old age is a side benefit of reaching childrearing age, but none of that matters unless fertilized eggs are perfectly fresh every single generation.

If virtually all your ancestors died from disease, predators, or injury by age 80, evolution saw no point in trying to build you to survive much beyond that age. If everybody’s hearts gave out at age 40, there would be no point in evolving lungs that can survive to age 80. As a result, evolution has resulted in us having organs that all have about the same life expectancy, which is roughly balanced with when our ancient ancestors would have died from extrinsic causes or been useless for bearing and rearing children. 

Point #6: You’re designed to fall apart from aging more or less all at once, at about the point in life when our caveman ancestors became a burden or died by predators and disease.

Let’s say a gene makes you a bit healthier in old age. The benefits won’t show up until after you’re no longer capable of bearing children. That means that unless your improved health helps your children survive and reproduce, that gene misses out on natural selection and will eventually drift out of the genetics of your descendents. If that gene also comes with a tradeoff that makes you a bit less fertile or healthy in youth, however, it will be heavily selected against by evolution. A gene that makes you more fertile and healthy in youth, but at the cost of suffering in old age, will be favored by evolution. This evolutionary favoritism of the young is termed antagonistic pleiotropy.

Point #7: Evolution is optimizing for childrearing, sometimes at the expense of health in old age.

Certain hallmarks of aging show up in every tissue in the body. Your immune system goes haywire. Healthy proteins are torn apart by reactive byproducts of energy production in the cell or get crusted up by sugars. Cells start making the wrong mix of proteins, their mitochondrial powerhouses break down, or they get so disorganized that they shut down and start spewing out weird chemicals. The FDA doesn’t recognize these as diseases, per se, but we have good reason to think they are the fundamental problems that lead to disease and death. To what extent does a healthy diet and exercise, stress management, and clean air make us live longer by avoiding these destructive underlying issues? Can we slow or prevent many diseases at once by treating these underlying issues? We call this idea the geroscience hypothesis.

Point #8: A powerful way to improve human health and wellbeing might be to treat the hallmarks of aging before they manifest as disease.

  1. ^

    The principle that we should reject layering on unnecessarily complex extra hypotheses when we already have a stronger, simpler explanation for what we observe.

  2. ^

    On the order of thousands or millions of years, anyway. Live long enough and the whole universe will turn to dust, and there's nothing we can do about that.

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14 comments, sorted by Click to highlight new comments since: Today at 10:57 PM

It's quite cool that you're doing this. Thank you!

 

It’s a physical law of the universe that you will age.

This, as a summary of one of the book's points, slams my deathism alarm bells. It causes me to go on alert for where the author is trying to confuse me with their own deathist confusions.

I assume the author is hinting at entropy. How life can be thought of as an entropy pump, keeping internal entropy low even at the cost of increasing net entropy. And yes, on long enough timescales this is guaranteed to eventually fail. Even if nothing external destroys the pump directly, eventually entropy will affect the pump itself, resulting in a downward spiral of its functionality. And sure, we could call that last effect "aging" in some generalized sense.

But this is hugely dramatically different from the claim that our bodies have to break down within about a century. That it's inevitable that the thing we normally think of as aging absolutely has to happen in roughly the way it currently does.

This conflation is a common deathist refrain. It reminds me of the argument against curing aging that goes "Well, you still might die in a meteor crash or from murder or from any other of a number of things, and the longer you live the higher the probability accumulates to something killing you… so it's not really immortality."

As though the fact that curing aging wouldn't count as "true" immortality makes it irrelevant.

Whenever someone conflates these two elements — the entropic inevitability of death vs. the engineering complexity of dealing with aging as it currently appears — I usually find deathist ideas woven elsewhere in what they have to say. They'll say a bunch of objective and often informative things… and then slip in something about how "You wouldn't want to live forever anyway" based on getting tired or bored or watching people you love die or something.

Often it's more insidious than that. Like a general defeatist tone. "Well, gosh, there's no real point in honestly trying to cure aging, but given these biochemical facts we might be able to make the decline a little more pleasant in thus-and-such a way."

I'm still grateful you're putting this summary together. I don't mean any of this as a criticism of you or of what you're doing! I liked reading through the rest of what you've written here.

I just mean to issue a memetic caution about the book for anyone who might have missed the signs based on what you've summarized here.

(I'm particularly sensitive to these signals. I was raised immortalist. Homeschooled by transhumanist cryonicists. This stuff just really stands out for me.)

Thank you for the encouragement! I would suggest reading the complete post once more, because the post/article specifically points out that that aging, which is indeed entropic and inevitable, is counterbalanced by repair: “We can overcome the extrinsic damage and gradual aging of our houses, cars and clothing with cleaning, maintenance and repair.” The key to geroscience medicine - targeting aging - will be to slow the aging process (it can’t be stopped), but also to enhance repair (which can in theory indefinitely prolong life by replacing worn out parts to keep the system as a whole functioning).

It also discusses the principles that explain why we can expect scope to improve longevity via modern medicine, such as antagonistic pleiotropy and the loss of selection pressure beyond child rearing age. Evolution isn’t trying very hard to optimize for longevity and health span, so we can do better.

Finally, the whole chapter is on the geroscience hypothesis, advocating a new approach where we treat disease by targeting aging itself. I didn’t include the fact that it specifically mentions the SENS foundation, cites de Grey, etc, but it does!

My aim in these posts will be to pretty faithfully track the order of ideas and main biological points as presented by the handbook, rather than layering in my own interpretation about the political or long-term research prospects and ethics if they’re not explicitly mentioned in the book. But the book is certainly not “deathist.”

One thing you, as a transhumanist-diaper baby and (perhaps) a person who doesn’t work professionally in biomedical research, may not know, is that there’s quite a lot of pressure in biomedicine to make measured, noncontroversial public statements about topics like this. Some writers like Aubrey de Grey just ignore all that (I believe de Grey is independently wealthy which may enable him to do so), but many are for whatever reason going to make careful statements that fit within the conventional vibes of the medical field, but still read intelligently point in a radical direction. Figuring out how to make geroscience sound conventional, safe, and like everything else we study in medicine is an important normalizing step within the research community to counterbalance the hype and controversy machine.

I edited the first point to make the non-deathism more clear, since I would hate to lose my audience at paragraph 1! Thanks for giving me your reaction.

This is a test post to check audience reaction. If there are ways that the basic structure of this post could be improved, please let me know!

I am interested in seeing more of these. Thanks.

The one thing that tends to gloss my eyes over was the multiple claims about how genes or evolution care about us living until reproducing and then we can be tossed aside (okay, not quite what you said but....)

Neither genes nor evolution really gives a damn about that or anything else. Neither have any awareness of anything. We're really just talking about chemicals and chemical reaction that occur in what seems a fairly stable organism. Yes, the species, and pretty much all larger life dies out if it fails to reproduce at some rate. But I find the claims that something cares or is following some type of plan (certainly not of the Intelligent Design type but seems to be some purpose or telos implied). I think that is mostly humans projecting and doesn't really help understand.

So for me the focus more on the how rather than some why aspect is of significantly more interest.

Thanks for the feedback! I plan on anthropomorphizing evolution freely in this series of posts, because I think that for most readers, describing evolution in this way is more intuitive. I am making the assumption that any serious reader is fully aware that evolution has no actual teleology. Since this isn't focused on explaining the basics of evolutionary theory to readers, it unfortunately won't cure somebody who's so confused about evolution as to think it actually has a teleology or goal.

This seems a bit counterintuitive. The "serious reader" by definition is willing to spend more time to carefully read something that's unintuitive. 

Why is the anthropomorphizing for more intuitive reading necessary if that's your target audience?

Good question. Anthropomorphizing isn’t necessary, it is just easier to write quickly in colloquial language, which is the tone I’m striving for here. I can’t think of a clearer short colloquial summary of antagonistic pleiotropy than “evolutionary favoritism of the young,” and though it does anthropomorphize, I think it gets the point across effectively as long as one doesn’t object to anthropomorphizing evolution on principle.

There is a counterargument to claims 6 and 7: there is only one known warm-blooded species with longer lifespan than humans (the bowhead whale), and it is large and has slow metabolism for a mammal. In contrast, there are plenty of cold-blooded long-lived species. So, it is entirely plausible that humans live about as long as possible for given metabolic level.

Also, note point 5 - we expect that evolution will build us to be robust enough to survive only to the point where intrinsic and extrinsic causes of death are balanced out. So a viable alternative explanation is that humans and bowhead whales are two animals that are particularly resistant to extrinsic causes of death, which makes some sense in both cases.

Whether or not this hypothesis is correct is uncertain and may be context-dependent, and I haven't delved into the literature on this specific point enough to give any kind of authoritative opinion.

On the other hand, my understanding of the warm-blooded naked mole rat in captivity is that it doesn't show clear signs of increasing mortality over time. We haven't kept enough naked mole rats for long enough to see how long that lasts or whether that result is robust. But we should care at least as much about increasing rates of mortality over time - which is what it conventionally means to "age" and is captured in the concept of "healthspan" - as we care about lifespan.

 

Edit: I’m wrong! Naked mole rats are basically cold blooded.

Apologies - I accidentally moved this to drafts while making minor formatting edits and had to republish, which put it on the front page again.

Point #4: Your genes only care about your survival insofar as it helps you to reproduce.
Point #5: Old age is a side benefit of reaching childrearing age, but none of that matters unless fertilized eggs are perfectly fresh every single generation.

Have you heard of the grandmother hypothesis?

I don't think humans are bunnies where we accidentally live far past reproductive age and e.g. have menopause

The reason I didn't include material on the grandmother hypothesis is not covered in this 8-page chapter. It's not a key feature of most of the research on decreasing selection pressure with age, which assumes the overwhelmingly most important contribution to the germ line is via reproduction rather than nurture.

The grandmother hypothesis is mainly attempting to explain menopause, which is indeed an evolutionary mystery.

The ability of parents to provide nurture, and the difficulty of producing survivable large offspring, drives some organisms, like humans, away from a K-selection strategy (lots of offspring, small short-lived organisms, aiming for a few survivors) toward an R-selection strategy (a few offspring, large long-lived organisms, aiming for high likelihood of survival and reproduction in all offspring). But raising reproductive age, which enforces pressure for long life and thus the tendency for R-selected organisms to reach an older age, is an evolutionary cost. If evolution could engineer humans to become reproductively fertile at age 3 without any other costs, it would do so.

In R-selection, evolution is sacrificing opportunities to produce more young at a younger age in exchange for greater survivability and the ability to exploit new sources of energy. That can push reproductive age up, as we see in humans, and the effort to build us robustly enough to ensure we reach that later reproductive age both raises the likelihood we live much longer and allows surviving grandparents to confer benefits on the young, the latter of which is a straightforward adaptive "win" from a gene's perspective.

But my take is that whatever nurture grandparents can provide is a side benefit that doesn't change the overwhelming evolutionary pressure to make ~all tradeoffs favor the young, meaning that the arguments from antagonistic pleiotropy and limited/loss of selection pressure in old age still apply with full force. That is an encouraging take, because it means that there's plenty of scope for modern medicine to improve healthspan and lifespan - not to mention that there are plenty of things we can do using technology that are just not evolutionarily accessible. For example, we can build mechanical replacements for our organs, design and manufacture molecules arbitrarily with a much greater level of purity and under more controlled conditions, and of course we can eliminate threats and artificially extend the age of first reproduction in ways that tend to drive evolution toward longer life and healthspans.