An Interview with a Programmed Aging Theorist


Pioneer Founding member

Josh Mittledorf holds an interesting somewhat group selection based view on the evolution of programmed aging, and here is interviewed by the Life Extension Advocacy Foundation volunteers. I have long said that the important divide in the research community is between (a) those who think that aging is programmed, in the sense that evolution selects for epigenetic changes in later life that are a primary cause of damage and dysfunction, and (b) those who see aging as a stochastic process of damage accumulation, that occurs in later life because there is little to no selection pressure for ways to prevent it, and this damage causes epigenetic changes and dysfunction.

This is an important divide because the two views lead to very different strategies for the development of therapies to treat aging. The programmed aging theorist wants to force reversion of epigenetic changes to a youthful pattern, and expects damage and dsyfunction to be reversed as a result. In the damage accumulation view, exemplified by the SENS research programs, repair of damage is the right path, with the expectation that dysfunction and epigenetic changes will revert themselves once the damage is gone. In either case, if the other side is right, the chosen strategy will produce poor results. Now that the research community is earnestly engaged with the idea of treating aging, whether researchers and institutions invest in good or bad strategies is of great importance to the near future of medicine and our own lives.

It seems like the field of aging science has grown remarkably. Are you optimistic that we're on the verge of real breakthroughs in longevity improvements?

I'm not as optimistic as I was a few years ago. The Next Big Thing in the field is likely to be senolytic drugs. These are able to selectively remove the body's worn-out cells that have become toxic, without poisoning our healthy cells. I think they'll add a decade or more to the human lifespan. Calorie restriction mimetic and exercise mimetic drugs will be another boost if they can be made safe. After that, I think the big challenge will require taking control of our epigenetics (heritable changes that don't require changes to the genome itself). Epigenetics, I believe, is in control of aging at a deep level. Epigenetics is so complicated that 20 years into the age of epigenetics, we're still just beginning to understand how it works.

Why are you less optimistic about the potential for major breakthroughs in aging science now in 2018 than you were previously?

Originally, my thinking went like this: The conventional view has been that aging exists despite evolution's best efforts over hundreds of millions of years to eradicate it. Evolution is already trying to make us live as long as possible, and for humans to extend our lifespan, we'll have to do some pretty fancy thinking to come up with something that evolution hasn't already tried. However, this conventional view is wrong. In fact, evolution has preferred defined lifespans to indefinite lifespans. So, we might hope that we can eliminate aging entirely by understanding the mechanisms of self-destruction that evolution has built into our life history and biochemically disabling them. I had thought that this could probably be done by blocking the signals, jamming the works. Pharmaceutical companies are generally quite good at turning off a hormone or a whole biochemical pathway once it's been identified.

The reason I'm less optimistic now is that I believe that the evolved mechanism of self-destruction involves gene expression, which is to say epigenetics. Different genes are turned on at different stages of life (this is a big part of what epigenetics is), and the genes turned on late in life turn the body against itself. Mechanisms like apoptosis (cell death), autoimmunity, and inflammation are all dialed up. The reason my expectations are scaled back now is that epigenetics has turned out to be enormously complicated. We once thought that a few transcription factors controlled a large number of genes, turning them on and off en masse. We now know that there are thousands of different transcription factors, almost as many as there are genes. And there is wide overlap between genes that have transcriptional functions and genes that have metabolic functions.

Could you flesh out a little your contributions to aging science, in terms of the evolutionary theory of programmed death in humans and most other species?

In the modern understanding of evolutionary fitness, evolution is highly motivated to make you live as long as possible, so long as you are still churning out babies. So, where does aging come from? The standard answer is that there are genes that tie fertility directly to deterioration late in life, and evolution has not found a way around this; it has not found a way to have lots of fertility early in life without incurring damage later on, despite hundreds of millions of years of trying to overcome this limitation.

I have described a great mass of evidence against this picture. Much of it is common sense, but there is a lot of technical, genomic evidence as well. The evidence strongly points to the inference that natural selection has preferred shorter lifespans to indefinite (or very long) lifespans. Why might this be? My theory is that it is about ecosystem stability. It's not possible to construct a stable ecosystem out of selfish individuals that are each trying to live as long as possible and produce as many offspring as possible. In order to have stable ecosystems, nature has had to accept limits to fertility and to lifespan.

The reason that the evolutionary community is so resistant to this idea is that it requires natural selection to occur within entire ecosystems. In other words, this ecosystem persisted because it was stable, while that one collapsed because it was way out of balance. For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene. Most evolutionary biologists today believe that the selfish gene is the only mode by which evolution operates, though they could not articulate a reason why, if challenged.