LC: I know life history theory explains some of the macro-features of organisms in terms of evolutionary benefit like how long organisms live and how large they are. Can you explain the basic correlation between there are a lot of large animals that live for a long time and have few offspring and a lot of small animals that live for short periods and have very many offspring. What explains that basic trend?
SS: Well that’s one of the big questions in the field. And I have been involved in the controversy about how to explain it. My own take on it is that we understand that best if we combine the idea of age-specific and size-specific extrinsic mortality rates with intrinsic tradeoffs.
If you shift a given population with given characteristics into an environment in which the juvenile mortality rate goes up and the adult mortality rate goes down, perhaps by moving it into an environment in which there are more predators that eat small things, then it will pay that population to invest more into maintenance so that the organisms can live longer because they then have a better chance of doing so. They will shift their allocation schedules internally to do more maintenance and less reproduction because the adult body has become “worth more” as a way to increase reproductive success. Thus the population evolves longer life.
In contrast if you were to take a population in a given state and shift it into an environment in which the extrinsic mortality rate on adults or big things went up and that for small or juvenile organisms did not change, then it would not be worth as much to a gene that is sitting in those bodies to invest in the adult state because the adult is going to get killed anyway by things that it could not control. And if you can’t control those extrinsic sources of mortality, then the best thing you can do is try to get more reproduction to get more copies of yourself into the next generation rapidly before you are killed for other reasons. That’s an elevator speech on the evolutionary theory of aging.
The other side of that question has to do more with eco-evolutionary dynamics, as I’ve just explained with the guppy example. That involves density effects, the idea being that when you are at consistently higher population densities, it can under some circumstances pay, in terms of lifetime reproductive success, to invest more in maintenance and less in reproduction. But as I pointed out in the guppy example, it all depends on how the density effects fall on specific age classes and whether they are more serious for juvenile than for adults. Working out the details of such processes is occupying a lot of attention right now.
For humans it is more important to realize that the internal trade-offs between reproduction and survival have medical implications. We evolved in an environment in which our expected lifespan was 35 or 40 years, not 70, 80, or 90 years. We were on a buy-now-pay-later plan where we never had to pay later because we rarely lived long enough to pay. But now, because we have gone through the demographic transition and we’re in a post-industrial age where we survive to later ages, we are seeing the effects on chronic disease that these genes that were selected for their impacts on reproductive success earlier in life had all through evolutionary history.
We have some fairly dramatic examples. One of my favorites, because it produces a beneficial impact on reproduction so early in life, is a mutation in an allele of P53. P53 is a cell cycle control gene that is implicated in many cancers. The allele that makes us more susceptible to cancer as we age gives us a benefit when we are just implanting in the endometrium. You’ve just been fertilized, you’re a zygote coming down the fallopian tube, you make a little blastocyst, and you want to implant in the embryo. That version of P53 gives you an advantage in implanting into the endometrium. It’s about as early in life as you can get a benefit.
There are lots of others. It turns out that there are about seventy genes that GWAS has identified as increasing the risk of heart disease. The top forty of those all turn out to have signatures of selection and to improve reproduction or survival earlier in life in one way or another.Thus it appears that our bodies are bundles of tradeoffs, and that natural selection has not cared about whether we have a long or short life as long as we get more copies of genes into the next generation. The result is one explanation of why we are vulnerable to chronic disease. I think that that’s very interesting and important for research, but it is also important for the part of every medical scientist that’s curious about why things are the way they are. It’s part of the general scientific answer to the question of “What is a patient?” A patient is a bundle of tradeoffs; those tradeoffs are there for good evolutionary reasons; and each one of them gives us a clue as to what particular biochemical or physiological process we should look for when we are trying to figure out the origins for chronic disease.
So I think some aging researchers might argue that evolution hasn’t had much reason to regulate the years of human life past 40 or 50 because we never lived that long in the first place, so perhaps we can come up with a treatment that avoids tradeoffs and introduces a significant benefit by regulating the results of aging.
Well first, the reason evolution hasn’t done a terribly good job is that we are now exposed to environments that we have never encountered before. That’s called mismatch–we are mismatched for the current environment, but natural selection is practically a synonym for mismatch. In other words, when things become mismatched, some of them are going to be reproducing better than others, and there will be a genetic competition going on. We are currently in a dynamic state where our populations are evolving to be better at living longer. Now I would tend to trust the evolutionary process more than I would trust the biotech company to change my genome in a way that increases my health and reproductive success. Simply because of the way that natural selection works, it is going to weigh all of the trade offs all the way through my whole life cycle when changing any gene in the population.
So for a person in a biotech company to say that they are going to be able to extend the human lifespan without any negative consequences implies that they think they know more about human biology than anyone in fact does. My guess is that once in a while we will get away with it, but many times we won’t, and that the way we will find out is probably going to involve some human suffering and possibly even death. It’s a high-stakes game.
I know that Larry Ellison and Larry Page are both interested in this. Most of those in Silicon Valley are trained in physics and chemistry or engineering if they have training in anything other than computer science. Their explanatory paradigm is thermodynamics, not evolution, and they have a tendency to look at the human body like a machine that has parts that break. You can take it into the repair shop, take the right part off the shelf and plug it in, and it’ll run again just like it was new. That is not the way that organic integration occurs in real organisms. It is a much, much more complex network of trade offs, but also many other interactions that you know about. I think they’ll pick the high-target items like diseases with an onset at say 60 or 65, and they’ll try to fix those. And maybe they’ll have some success and people will start to live to be maybe 68 on average, then they’ll fix those, and we’ll live to be maybe 72 on average, and that will continue, with, I think, diminishing returns. Everytime they fix something another thing is going to pop up.
That is in fact what we have already experienced. In the 20th century, we have pretty much eliminated infectious disease, the current Covid pandemic notwithstanding. Because of that, other diseases became the important killers. We learned about the impact of smoking and obesity and cholesterol and exercise on heart disease, and got heart disease under much better control. Well as a result of that, many more people are dying of cancer. And as we improve our treatment of cancer, we’re saving people so that they can die of Alzheimer’s. I think you can see the trend, right? It really is just one damned thing after another, and it is not clear that the average person now dies a better death, or lived a better last decade of life, then did those in centuries past.
So that represents my understanding of why we age and how our bodies are put together. There are hundreds of thousands of different reasons that people die.At the population level a few of them are important and others are less important, but everytime you treat a more important one something else is going to get you. And so the idea that we could possibly live forever, which is what’s driving some of these people–they talk explicitly about immortality–I think is a pipe dream.
By the way, it’s interesting to do a calculation. Suppose we could eliminate all intrinsic sources of mortality – no more cancer or heart disease or Alzheimer’s or epidemic diseases. We would still have to deal with accidents–car accidents, meteorites falling on your head, trees falling on you in the backyard. There are various ways of calculating the consequences, but the answers are all that we live somewhere between 350 and a few thousand years, no more than that – far from immortality. And that doesn’t include anything about the boredom of the incredibly old (laughs).
When I think about this I think more about David Sinclair, who is a scientist at Harvard who works on sirtuin genes, and his, I think, argument is basically that the aging process is a process that’s biologically regulated and can be slowed. He’s not as much “We can be immortal” but there are many diseases that onset at some point in the aging process and if we study aging more thoroughly, I think he said I don’t know if I could find it, but if we had put as much money into studying the process of aging as into some other random “insert research topic here” we would have this aging process biologically figured out and we could probe it or interrupt it. I think there are studies in mice that show extended life or in somewhat simpler organisms that do the same thing.
I know about that, in fact I know quite a bit about the whole sirtuin research program, which by the way got off to a rather difficult start. Let me first tell you about an incident that took place some years before the sirtuin story started. Walter Gehring had a postdoc in his lab in the Biozentrum who was a physicist who didn’t really understand biology too well. He tried to extend aging in drosophila by inserting an extra copy of a gene for an elongation factor, something that helps make protein. He claimed that he had extended lifespan by about thirty percent. This was in Basle. Swiss farmers were calling up and asking for injections of this gene! The result got a full page in Die Zeit, it got a full page in Le Monde. But when we investigated it, it turns out that all of the effects that they had measured in that lab were due to the position of insert and to genetic background, and we even found that the gene itself was not actually expressed. This was early in genetic engineering.That didn’t make me any friends with Walter, but it showed that you have to be very careful about controlling genetic backgrounds and insert positions. It pointedly raised the question of whether or not whatever effect you see in your lab population is also going to be true in an outbred, wild type population. That is a critical question for genetic engineers.
Now, to go back to sirtuins and the group at MIT who decided that sirtuins are really interesting because they had an important effect on lifespan in nematodes. Their genetically engineered nematodes with alterations in sirtuin metabolism that appear to make them live a lot longer. They set up a company and attracted venture capital. Then they had a run of experimental successes with sirtuin in nematodes, and then I think in mice, that caused a real influx of investment. When they sold out, it was for 700 million dollars,but that came just months before the first failures of the human trials. An analysis of their experiments done by a group at University College London showed that exactly the same thing had happened in those sirtuin experiments that had happened in the fly experiments I described in introducing the story. They had transformed their organisms without taking care to control the genetic backgrounds and the positions of inserts as carefully as they should have. When the London group did the controls, they showed that there was no effect of sirtuin in such experiments. Now that doesn’t mean that sirtuin doesn’t have an effect or that Sinclair doesn’t have something to show for his work, it just shows you that the logic of these transformations is nuanced and you have to be pretty careful about how you do it.
That said, what are sirtuins doing? They’re in the insulin and insulin-like receptor pathway. They are involved in controlling the level of metabolism and therefore part of a process that can be described from a couple points of view. One is that when we eat and use energy to make stuff, our mitochondria leak protons, and protons cause damage. If we can just cut down the rate at which we are leaking protons from mitochondria we will age more slowly. So that’s a mechanistic sketch of what’s going on, one of the effects. I think that there may very well be some benefits. There may be benefits that can be realized by going on a low calorie diet, although the diet has to be so low in calories that frankly you get into the issue of do we want a happy short life or do we want a long miserable life. If you have to go onto an 800-calorie-a-day diet you’re going to look like a prisoner in a concentration camp – you’re not going to be happy.
The question is, could you use these insights into sirtuin metabolism to give people a pill where they wouldn’t have to go onto that diet and they could live longer. If you want to read about stuff like that, Steven Austed, just retired as the head of the aging unit at the University of Alabama, actually has an interesting bet that he made with somebody about whether or not there would soon be a 150 year old human. They each put 300 bucks into an investment account and set up a trust to let it accumulate interest and dividends. Do you know about this bet?
I’m just reading about it on wikipedia.
Yeah, so they each put 300 bucks in and it’s supposed to pay off at billions at some compound interest rate that is not affected by the COVID crisis. I have a lot of respect for Steve. He’s a good scientist, he’s a very very bright and creative guy, and he’s somebody who takes risks. He was a Hollywood lion trainer until he got a deep bite in his thigh from a lion and decided to become a scientist, and he ended up being a very successful researcher. So he thinks that it will be possible to help humans to be 150, and of course the whole point is to make sure that they’re healthy and happy and running marathons until they’re 149 and a half or something like that.While I don’t have any objection to that kind of research, if I were an advisor to the board of a company I wouldn’t invest in it myself. Actually no, if I were cynical I would, because I would say that it might not work, but you’re always going to be able to sell it because people are so afraid of death that they will let their hope cloud their reason.
There’s certainly some snake oil that gets peddled, as you have detected.
See more in a talk by Professor Stearns titled “The Evolution of Aging, the Great Transition, and the Increasing Risk of Chronic Disease” here.