Transcript of interview 10/14/19.
IP: We've been spending time on hierarchical levels of the aging process: the genome, the microbiome, systems biology. There is an extensive catalog of hallmarks of aging. This lengthy list includes inflammation, oxidation, microbial burden, somatic mutations, epigenetic modifications, stem cell exhaustion, senescent cell accumulation, damaged mitochondria, telomere erosion, and on and on. All very interesting topics, and good topics for intervention. But we have not found a unified picture of why we age. We have not touched the paradoxes that challenge the prevailing theories. Why do some damaged organisms live a long time? Why do pristine animals drop dead after reproduction in some species? Why do some of these hallmarks of aging appear, sometimes, in the earliest stages of life, when we're first developing? So we have an incomplete picture of aging. Joining us today is Dr Josh Mitteldorf. Dr Mitteldorf earned a PhD in astrophysics here in Philadelphia at UPenn, and spent a decade or so in that field, "wandering in the plasma physics of extragalactic radio sources." (This is after earlier careers working in optical design and energy conservation.) Then Dr Mitteldorf made a move into evolutionary biology, where he currently studies evolutionary biology of aging using computer simulations. He spent a lot of times correcting what he feels are errors in the foundations of evolutionary theory. Maybe the theory has focused too much on selfish genes, as opposed to the ecological context that determines a relative notion of "fitness". In his paradigms, this has a lot to do with why we age in the first place, and, by extension, what we can do about it with medical interventions. Dr Mitteldorf has lectured extensively at Harvard, Berkeley, MIT, her in Philly at LaSalle and Temple Universities. He is the author of two books:
Cracking the Aging Code: The new science of growing old and what it means for staying young.
Aging is a Group-Selected Adaptation: Theory, evidence and medical implications
He is also responsible for the Aging Matters ScienceBlog, and he is organizing a new study called DataBETA, in cooperation with the UCLA lab of Steve Horvath, evaluating combinations of anti-aging supplements and interventions, looking for possible synergies which so many studies focusing on single interventions may have missed.
JJM: Wow! You've said it all. I think we're done.
IP: We can do a lot more. Can you introduce yourself, your background, how you got in astrophysics, then evolutionary biology, and where you find yourself today in terms of these innovative theories of aging.
JJM: In 25 words or less?
I grew up in New York and New Jersey. I was a wunderkind and went to Harvard early, and then I just dropped back, became a hippy for awhile, went to Taiwan, learned to speak Chinese, started a skills coop, became a yoga teacher, wandered back into science a few years later with a commitment, not just to solving equations but trying to figure out how the world works. My generation grew up with a disdain for the Military-Industrial Complex and all things capitalist. I have just enough money in the family that I don't have to depend on a salary from industry or academia, and I have the privilege to investigate what I want to investigate. If I have anything to offer this field, it's that I have a broad perspective and sometimes I can tie things together.
IP: I find your background in astrophysics fascinating. I come the pharmaceutical industry, a very siloed place. One of my critiques of anti-aging biotech is the belief that if you're not a specialist in cell biology you can't contribute to the discussion. On this show, we've talked to people about the very small (quantum biology) to the very large (chronobiology). Before we get into your theories, talk about what it's like for you as an astrophysicist coming into the field of aging biology as an outsider.
JJM: Not so much the outsider. Actually, the field was already dominated by mathematicians when I came aboard. Evolutionary biology during the first half of the 20th Century was two different fields. There were the mathematicians who knew precious little biology. These were brilliant people, including R.A. Fisher who invented the whole idea of correlation coefficients, analysis of variance--the foundations of how we evaluate significance in all fields of science today. But Fisher was also a passionate eugenicist. He felt the world was going to hell in a handbasket because the poor were having too many children. The rich people, who are intellectually superior to the poor, were not reproducing themselves, and he developed the whole theory now called "the selfish gene" based on fitness as a property of individual genes. He recast Darwinian evolution as a 20th Century theory, making it quantitative, he modeled exclusively the competition which was part of Darwin's thinking, and de-emphasized cooperation, which Darwin was very aware of. Darwin was a naturalist, who traveled the world describing what he saw. So, back to the 20th Century, we have the naturalists, continuing in Darwin's tradition: "This is what we see, and this is the explanation in terms of natural selection." These people were observers of nature, using qualitative reasoning. On the other side, we had the mathematicians, who were developing selfish gene theory as a mathematical abstraction. This came to a head in 1964, with a book by George Williams , who had training in biology, but also deep respect for the mathematicians. He said, "You observational biologists, you naturalists will have to get your act together. You have not been rigorous in your idea of what fitness is and how evolution works. You have to embrace this mathematical theory and use it in every evolutionary explanation. Along with John Maynard Smith, he engineered a hostile takeover of the naturalists by the mathematicians, and the naturalists didn't have the mathematical chops to challenge them. The idea of the selfish gene became dominant; cooperation was swept aside. "We know by theory that the only kind of cooperation that can possibly evolve is in lineages that share genes. For example, I share half my genes with my brother. I share one eight of my genes with first cousins. There's a quip attributed to the mid-century theorist J.B.S. Haldane , asked whether he would ever sacrifice his own life for his brother's sake. He replied, "No, but I would lay down my life for 2 brothers or 8 cousins." This idea of "inclusive fitness" became the narrow lens through which all examples of cooperation in nature had to be explained.
Back to your question, What was it like for me to come into evolutionary biology as an outsider from mathematical physics? Well, the field was already dominated by mathematicians. I saw my role as taking the field back for the observational biologists. In science, observation is the highest authority whenever there is conflict with theory. I hoped that I might give the observational biologists the rigorous mathematics they needed to take back the field from theorists who had imposed a paradigm, a paradigm that didn't fit the facts.
What facts in particular? If you think just about selfish genes, then what is aging? Aging has to be a mistake. Aging only detracts from individual fitness, and you're not allowed to think about the fitness of the community because there's no such thing as cooperation. Well, over the long haul, evolution doesn't make mistakes, so there must be constraints, physical limitations or parts of fitness space that were unavailable. There were tradeoffs imposed, and therefore evolution is not able to make animals and plants that live and grow stronger for an indefinite period of time. This "wearing out" that we observe is an inevitable consequence of physical constraints that are imposed on evolution.
When I first learned this in the mid-1990s, I thought, "this has got to be wrong." There is so much cooperation in nature that is not between close relatives. And not only this, aging has a deep heritage. There are genes that control aging in us that have been around for a billion years. They're the same genes that control aging in worms and in yeast cells, separated from us by half a billion and a full billion years, respectively, since our last common ancestor. So maybe evolution has some constraints, but what constraints could conceivably apply equally to yeast cells and mammals? Any gene that's been kept around for a billion years has to have a purpose. Of course, there are many genes that we share with these primitive eukaryotes, and these genes program the basics of cell chemistry, energy metabolism, and protein synthesis. These genes control functions that are so important that evolution does not want to mess with them. Well, genes for aging are in this same category. Evidently, the genes for aging must have a purpose that is just as central, just as important as genes for the metabolic machinery of the eukaryotic cell.
IP: When you talk about a billion years, I think of deep lineages with evolving purpose. For example, the amoeba dictyostelium , pond scum has genes that are used to swim around and hunt for food, but when food is scarce, these same genes are used to organize the cells into multicellular structures. We find that a billion years later, these same genes lead to tumor formation and metastasis. So there are these fascinating connections across time. Take us a little further now into your book. What are we missing when we look at aging from a cell perspective and not considering the organism or the ecological context?
JJM : Let me add one more hint that brought me into this field, the thing that lit the lightbulb in my head. It was 1996, and there was a cover story in Scientific American by Richard Weindruch about caloric restriction. We all know today that animals that eat less live longer, pretty much across the animal kingdom. But this was new to me at the time, and it got me thinking, what can an individual do when it's starved that it couldn't do when it was well-nourished? We're not just talking about 10% less food. In a cohort where some of the animals are dropping dead from starvation, the ones that survive are living almost twice as long. What can an animal do in extremis of caloric deprivation that it couldn't do when fully fed? This led me at the time to think that lifespan must be a choice the metabolism is making. The individual is programmed to live a shorter time when fully fed so that it can live a longer time when the community needs them most. The fully-fedanimals are programmed by evolution for lower individual fitness. If this is true for so many species, there must be a deep and quite general explanation.
An aside here -- I learned later that one well-accepted way to get around this conclusion is to posit that there's an energy tradeoff, that food energy can be used either for longevity or for reproduction. When there's plenty of energy, it all goes into reproduction and this somehow causes a shortage of the portion for reproduction. Then, when energy is in short supply--this makes no sense, but it's part of the canon of what's called Disposable theory --when food energy is severely restricted, there's actually more of it available for keeping the body in repair long-term. I wrote a rebuttal at the time, pointing out some of the cheats that the author was using to reach this paradoxical result, which he needed for his theory. For one thing, his model only worked for pregnant females, not for females kept in lab conditions in cages with other females, and certainly not for males, which can maintain their fertility when calorically restricted.
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