Are we on the verge of major breakthroughs in anti-aging?

An interview with Dr. Josh Mitteldorf.


Today we bring you an interview with author and researcher Dr. Josh Mitteldorf who runs the aging research blog Aging Matters.

Aging is not always the default

Dr. Josh Mitteldorf is an evolutionary biologist and a long-time contributor to the growing field of aging science. His work in this field has focused on theories of aging. He asks the basic question: why do we age and die? This can seem like a silly question to people encountering it for the first time because most of us would quickly respond, “Because that’s just how it is; all creatures age and die eventually as their bodies wear out.”

Essentially, Josh is saying, “Not so fast. In fact, a lot of creatures don’t age and die. Humans, as well as most other animals that do age and die, are programmed to do so. So, humans are programmed to die in much the same way that salmon are programmed to die after spawning.”

Wait, what? Yes, Josh argues, we are not that much different than salmon in this regard – we just have longer to enjoy our inevitable fate than salmon do. However, our ultimate fate is the same. This is important because an accurate understanding of how and why we age will lead to more effective therapies and interventions to mitigate or even eliminate aging.

I discussed my thoughts and reactions upon learning about Josh’s ideas in his excellent 2016 book co-authored with Dorian Sagan, Cracking the Aging Code in my article entitled: Like Tears in Rain, We Are Replicants.

What follows is an interview with Josh about his ideas and his thoughts on the field of aging science more generally. This interview was conducted by email in early 2018.

It seems like the field of aging science has grown remarkably in the last decade or so, with many new books and more research money and scientists devoted to the many problems of aging. Given this growing interest 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. The “exercise pills” popularized by the New Yorker last fall 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.

You have a Ph.D. in astrophysics, and you work in mathematical modeling and evolutionary biology – not exactly a set of credentials we’d expect for someone focused on aging science. What was your personal path for becoming a biologist who studies aging? And what is your preferred designation: biogerontologist, “aging scientist,” or something else?

I was and still am fascinated by cosmology, the study of the large-scale structure and the history of the universe as a whole. However, I was frankly intimidated by how many really, really smart people there are in the field. I came to doubt that I would be able to see something that they missed and to make a really fundamental contribution.

Then, in 1996, I figured out that the whole biological community had missed the point about what aging is and where it comes from. Here was a fundamental error that I might be able to help correct, and it is about a question of interest to scientists and non-scientists alike. Truly low-hanging fruit in the world of research, waiting to be plucked. I found my calling.

What I didn’t realize is that science is so well-defended against challenging ideas. Within five years, I had worked out an understanding and a resolution of the basic paradox that aging evolves despite the fact that it is the opposite of traditional notions of evolutionary fitness. Here we are, 17 years later, and I’m still working with the public relations aspects of this new science and entrenched conservatism.

Is it indulgent for scientists to focus on extending lifespans and healthspans when there are so many diseases that still afflict kids and adults?

I don’t think so. Diseases of old age take the biggest toll on human health, by far.

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. Sigh.

There are more than 100 known mechanisms of epigenetics, and the only one that we have a handle on is methylation; that is, we can measure it and, clumsily with gene editing tools like CRISPR, re-program methylation one site at a time.

In short, I think that turning aging processes off completely will require a mastery of epigenetics, and we have a long way to go before we even understand, let alone take control of, epigenetics.

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? I found your book Cracking the Aging Code very interesting and enlightening on these issues, but these ideas are hard for most people to get their heads around.

Thank you, Tam. I do hope that this book will turn around the way people think about the evolutionary origin of aging, causing ripples that affect our understanding of the metabolism of aging and leading to improved medical research. It’s gratifying that my theory is receiving the recognition that was completely absent 20 years ago, but it’s also frustrating that the entrenched theory refuses to die.

Briefly, the entrenched theory is based on the “selfish gene” notion that Richard Dawkins and others have made popular. Darwin had a broad and multifaceted view of what constitutes fitness. He was appropriately vague. But in the 20th century, “fitness” came to mean just one thing: fertility. How many offspring can you produce, and how fast can you produce them?

In this picture of 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.

In my book, I describe 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.

So, stable ecosystems spread to take over the territory of collapsed ecosystems, and all the species in the stable ecosystem benefit. This is a much broader notion of how natural selection works than the selfish gene model.

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.

If we are indeed programmed to die, what does this insight suggest about the most promising pathways for anti-aging breakthroughs?

The death program seems to operate primarily through inflammation, apoptosis (programmed cell death), autoimmunity, and cellular senescence through telomere shortening. My understanding of aging suggests the following:

  • Anti-inflammatories are already well-studied and represent the state of the art in anti-aging medicine.
  • Apoptosis is trickier because the body needs apoptosis to get rid of cancer and infected cells. We can’t just dial down apoptosis; we need to make it smarter and more discriminating.
  • Autoimmunity occurs when the thymus gland shrinks throughout a person’s lifetime. The most promising therapies to restore the thymus involve FOXN1.
  • Telomere maintenance will have to be part of any full-spectrum anti-aging program.

How many additional years of healthspan and/or lifespan do you think good nutrition, exercise, attitude, supportive social bonds, etc. can contribute?

Look around you. The people who are doing everything right live about 10 extra years. However, after age 90 or maybe 95, the genes take over. If you don’t have centenarian genes in your family, all the healthy habits in the world won’t get you to age 100.

Let’s dive into what you identify above as perhaps the most promising area of research: senolytic drugs and apoptosis. What are these drugs, and how do they work? Are there over-the-counter or prescription options available yet?

Senolytic drugs kill senescent (old) cells without harming normal cells. The best evidence we have about the potential for this therapy is that when senescent cells are efficiently eliminated in mice, the mice live 25% longer. However, the catch is that the way this is accomplished in mice is to genetically engineer the mice before they are born, giving them a self-destruct mechanism built only into their senescent cells. Then, the lab scientists can administer a drug that doesn’t directly kill the cells but only signals them to kill themselves.

Without genetic engineering, human cells don’t have these self-destruct mechanisms built-in. Genetic engineering has to start with the fertilized egg; it’s way too late for you and me under this approach. So, for senolytics to be implemented in humans, we need a really smart poison that only affects senescent cells without harming normal cells. There are several pharmaceutical companies working on this idea. The record-holder so far is FOXO4-DRI, and it is about 10 times more toxic to senescent cells than to normal cells. That factor of 10 isn’t enough margin of error for a practical drug. To get rid of all your senescent cells, you’d have to take too many healthy cells as collateral damage.

A combination of dasatinib and quercetin has been suggested for senolytics. Quercetin is found in fruits and berries, but by itself it doesn’t extend lifespan (in mice). Dasatinib is a chemotherapy drug that is far too toxic to be a practical life extension medicine.

The best senolytic treatment we have now is fasting. When we go without food for three days at a time or more, senescent cells start to die off, but normal cells dial up their resistance and become healthier during a fast. Valter Longo has experimented with fasting and has designed a low-cal, low-protein “fasting-mimicking diet” that allows you to get a lot of the benefits of fasting with much less hunger.

David Sinclair, a geneticist at Harvard, has made waves recently with his research on nicotinamide (a type of vitamin B3) and its potential to rejuvenate circulation and increase energy, among many other benefits. He’s talked about his 78-year-old father taking nicotinamide and feeling like a 30-year-old again–with the adventurous lifestyle to prove it. Sinclair’s recent paper found a strong association between nicotinamide and reversing vascular aging. Do you agree that nicotinamide and other methods of increasing NAD+ are promising for significant rejuvenation?

I’ve been behind the curve with the science of NAD all along. There may be evidence I haven’t seen. From what I know now, I’m not impressed with the idea that NAD or its precursors are a significant anti-aging tonic, though I don’t doubt that there are some people who have benefited from these supplements. Our metabolisms are so different, one person from the other, and I believe that individualized anti-aging programs will ride a wave of individualized medicine over the coming decades.

What researchers do you see as being mostly on the right track for major breakthroughs?

Recently, I’ve been much enchanted by Horvath’s aging clock.

But isn’t the “Horvath clock” a measurement tool rather than an anti-aging treatment?

Exactly so. What I believe is that our development of anti-aging technologies has far outpaced our program of testing, so, at present, we don’t know what works. For example, we now have something in the neighborhood of over 20 treatments that have been found to extend lifespan in mice by 5% to 15%, with a few up in the 20% area.

The biggest unknown of all is how all these technologies interact. I take about 20 different pills, plus intermittent fasting, a low-carb vegetarian diet, yoga, endurance exercise and interval training. All these things have been shown to have some benefit, but we know almost nothing about how they interact with one another. The great majority are likely to be redundant. That is, the benefit of taking two supplements is barely better than taking one, if at all; and with 20 different supplements, we can guess that most of them are doing the same thing, but not all. There are some combinations that actually synergize: 1 + 1 = 3.

How can we test all these hundreds of different combinations, when a single life extension trial in humans takes 10-20 years and costs hundreds of millions of dollars?

This is where the Horvath clock is a real breakthrough. The standard test at present would be to try a combination on 3,000 subjects and 3,000 controls, then wait and wait for 50 of them to die in the control group and only 40 in the test group, and we have a positive result that’s barely significant, statistically. However, the new Horvath clock, just out this spring, is so accurate that you can see the results in a single human in the course of a year or two. I predict that testing with the Horvath clock is going to be 10 times faster and 100 times cheaper than the present protocol.

Another great benefit is that early adopters and self-hackers are going to start testing themselves, trying an intervention and testing again the next year. If they do this with some discipline, they can learn not just what works in general but what works for their particular metabolisms. The Horvath clock will be a huge boon for individualized medicine.

That’s an inspiring development. Who else has captured your imagination with their research?

I’m a fan of Irina and Mike Conboy. Starting with parabiosis experiments (hooking the blood circulation of two mice together), they have progressed toward blood draws and blood infusions to study what factors in the blood are responsible for rejuvenation. I think that this is a very promising line of research. On the other hand, they haven’t published a major new finding in several years, and privately, they’ve told me that rejuvenation may be complicated, requiring a rebalancing of many different blood factors.

Dario Valenzano at the Max Planck Institute published a stunning finding last year, linking intestinal flora to rejuvenation in fish. Translated to humans, a 60-year-old might be able to add a dozen years to his life with rectal transplants of feces from his 30-year-old son or daughter. I don’t know of anyone who is trying this yet, but that’s a simple, cheap procedure. You don’t need a lot of money or even a doctor. Combine it with the Horvath clock, and see if it is working.

Of course, I’m a fan of what Nir Barzilai is doing with human trials of metformin. I’d like to see someone do the same with rapamycin. The Russian labs of Anisimov and Skulachev are doing remarkable work, but without proper controls or replication. I’d like to see some Western labs pick up on their technologies. Elissa Epel, Barry Sears, and P.D. Mangan are among many people getting the word out about pro-longevity lifestyles that people can adopt right now.

In the debate over telomerase and telomeres, you’ve previously seemed to side with the more optimistic thinkers like Michael Fossel and Bill Andrews. Aubrey de Grey, another prominent researcher, has downplayed the potential for telomerase due to fears about increasing cancer, and more generally because de Grey’s approach is about simply cleaning up the detritus of the various aging processes rather than stopping the aging processes. Are you shifting over more to the de Grey camp now that your optimism about telomerase therapy is fading?

I’m less enthusiastic than I was about the potential of telomerase activators (which boost telomerase and thus telomere length). I’m not afraid of cancer, but the very recent results associating telomerase with an acceleration of the Horvath aging clock are a big warning sign for me.

Fossel has stated in his book The Telomerase Revolution that we should have affordable (about $100) IV drip treatments for telomerase therapy that rejuvenate the whole body by 2025 or so. Is this wildly optimistic, or is Fossel onto something that most others just aren’t recognizing yet? He’s an M.D./Ph.D. with over thirty years of aging research behind him, so he’s hard to dismiss, but this kind of statement may seem over the top to many.

I like Michael and have enormous respect for him. He saw the potential for telomerase technology more than 20 years ago, when it wasn’t on anyone else’s radar, except Michael West’s and maybe Bill Andrews’. Now, we have so much more data, and I believe the data is telling us that the potential life extension from telomerase therapy is limited to a few years–maybe five at most. I’m glad that Fossel and Andrews are doing what they’re doing, and we should know before long if there are dramatic benefits from telomerase therapies.

What do you think of using de Grey’s approach to clean up the detritus of aging while using things like telomerase therapy, stem cell therapy, and gene therapy to prevent future aging, combining them into a promising “big picture” approach to rejuvenation?

I’ve always said that Aubrey’s repair-based program is going to turn out to be unnecessary. The body knows how to repair itself if we can just adjust the signaling environment appropriately. We shouldn’t have to engineer all these workarounds. However, this is just my theory versus Aubrey’s theory, and time will tell how much can be done with signaling and how much needs engineered repair. (Actually, Aubrey’s view and mine have been converging from both ends in recent years. He is much more aware of the potential for signaling approaches, and I’m coming around to believing that some things will have to be repaired.)

What is your personal balance between “aging gracefully” (accepting the aging process and all that it entails) and staying abreast of all the aging science over the years as well as making original contributions in this area, as you have?

I’m no believer in “aging gracefully.”  I’m much more in the camp of “Do not go gentle into that good night–rage, rage against the dying of the light!” (Dylan Thomas). Or Edna St. Vincent Millay: “Down, down into the darkness of the grave they go… I know. But I do not approve. And I am not resigned.”

At age 68, I’m starting a new career, learning new things not just in the sense of adding to my knowledge; I’m revising old theories as new evidence comes in and overturning the way I see the world.

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About the author

Tam Hunt

Tam Hunt is a lawyer and writer with a background in biology. Among other things, he runs a blog on Medium.com called Forever Young? devoted to the science, technology, and philosophy of combating aging.
  1. April 17, 2018

    Dream: Once they find out a cure is possible (Aging), BILLIONS will be poured into [ Biomedical Gerontology ]

  2. April 17, 2018

    Fascinating interview! Love Josh Mitteldorf’s blog & book. Any consideration given to bioenergetics – specifically the notion that age-related degradation of mitochondrial electron transport chain stability can cause dysfunctional mito-nuclear signaling? The work that sealed the deal for me was Nick Lane’s wonderful “The Vital Question” where he goes into the exquisite chemistry required to keep that flow of electrons humming along – that the mitochondrial super-complexes are mere 10-14 angstroms apart and the electrons move via quantum tunneling. Perturbing that system greatly diminishes the rate of electron flow. That means if you don’t have enough NAD+ or ubiquinone because they may be used elsewhere (NAD+ is depleted by PARP’s and CD38), that can have some damaging impact on the mitochondria’s ability to complete OXPHOS cycle. Considering the eukaryotic cell generates up to a whopping 36 ATP per cycle, mismatch between ATP generation & demand may be a major trigger for age-related epigenetic signaling, right? It seems to me that a low ROS/ATP ratio will signal need for more mitogenesis – but a hugely out of whack ROS/ATP ratio could trigger senescence or apoptosis. Anyways, that’s my hypothesis!

    • tamhunt
      April 21, 2018

      I’m not familiar with this presently but I’ll look into it

  3. Ariel Feinerman
    April 18, 2018

    “The best senolytic treatment we have now is fasting.” — Josh do not follows progress and do not aware of Oisin’s genetic universal framework or SIWA immunotherapy?

  4. April 20, 2018

    SENS seems a lot less complicated to be honest. And there are things which the body does have issues with removing and repairing.

    It seems like trying to clean up the environment and tweaking gene expression may be a losing battle, although I guess it could give us significantly more time.

    Utlimately I thing we need an approach like SENS.

    • April 21, 2018

      “SENS seems a lot less complicated to be honest” it is but that does not imply it is correct (partially or fully). I think it is important to be open to other views and let the data guide us. I personally believe that aging is a mixture of programmed elements and damage and this is why for me, Hallmarks of aging resolves that nicely. We will find out in due course I am sure.

    • tamhunt
      April 21, 2018

      The problem I see with SENS is that it is widely acknowledged that the problems of aging get more and more severe as we get older. Fossel likens the situation to walking down a steeper and steeper slope. Or a faster and faster treadmill. So if we focus only on cleaning up the damage wrought by aging, it doesn’t seem to me that we’ll be able to keep pace with all the stuff that goes wrong. That’s why I asked Josh about combining proactive approaches to stop aging processes with SENS approaches for cleaning up existing and future wastes/damage. What do you think?

  5. May 12, 2018

    I think Josh is too quick to dismiss the potential of telomerase therapy because of some indications telomerase accelerates the Horvath Clock. There are many reasons this might be, and have nothing to do with real aging. Horvath’s newer PhenoAge Clock has no such issues and correlates in the right direction with leukocyte telomere length. Anyhow, we should have more data on telomerase therapy soon (fingers crossed) and we can settle this question for good.

    • tamhunt
      June 26, 2018

      Great points, Mark. Can you elaborate a little?

  6. September 22, 2019

    Ok, my comment might seem stupid, but I don’t really know anything about aging in general. I’m completely new on the subject. If Aubrey’s work might turn out to be way less efficient than others, does that mean we’ll still get to “cure” aging in less than 50-60 years? I’m 16 right now

    • September 22, 2019

      It is very hard to predict if and when this might happen. There are multiple approaches to the problem currently ongoing, which will be better at this point is anyone’s guess. I personally think there will be need for repair approaches and partial cellular reprogramming approaches. We are already seeing the first in human results of repair approaches in the form of senolytics and so far the initial results have been promising. I think the next 10 years will be very interesting and will greatly inform the direction researchers take.

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