Is Aging an Active Process of Self-destruction?

Most people think of aging as passive – something that happens to your body. Random mutations occur faster than the body can fix them. Cholesterol deposits build up in the arteries. Above all, oxidation damages the body’s delicate chemistry, and this affects the ability to fix other damage.

But a new view is emerging, in which aging is an active process. Much of the damage appears avoidable, if only we kept churning out the same hormones we did when we were young, instead of changing to a less effective mix as we get older. Worse – some systems actually turn against the body, destroying perfectly good tissue, as if “on purpose”. There are four such processes: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. They make promising targets for new anti-aging research. More on this next week.

What’s up with evolution?

It has been a surprise for evolutionary biologists in recent years to discover that there are genes that regulate aging. More curious yet – some of the genes for aging have been around for at least half a billion years, from a time when eukaryotes (nucleated cells) were new on earth. Usually, evolution is very good at holding on to what works, and getting rid of genes that are harmful. Aging ought to be in the second category – aging destroys fitness. Why would evolution preserve harmful genes and pass them on?

This sounds like a question for theorists, or even philosophers. But the question has taken on a practical importance now that biochemists know how to turn genes on and off. Should we turn off the aging genes? Would terrible things happen to us as a side-effect – sterility, or maybe cancer? Or would this be the shortcut we’ve all been waiting for – a new and more effective path to life extension?

Discovery of Genes for Aging

Nematode worms, fruit flies, and yeast cells are the most common lab organisms used to study aging because their life spans are conveniently short. Beginning in the 1990s, geneticists knew how to identify individual genes and remove them – mutate or snip them out from an egg cell, which contains a single copy of the genome that will be replicated into every cell of the adult. Here was a surprise that transformed aging science: for each of the three lab organisms, there were genes that could be removed, causing the animal to live longer. What is more, these genes were closely related, underscoring the inference that they were no accident, but a surprising and paradoxical product of evolution. A common genetic basis suggested that what we learned from simpler animals might also apply to humans.

Some of the earliest genes discovered to regulate aging were related to the insulin metabolism, and presumably mediate the mechanism by which aging is slowed by caloric restriction (or shall we say, “aging is accelerated by abundant food”?) In worms, DAF-2 was one of these genes.

It was natural to ask about the metabolic effects of DAF-2: what is its role in the metabolism? The Harvard laboratory of Gary Ruvkun was able to prepare “mosaic” worms that had different genes in different parts of their bodies. Before asking “how”, it would be interesting to know “where” DAF-2 was acting. Ruvkun and team tried mutating DAF-2 just in the muscles. No life extension. They repeated the experiment with DAF-2 mutated in just the digestive system. No life extension. But when DAF-2 was disabled in the nerve cells, that was sufficient to double the worms’ life span. The nervous system suggested signaling and active, intelligent control. This finding helped to solidify the new paradigm: life span is actively regulated by the body.

Sharpening the evolutionary paradox

Here’s a detail that underscored the evolutionary paradox: The principle that “natural selection can only generate adaptations that are good for an individual’s fitness” is so fundamental to evolutionary theory, that theorists looked for an interpretation of the data that would support this axiom. The axiom might still be true if these preserved genes were selected for some powerful benefit, such that accelerated aging was a side-effect of genes whose primary effect was beneficial. This theory goes by the name antagonistic pleiotropy, and was first proposed by George Williams back in 1957.

The gene DAF-2 did indeed have benefits, and the long-lived mutants appeared fat and lazy. But the benefits appeared when the gene was turned on in muscle cells, while the life-shortening effects came from the gene’s presence in nerve cells. It is normal for gene expression in different tissues to be separately regulated.  Ruvkun emphasized that the costs and benefits were easily decoupled. If he could separate the two effects in a simple lab manipulation, why hadn’t nature learned to do the same over the aeons?

Evidence accumulates for active aging

The more we learn about the physiology of aging, the clearer it becomes that the standard evolutionary view doesn’t work. Two of the body’s systems that are highly evolved for self-protection morph, as we age, into means of self-destruction. These are inflammation and apoptosis. It is common to speak of this as “dysregulation”, as though it were just a mistake. But you have to wonder about such costly mistakes. Natural selection ought to be quite efficiently weeding them out.

Inflammation is the body’s first line of defense against invading microbes, and it also plays an important role in eliminating diseased cells and damaged tissue in wounds and bruises. However, as we get older, inflammation turns against the body. Inflammation in cartilage is the proximate cause of arthritis, and in our arteries, inflammation creates the plaques which can lead to heart attacks and strokes. Inflammation damages DNA, and can turn healthy cells into cancers.

Apoptosis is the biologists’ word for cell suicide. It is vitally important to be able to get rid of cells that are unneeded, or cells that have become diseased or cancerous. We need apoptosis, and would be more vulnerable without it, but as we get older, apoptosis develops a “hair trigger”, and cells begin to commit suicide when they’re still healthy and useful. Overactive apoptosis is to blame for sarcopenia – the loss of muscle mass with age. Apoptosis is also implicated in the loss of brain cells that leads to Alzheimer’s Disease.

A third self-destruction mechanism is cellular senescence.  This is the telomere metabolism, which I discussed in two earlier posts here and here.  Unlike inflammation and apoptosis, cellular senescence serves no useful purpose for the body.  (Theorists have proposed a role for telomeres in cancer prevention, but it has turned out that animals and people with short telomeres have consistently higher risk of cancer.)

.The future

As a strategy for research, study of the body’s signaling holds the best promise for big strides in life extension. We can work at fixing what goes wrong, engineering solutions to the damage that appears at many levels, and in many tissues as we age. But if much of this damage is self-inflicted, it will be easier to prevent it than to fix it. The fact that aging is highly regulated suggests it should be possible to modulate aging from the top down by intervening in the regulatory chemistry.

Evolutionary theorists are still adamant that aging could not have evolved as an adaptation, but their theory is holding back progress. One of these days they will have to face the overwhelming evidence that aging has evolved as an active process of self-destruction. Both evolutionary theory and geriatric medicine will be profoundly affected.

13 thoughts on “Is Aging an Active Process of Self-destruction?

  1. Hi Josh,

    I realized that there was a significant area that I was not addressing in my aging theory paper, I have included this new section below, I will appreciate any thoughts you might have as to my logic ect.

    Thanks Josh,

    PS I really like you blog site, I think you have achieved the best balance between theory and practical advice that I have seen on health and aging. As more people discover your site, its impact is only going to grow, I hope you continue it.

    The Evolution of Death Mechanisms
    Asexual Reproduction and Death Mechanisms

    It has been proposed by Nick Lane in his book titled “Life Ascending” and others that cellular death mechanisms are required in the creation of complex life forms for the production of differentiated tissue types. But why would this be the case, since cells show great capacity to de-differentiate, re-differentiate and migrate to needed locations to build and grow the complex body form. However, I do agree with Nick that death mechanisms at the cellular level and at the level of the multicellular individual evolved as a way to deal with parasites. Here I go further to propose that death mechanisms evolved specifically in organisms as a direct consequence of the asexual reproduction strategy and as a result, mechanisms of death, senescence and negligible senescence have all been profoundly molded by asexuality.

    Many obligately asexual species today are recently derived from sexual species and utilize aspects of the remaining sexual apparatus to accomplish asexual reproduction. These species are not the ones under discussion as they are not the precursors to the evolution of sexual species and do not account for the evolution of mechanisms described here.

    It has been propose that the cellular death mechanisms employed by single cellular life were simply modified for use by the very first multicellular organisms to accomplish death of the multicellular individual as there should have been strong selective pressure due to the likelihood that all of the cells constituting the individual were likely infected as well.

    Asexual Clones and Death

    From the perspective of the selfish gene metaphor, since all member of a clone of asexual individual can stand in for any and all other individuals in in the clone relative to reproduction, the death of any subset of individuals in the clone that prevents the extinction of the entire clone is adaptive and should be selected for. Therefore it is adaptive for any individual in a clone that becomes infected by a parasite to kill itself to stop further spread of the parasite. This I propose is the driving logic behind the evolution and persistence of death mechanisms. Since obligately sexual organisms are not capable of employing this kind of selection logic, I propose that death mechanisms predate evolution of sexual reproduction and that sexually reproducing species have cooped and modified preexisting death mechanisms for there use and in the production of mechanisms of senescence.

    Asexual Clones and Negligible Senescence

    Individuals of a obligately asexual clone that reproduce by budding for instance can only effectively employee death mechanisms as an effective strategy if other members of the clone do not utilize death mechanisms and do not have finite life spans thus ensuring the continued reproduction of the clone. Therefore I propose that death mechanisms and negligible senescence co-evolved as complementary mechanisms in the same asexual species, as both capabilities must exist in the shared genotype across all the individuals to ensure the rationality of death mechanisms as a way to counter parasitism.

    I propose that the initial complementary co-evolution of death mechanisms and unlimited life span or negligible senescence has persisted to this day within the same species and accounts for the high degree of plasticity of lifespan as has been demonstrated over short periods of evolutionary time in nature.

    Sexual Species and Death Mechanisms

    In obligately sexual species no individual can represent the complete reproductive interest of the entire phenotype of another individual unless they happen to be an identical twin. For this reason the selection pressure for the maintenance of viable death mechanisms for the purposes of protecting other individuals that can reproductively stand in for the sexual individual does not exist. Therefor other sources of selection pressure must be employed to account for the specific form and persistence of death mechanisms, senescence and negligible senescence exhibited by sexual species and is the next topic considered.

  2. Perhaps I’m oversimplifying things, but I can imagine scenarios where short life spans could have been evolutionarily advantageous.

    For example, adaptation to climate change: An overly long-lived species might not have enough time to iterate through various mutations across successive generations, and thus may be less likely to create a mutated offspring capable of surviving in the new climate.

    It may also just be that the only bloodlines to survive ice ages/etc were the ones that happened to have shorter life spans. I mean let’s face it: Natural selection only matters up to the point where an individual produces successful off-spring. Even if that individual dies shortly afterwards, their genes have passed the test of natural selection for that generation.

  3. Then there is the theory that aging just does not matter. Suppose the maximum life expectancy of humans during the last 200,000 years were only 30 years old, due to accidents, disease, death by large carnivores or murder; what reason would evolution have to extend maximum life expectancy past 100 years of age?
    Suppose the maximum life span of a fly were only 10 days before it was eaten by a spider, a bird or a bat; what advantage would a long life expectancy be?

    • This is actually the mother of all accepted aging theories today, an idea put forward by Peter Medawar in a series of lectures made into a monograph in 1952, “An Unsolved Problem in Biology.”

      Decades later, the idea was thoroughly disproven by surveys of ages at death in the wild of fish, birds, and insects. Indeed, aging causes enough animals die earlier than they would have without it that there is a large fitness cost to aging that evolutionary biology is on the hook to explain.

  4. Selfish gene: It appears to be the mitochondria that initiate apoptosis, and maybe the rest of aging as well. Perchance we are looking at aging from the wrong perspective when we look for an advantage to aging from the animal’s point of view. Let’s look at it from the mitochondria’s advantage. Think of mitochondria as pathogenic bacteria. They grow in their host and pass into it’s offspring; but that is not the end of the line for a bacterium. After the host’s reproduction, the mitochondria as pathogens execute a sinister plan to kill their host; in the hope that scavengers will eat the carcass; so that the mitochondria can infect the scavengers and spread their DNA far and wide. 😉

    • I can’t make sense of this, because there is no advantage for the mitochondria in killing their host. When you eat a plant or animal, its mitochondria don’t go on to live inside you – they die with the host.

      Certainly it was once true that mmitochondria were infecting bacteria. But that was a billion years ago. Mitochondria were already tamed in the early eukaryotes, and their genes have no prospect for reproduction except under direction of the cell as a whole.

  5. A few years ago a researcher found an Age-1 gene mutation in the nematode worm called C. elegans; The mutation had the strange ability to lengthen the post-reproductive lifespan by 40% in this tiny animal, while development and reproduction remained normal. She named it Age-1, expecting to find more such mutations. Since then a nonsense mutation in the Age-1 gene has been found to extended the lifespan of C. elegans by 10 times. No other intervention or supplement even comes close. They have also found an Age-2 mutant which also extends the lifespan. When Age-1 and Age-2 mutations are in the same animal, the life extensions add together, indicating that they work by 2 different mechanisms.
    So what does the normal Age-1 gene do? It codes for a protein called phosphatidylinositol-3-OH kinase, which adds another phosphate group to phosphatidylinositol-3-OH by replacing the -OH group with
    -PO3. So what does this compound do? Well, it is a signaling compound which carries a signal eventually to FOXO3 (the Forkhead protein) in charge of controlling DNA repair, among other things. It also sends a signal to TOR (target of Rapamycin), a protein complex which also is in charge of a lot of different regulatory functions, such as the production of antioxidants. Judging from the fact that when the Age-1 gene is replaced by a nonsense gene, life is extended 10 times; my guess is that this message sent to FOXO3 and to TOR is not a nice message. Since then the Age-1 gene and its mutations have also been found in Drosophila melanogaster.
    Oh well, no problem. We don’t want worms and fruit flies living any longer than necessary anyway, now do we? At least the Age-1 gene is not found in humans. Oh wait, no I am wrong; my bad. The Age-1 gene is found in humans, having been conserved by evolution for some 500 millions years, or so.

  6. Okay, so we have a problem with the AGE-1 gene (CLK-1) and AGE-2 and at least 1 or 2 other genes. We know AGE-1 codes for the protein phosphatidylinositol-3-OH kinase (a kinase adds a phosphate group to another compound, in this case a signaling compound). If I were a researcher (which I am not) my plan would be to develop an antigen to phosphatidylinositol-3-OH kinase and test it in a mammal such as a mouse to see if it would extend the lifespan of said species. A further plan would be to knock out AGE-1, AGE-2 and any other such genes found in mice to see if it would increase lifespan. I can imagine that this has already been done, although I don’t have any research report to that effect. If it did increase lifespan, the next step would be to knock out such genes in a human embryo. Although this would probably be illegal in most countries, we can be sure the Chinese or someone would do this. Can we modify the human genome and produce a long-lived human race? I think someone will eventually do this.

  7. It seems counter intuitive to me that the supplements that extend lifespan tend to reduce the synthesis of proteins. For example, resveratrol and curcumin down regulate nuclear factors like NF-kB and TOR (target of rapamycin), which activate various genes on the DNA. They also activate SIRT1 the product of which deacetylates chromatin causing it to bind tighter and reduce DNA activation and thereby reduce protein production. Calorie restriction, protein restriction and methionine restriction all tend to reduce protein synthesis, since methionine is the start codon for all proteins. In addition CR also activates SIRT1.
    My intuition tells me that a supplement that extends lifespan should function through activating various antioxidants and repair mechanisms via the production of proteins, and that a high protein diet would be beneficial; but apparently not.
    As a 75 year old man myself, I don’t believe in sarcopenia. I think it is just a lack of exercise. I find that by lifting weights I actually grow a little stronger every month. I also have found that a vegetarian diet is not conducive to growing stronger muscles; but rather that I need a high protein diet, with sufficient calories to maintain my weight or increase it slightly. Of course the exercise I do and my diet are just the opposite of what I just listed in my comments above about a longer lifespan; so if you are confused, well so am I!

  8. Let’s think about the DAF2 experiment with worms: When DAF2 is knocked out in nerve cells in C. elegans, the worms lived longer. Because nerve cells don’t do much cellular division, it argues against the telomere theory. What else is there aboutnerve cells? Well, there is usually brain involved, and inside the brain is usually one or more glands, such as the pineal gland and the pituitary gland. So by knocking out DAF2 in nerve cells, maybe the researchers were knocking out a gland at the same time, which rather than the nerve cells, is responsible for lifespan.
    Let us assume that C. elegans has a master gland in its ‘brain” like the pituitary gland. The pituitary is responsible for growth and then activates reproduction. So it may also be responsible for the last phase of life: aging and death. Maybe it sends out an aging hormone, or maybe it just stops producing the hormones necessary for repair?

  9. It is starting to look like all of this aging is induced by aging genes, apparently through the regulation of various hormones. Every time we find a way to extend lifespan it seems we do so by either shutting down or reducing production in some one or more aging genes. The corollary to this is that if there were no genes regulating aging, then the animal would never age. In other words aging is not natural; it is programmed into the animal. Without aging genes, the animal would simply repair all damage, and live until it met a violent or accidental death. There are some animals that seem not to age; that would be the lobster, the tortoise, the whale, certain fish; animals that do not reach an adult size and do not quit growing. As such animals grow older, their mortality rate goes down, instead of up, like the mortality rate of aging animals. This leads me to suspect the switch that is thrown to limit adult size has a lot to do with aging. If I were a researcher, I would be taking a close look at animals that do not age; and try to understand the difference between them and the rest of us mortals. It would also help to study trees that do not age.

  10. The question comes up; why would evolution want to limit lifespan? It seems obvious to me that by killing off the older generation, it makes room for the younger generation. That would be an advantage to a species; but maybe not to an individual. However, what good would it do for the individuals to live twice as long, if it resulted in an overpopulation, resulting in such a severe population crash that the species became extinct?
    It may be extreme; but I can imagine the human population growing too large, with every country developing a vast stockpile of nuclear weapons. Then the countries get into a free-for-all war, and the human race becomes extinct.

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