Why Do We Age? Because of parasites. Or, the Red King Theory

So there’s this paper I’ve been trying to get published for a little while. It lays out my hypothesis for why we age. You can see the preprint here on the bioRxiv server. The journal editors really don’t seem to like it, probably because it is completely against the grain of current thinking, although a handful of people who have seen it on bioRxiv seem to like it quite a bit.

In the past, I had never been that interested in aging, because I get depressed when I think about degenerative diseases. I think it comes from when I was training as a doctor and I would see patient after patient with hypertension, diabetes, and heart disease. The older doctors taught me that our job was not to cure these patients–that was impossible–but to slow down the inevitable progression of these diseases. I didn’t like that. I like to fix people, I like to fix problems, I like to fix companies.

But my interest was piqued when I read a review article in Science couple of years ago that declared that it was just a matter of time before we could reverse aging.

Aging as a reversible disease? Not a progressive, inexorable degeneration? Really? Now that’s something worth pursuing.

We used to think that the body just wore out

Historically, aging has been considered to be the result of the body wearing out, much like a used car. There’s a limit on how long an organic being can last. After a while, your repair mechanism just wears out. Makes sense, right?

A popular variant of this hypothesis is the theory that after you reproduce, there is no longer an evolutionary pressure on genes. So genes that make your body run down after you reproduce don’t get weeded out by Mother Evolution. That sounds logical too, right?

Except… wait a sec. Human males can reproduce into their 90s and beyond. Why are men getting old and dying? Shouldn’t men live a lot longer than women, who stop reproducing in their 40s?

And except except… why do women stop reproducing in their 40s? Because they get old. But why do they get old? Because they stop reproducing in their 40s. Say what?

Both of the above theories, and several other in the same vein, are degenerative theories. Basically, the body tries to keep going for as long as it can, and then poops out.

But maybe aging is programmed

The alternate theory, which is looking like a bright shiny object, is the theory that aging is programmed. We have a clock that makes us age at a certain rate. We have been evolutionarily programmed with planned obsolescence. When the clock strikes twelve, we turn into pumpkins by design.

This theory has been… not popular… among biologists. I think one of the main reasons is that no one has come up with a convincing reason why it would be a good thing for us to age. (Back to that question in a sec.)

But evidence is piling and piling up that aging, in fact, is programmed. That aging can be reversed.

One of the strongest lines of evidence for this is that there are certain genes that control aging. In particular, IGFR, or insulin-like growth factor receptor gene, has been giving a lot of people pause. In nematode worms (yes, our favorite worm), mutation in this gene increases lifespan by 100%, or two-fold. The same mutation is found in dwarf bats that live much longer than other bats–40 years in fact.

In dogs, mutation in the same gene is responsible for miniature breeds, which as many readers will know live twice as long as large breeds. You may not know, however, that miniature breeds of dogs also almost never can get cancer. Cancer is the most common cause of death in most dogs except for tiny ones.

In humans, mutation in the same gene causes Laron dwarfism, which is found concentrated in one area of South America. People with this mutation hardly ever develop cancer or diabetes, although the effect on longevity is not clear.

Scientists have been finding other genes that seem to control aging across multiple species.

The point is, that there gene that seem to control the rate of aging, which you would expect if aging was programmed, and not if it was not programmed.

Furthermore, it appears that transferring blood from young mice to old mice make old mice younger. And transferring microbiome from young killifish to old killifsh seem to make old killifish younger. (OK, on this one, I have write out the journal article title: “Young poo makes aged fish live longer“)

There are even studies, almost completely ignored by the scientific community, that show that once flies get past a certain age, they seem be immortal, at least their risk of dying from aging seems to decrease. You can find them here and here. The studies are rather odd. They took millions of flies and tracked their lifespan. Most flies aged and died, but a small cohort basically seemed not to age. To tell you the truth, I don’t know how to interpret this. Either there is something different about flies (horrors – that would mean flies are different from humans) or that there are a few humans on earth who stopped aging and they’re hiding out somewhere… I mean, I like the TV show Highlander, but come on…

So, how do we explain aging? Why on earth would we be programmed to age? I mean, it would be great if that were the case, because as a drug developer, I would be much more excited about trying to reverse a programmed process than about reversing a non-programmed degeneration. The first is doable: if aging is programmed, we will one day be able to reverse it. The second is a Herculean task, and at best would be a patch job.

To answer that question, I’ll have ask you for patience while I take you on a little detour. Two detours, actually.

How do other organisms Age?

The first is to step back and think about aging across species. Almost all species age. But they do it differently. Some organisms slowly age then die. Others hardly age at all for a long time and then suddenly age and die. Salmon is a prototypical example. They age very rapidly as they swim upstream to mate, and then die after mating. And it’s real aging. They get cataracts, their muscles degenerate, they get Alzheimers plaques (!) they look horrible by the time everything is done. And it’s not just that the journey upstream is too strenuous. If you remove their endocrine organs, they look perfectly fine even after their upstream migration.

In fact, many organism only mate once in their lives. And they tend to age and die right afterwards. Humans, who reproduce multiple times, have a slow aging process, and die long after reproducing, are not really prototypical.

In many organisms, if you prevent them from mating or reproducing, you slow down aging dramatically. This is true in octopus–instead of dying within ten days, they will live for several months. In some annual plants, if you prevent the seeds from developing after flowering, they won’t die.

The reverse is true as well. In many organisms, you can accelerate aging by mating or sometime simply by exposure to individuals of the opposite sex. This can be seen in nematode worms and in some insects.

So aging seems to be linked to reproduction, at least in many species. But not just any reproduction. To sexual reproduction. I haven’t found much evidence of aging after asexual reproduction.

So that brings us to the second detour. Why do we have sexual reproduction?

That’s actually a greater puzzle than aging. Aging you could at least explain (wrongly) that your body wears down. But why on earth would you take an organism that successfully lived until adulthood, take half of its genes, and shuffle them with half the genes from another organism? Why would you break up an NBA championship team when all the players are working well together?

The best explanation would be if the environment faced by the progeny were going to be different from the environment faced by the parents. If you knew your NBA team was going to face different kind of teams the next season.

This in fact, is the leading theory about sexual reproduction.

Red Queen Theory

Robert Trivers, one of the most original thinkers in biology, proposed what is known as the Red Queen Theory for sexual reproduction. The theory goes as follows. Organisms and pathogens are engaged in an arms race. Each is trying to stay one step ahead the other. As the pathogen evolves to better infect the host, the host evolves to be more resistant to the pathogen.

In order for the host to stay ahead of the pathogen or the parasite, it constantly shuffles it genes. It does so by sexual reproduction.

The name Red Queen comes from Alice in Wonderland, where the Red Queen tells Alice that in Wonderland, you run and run and end up in the same place, unlike in Alice’s world where running gets you to a different place.

The theory has not been easy to test, but there is now evidence that higher parasite load triggers hosts to switch from asexual cloning to sexual reproduction. And there is also evidence that hosts and parasites do undergo cycles of genetic variation, host running from the pathogen and the pathogen running to keep up. And did I mention that in our friend, the nematode worm, that it switches from asexual to sexual reproduction under conditions of stress, and that sexually reproducing nematodes are much more successful resisting parasite infections?

So basically, hosts and pathogens are engaged in an infinite game of rock-paper-scissors. Sexual reproduction allows hosts to change from rock to scissors to paper. (Not to be too… geeky… but those who play Magic the Gathering will recognize this as switching of the meta: the card decks that are very successful when your opponents are all playing one strategy becomes very unsuccessful once your opponents start using a different deck.)

Red King Theory

So if I may be as bold to proposed the “Red King Theory”: programmed aging allows faster switching of the pathogen resistance genes.

See, if organisms lived forever, then switching from rock to scissors to paper would be really slow. What you want to do, to keep ahead of the pathogens, is wipe the slate clean and reboot the population with the next iteration. Faster you can reboot the population, more successful the hosts will be.

Some organism do this in a really big way. Bamboo of a species, for example, will all flower at the same time and then all die. Same thing with cicadas. Biologists generally believe these species to evade macro-pathogens (i.e., the predators) but there is no logical reason why they wouldn’t use the same strategy to evade micro-pathogens (parasites and infectious organisms). In fact, micro-pathogens are in general much more dangerous than macro-pathogens. Besides, parasites have evolved a counter-strategy to mass die off (multiple host lifecycle) and the poor macro-pathogens never had to (e.g., the poor pandas who starve when the bamboos flower).

I don’t simply mean that by dying the hosts are reducing the total parasite load. That happens too, but what’s more important is that just as the pathogens are evolving to be successful in infecting one type of host, the host pulls the rug out from under them and switches around the pathogen resistance genes.

(I know some people won’t like this theory because it smacks of group evolution, but I think the knee-jerk allergic reaction to group evolution is overblown.)

There are some implications of this theory. It suggests that during asexual reproduction, organisms shouldn’t age, or at least not age as quickly. It suggests that under high pathogen or parasite load, organisms should age faster. It suggests that aging, inflammation and reproduction should be linked.

It’s certainly true that many aspects of aging, such as cardiac disease, diabetes, and Alzheimer’s disease are driven by inflammation. And there is evidence suggesting that aging and reproduction is linked. For example, lower levels of GnRH, an important sex hormone, has been linked to aging.

(It also suggests that thinking of evolution at a single organism level may be too simplistic. Environment is not static, and the most important part of the environment, namely the pathogen populations, may vary very rapidly. Success in the natural selection process may require success not just in one generation but over multiple generations, suggesting that a better model for natural selection may require viewing evolution in a multigeneration context. Specifically, rather than concentrating on the set of genes that are phenotypically expressed in one generation, it may be useful to consider also the unexpressed genes, that are available to be expressed in future generations and that have been expressed in previous generations, in evaluating fitness. It may also be useful to consider the ability to quickly switch expressed and unexpressed genes across generation when evaluating fitness.)

I any case, the take-away is that aging is probably a programmed, evolutionarily selected, trait. And that means that it may very likely be modifiable with pharmaceutical intervention.

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