Pulsed Yamanaka Factors Set Back Epigenic Age

(without going all the way back to the womb, or causing cancer)

In a column last month, I posed the question whether the methylation clocks of Horvath are drivers of aging or responses to aging. If we intervene so as to set back the clock, are we signaling the body to be younger, or are we shutting down the repair mechanisms that the body has engaged in response to the damage of aging? 

There’s a preprint from David Sinclair’s Harvard laboratory, posted on BioRxiv but not yet published, with very encouraging news for those of us who think that resetting the epigenetic (methylation) clock is a path to anti-aging. They suggest that 3 of the 4 Yamanaka factors, administered in short pulses, can set back the Horvath methylation clock without turning functioning tissues back into stem cells. The same study offers evidence to support the hypothesis that the epigenetic clock is a lethal driver of aging, rather than an adaptive response to damage.

Cellular reprogramming slows aging in mice

Sinclair opens the paper with an un-footnoted statement that aging consists in accumulated damage, as if this is uncontested and incontrovertible. He refers to the straight-line methylation changes that happen predictably and consistently with age as “epigenetic drift”, as if these changes were random. He believes that they are ‘loss of information” when these changes show every sign of being predictable and directed.

In the standard evolutionary paradigm, the mouse is evolved to live as long as possible, all other things being equal. (To be explicit: I don’t believe this; I think the mouse is evolved for a lifespan optimized to its ecology, not longer or shorter.) If you believe this standard paradigm, then why doesn’t the old mouse reset its epigenetic clock without our having to do it for him? In Sinclair’s account, the mouse has lost information, and can’t do it. But the Yamanaka factors are all in the mouse genome, and if that is all the information the mouse needs, we have to ask why the mouse needs us to send the signals.

We wondered whether mammalian cells might retain a faithful copy of epigenetic information from earlier in life, analogous to Shannon’s “observer” system in Information Theory, essentially a back-up copy of the original signal to allow for its reconstitution at the receiving end if information is lost or noise is introduced during transmission17.

It’s cute that Sinclair invokes Claude Shannon’s foundational theory from the 1930s on transmission errors and signal correction. But is it relevant? The reason that Sinclair and many others assume the information (how to be a young mouse) is lost is that they believe that evolution has motivated the mouse to stay young and keep making babies if only it could. If the information isn’t lost, doesn’t that defeat the very premise of Sinclair’s “lost information” theory of aging?

The point is that Sinclair is a superb experimentalist. He is also realistic enough to accept the overwhelming evidence that aging is an epigenetic program, and that the best way to influence it is to reset our epigenetics. But he is still mired in the old theory that denies it is possible for an aging program to evolve, so his efforts to frame his work in the context of “lost information” and “random drift” are strained to say the least.

Now that I’ve got that off my chest, let’s get on to the substance of this new finding, and the carefully-designed experiments that support these findings. He and co-authors demonstrate that mice treated with OSK (the first 3 out of the 4 Yamanaka factors OSKM) have restored capacity to regenerate damaged nerve cells, a capacity which is normally lost early in life. They go on to show that OSK isn’t directly responsible for regenerative capacity. And they demonstrate that resetting the methylation pattern on the mouse DNA is necessary for the restoration.

Specifically, they engineer mice with a cellular switch that can turn on OSK in response to a applied antibiotics. They flip the switch in the eyes only, then crush the optic nerve to see if it grows back. Normally, a mouse is able to regenerate nerves only while it is in early stages of development.

Yes, the nerves grow back if the eyes are pre-treated with pulsed OSK. And the benefit is lost in the absence of methyl transferase enzymes. This last result was part of the experiment in order to demonstrate that the mechanism for restoration involves re-programming methylation patterns on the chromosomes.

rDNA methylation age of 12-month-old RGCs FACS isolated from retinas infected for 4 weeks with -OSK or +OSK AAV together with short-hairpin DNAs with a scrambled sequence (sh-Scr) or targeted to Tet1 or Tet2 (sh-Tet1/sh-Tet2).

Questions not addressed yet

I’m inclined to interpret this article as much for what it doesn’t report as for what it does.

In the main experiment, OSK was induced just in the eyes, so it was just the eyes that were rejuvenated. But they also report a “safety” test done, in which OSK was induced in the whole body at a low level for an entire year without toxic effects. Of course, it’s nice to know that the low-dose OSK was not toxic and that cancer risk did not increase. But did the mice benefit from the whole-body treatment? Did they show any signs of rejuvenation, or of enhanced stem cell function?

There is a Horvath methylation clock for mice. Did the mice get younger according to the Horvath clock? The authors report that damaging the retinal nerve made the nerve cells older according to the methylation clock, and that the application of OSK brought the cells back. But I don’t see anywhere in the paper a measurement of the eye’s methylation age before and after the OSK treatment, independent of injury. For that matter, there is no discussion of the methylation age of the mice treated with whole-body OSK for a year. These omissions are curious. Are they suspicious? Have they tried and failed to set back the methylation clock, and they don’t want to report it? Certainly it’s a question I would ask if I were reviewing this ms. Maybe we’ll know the answer when the paper is published.

Did mice live longer after treatment with OSK? Answering this one takes time, and perhaps the Sinclair lab has mice even now that are living longer, but it will be a few years before we know. Or perhaps the treatment has failed so far to extend lifespan, and Sinclair is reluctant to report a failure.

Telomeres: The Longer the Better

Mice have much longer telomeres than we do, long enough that telomeres never get critically short in a mouse lifetime. Yet, when designer mice were engineered to have even longer telomeres (hyper-long by any standard, longer than we can account for the use of them), these mice lived longer and were healthier in every way than mice with normal-long telomeres. Lab mice usually die of cancer, and these with the longer telomeres were protected from cancer, along with every other ailment that was looked at.


First, I ask your indulgence if I harp on the obvious: this result is not consistent with the prevailing theory of telomeres. In most vertebrates, telomerase is rationed so that telomeres are allowed gradually to shorten over a lifetime, and this is explained by most evolutionary biologists and geroscientists as an anti-cancer program. According to theory, in each species, telomere length has been optimized by natural selection as a compromise between longer telomeres (allowing stem cells to last longer without senescing) and shorter telomeres (which provide a firewall against cancer, a drop-dead signal when unchecked cell growth might be life-threatening). In contrast, experiments have frequently shown that longer telomeres lead to a lower cancer rate. Blasco’s new result is a clear case. We can’t explain telomere dynamics as a cancer prevention program.

(For background on what telomeres are and how they function, I refer you to my early blogs on the subject.)

But beyond this, there remain many mysteries. This study highlights the truth that we don’t understand the mechanisms. How exactly are hyper-long telomeres working on a biochemical level? What can a hyper-long telomere do that an extra-long (regular mouse) telomere can’t do?

Known mechanisms include:

  • Senescent cells. Much of the literature has focused on the importance not of average TL but on the shortest because a few cells run out of telomere and become senescent, and they poison the rest of the body. This is called SASP, for Senescent-Associated Secretory Phenotype.
  • Telomerase as an enzyme. Telomerase is best known for its ability to elongate telomeres, but there is evidence that it has other effects as well.
  • TPE – the telomoere position effect.  This is the only one that fits. Long telomeres wrap back around the end of the DNA, actually masking expression of the genes closet to the end of the chromosome.  The Blasco study raises the possibility that we’re better off when the genes near the ends of the telomeres are silenced.

In my story, genes that have legitimate uses are turned against the body in old age. But there are no pure “aging genes” because it’s hard for such genes to evolve uphill (against individual selection). Has Blasco discovered an exception? Are these genes near the end of the chromosometrue “aging genes”? Or is it an example of evolved pleiotropy [my blog; BioRxiv preprint].

From Munos-Lorente, 2019, https://www.nature.com/articles/s41467-019-12664-x/

Context

Maria Blasco’s Madrid telomere lab has been at the forefront of this field for more than a decade. The new experiment is right on the bleeding edge of biotech and genetic manipulation, where the Blasco lab has staked out territory.

I learned that you can’t make mouse egg cells with long telomeres because the body’s process of making the egg standardizes the telomere length as it wipes clean the epigenetic markers and rewrites a starting imprint. How to get around this? Blasco grew eggs just until the third cell division (8 cells), then injected embryonic stem cells that had been grown saturated with telomerase to give them the hyper-long telomeres. Yes, this tiny embryo, just 8 cells in size, was micro-injected by hand with many stem cells, cloned to be genetically identical, so they would not fight immunologically with the cells already in the embryo. The injected cells were marked with a gene for green fluorescent protein (GFP) so descendants of the long-telomere stem cells could be identified later. The article doesn’t indicate exactly how, but the original 8 cells were induced to bow out, so that 100% of the cells in the mice that grew from these embryos had the GFP marker, and presumably, they all had the hyper-long telomeres as well. Thus, the lab made “designer” mice out of cells, every one of which had telomeres that (AFAWK) were longer than nature has any use for.

The stated inspiration for the experiment was to determine whether the hyper-long telomeres led to any detrimental effects. What they found was that hyper-long telomeres were beneficial in every way. The effect seems to be related to caloric restriction, since the mice are noticeably leaner and their insulin sensitivity remains high at advanced ages when mice usually become insulin resistant. Perhaps independent of these changes, the hyper-long mice had less DNA damage with age and more efficient mitochondrial metabolism.

Telomeres are full of surprises, and this may signal a new telomere mechanism, probably epigenetic, that is undescribed previously. But if it is to be described with known biochemistry, the only candidate is TPE, the telomere position effect. Long telomeres fold back on the end of the chromosome, masking some genes that are located near the end. It is already known that unmasking those genes when telomeres become short has pro-aging effects. But the new result involves telomeres that are (presumably) longer than anything that is found in nature or in the mouse evolutionary history. It follows that the hyper-long telomeres are folding back so as to mask genes that just happen to be near (but not to near) the chromosome end. In this picture, these genes just happen to be pro-obesity, or insulin-blocking. The effect is not evolved, but just a chance occurrence. I don’t like such explanations from chance, so I’d bet on a new telomere mechanism that is yet to be characterized.

 

Related study from the Blasco Lab

Another study (last summer) from the Blasco lab looked across species for relationships between telomere dynamics and species life span. This follows on the work of Seluanov and Gorbunova a few years ago. The previous work concluded that telomere length is most closely related to the body mass but not lifespan across rodent species. The authors tried to relate this to Peto’s Paradox, which is the observation that large, long-lived animals ought to have much higher cancer rates than observed, assuming that cancer results from a random transformation event in a single cell. In the new work, Blasco finds the closest correlation between lifespan and the rate of telomere loss.

We observed that mean telomere length at birth does not correlate with species life span since many short-lived species had very long telomeres, and longlived species had very short telomeres.

In short-lived species, telomere erosion happens much more rapidly: 7,000 base pairs per year are lost in mice, compared with less than 100 in humans.

In the old story [as I have reported it], telomeres shorten over a lifetime because stem cells lose a little telomere length with each cell replication. But this huge difference in telomere attrition rates can’t be accounted for in this way. Stem cells in mice don’t replicate 100 times faster than in humans. So something else is going on. Probably, there is partial expression of telomerase in a way that is programmed under control of natural selection. Telomere shortening with age has evolved in a way that contributes to aging via TPE. But (probably, by my account) telomere shortening is not the principal means of programmed aging, because the correlation between telomere length and age is too weak. Mike Fossel continues to promote the idea that relative but not absolute telomere length is a good indicator, and indeed a driver of aging. That sounds like it accords in the abstract with the new results, but details remain elusive.

The Bottom Line

It’s clear that telomere shortening plays a role in aging, though not a dominant role. It’s clear that telomere shortening is completely under the body’s control, therefore an evolved adaptation. Beyond this, the subject seems complicated, and there is good evidence that there are mechanisms involved beyond what we know about.

At a given age, telomere length in humans does not correlate with health risks. On this basis, I have argued that various methylation clocks are far better measures of biological age, and perhaps the GrimAge clock is best.

Interview with Josh Mitteldorf

Transcript of interview 10/14/19.
IP = Ira Pastor, Health and Longevity Ambassador for IdeaXme, founder of BioQuark JJM = Josh Mitteldorf, author of Cracking the Aging Code, and the AgingMatters ScienceBlog


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 from 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. [These ideas are uber-politically incorrect at present, but in the early 20th Century, before the Third Reich, they were mainstream among British intellectuals.] 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 different life forms and their relations.

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 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-fed animals 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 repair. 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.

This one example was enough to make me question the Fisher model. Fitness is not just about getting more of your genes into the next generation. It’s also about sustainability, about community, about ecological homeostasis. This has been my major contribution to the field. I callit the Demographic Theory of Aging. The reason there is aging is so we don’t all die at once. Imagine a world in which we did not suffer aging, in which we got bigger and stronger and less likely to die with each passing year. Well, we wouldn’t live forever, of course. Something would kill us eventually. The population would grow so high that our food sources would be pushed to extinction. We would die in a famine. Or maybe our population would grow so dense and so homogeneous that conditions are ripe for an epidemic to come in and decimate the population. Aging evolved so that we die continuously over time, rather than everyone dying at once. Without aging, populations would cycle severely, with exponential rise and sudden population crashes. Ecology can’t sustain this. It’s terribly unstable. Maybe the population can recover once or twice from such a crash, but we’re pushing our luck, and one such crash will lead to extinction. Well, natural selection is highly motivated to avoid extinction–isn’t this the core of Darwin’s theory? We die individually of old age, one at a time, so that we don’t all die at once.

This was the evolutionary explanation for aging that I came up with in the late 1990s. It took a long time to get it into print. It’s very gratifying for me to see, 20 years later, that much of the medical community, the research community has embraced the idea that aging is programmed. Even some people in the evolutionary community recognize this. Aging is on purpose. It’s not something that “happens to us”. It’s internally programmed. And fitness is not just about individuals, but also about communities.

 

IP : Moving from your book to your blog, where you discuss different interventions– pharmacological, nutritional, lifestyle–can you tell us what your targets are. At the same time, you’ve created the DataBETA project, a new kind of clinical trial. You’re working with Steve Horvath’s group which developed this epigenetic clock for aging. You’re measuring combinations, and not just individual treatments. Regulators have traditionally been down on this. If you want to develop a combination treatment A, B, and C, you first have to prove that A and B and C are individually safe and effective. Only then can you put them together. Perhaps this is beginning to change. Our FDA and the PMDA in Japan are starting to recognize the potential of combined treatments. Can you talk about going beyond the pharmacological model of one treatment at a time?

JJM : I’ve been an advocate for the idea that we need to test medicines and anti-aging interventions in combinations, not just one-at-a-time. That the interactions among these treatments are just as important as the individual effects. We’re not looking for the magic bullet but maybe the “magic shotgun”. I think in terms of the Yamanaka factors. What a genius it took to find this combination of four proteins that together are able to turn a fully-differentiated cell back into a pluripotent stem cell. No one of these has that effect. No three of them together will do the job. How did he discover this synergistic combination of four factors? My hope is that anti-aging research will also discover such combinations that have synergies.

Before we get into that, I want to go back and fill in the gaps: How did I get from an evolutionary theory to an attitude toward medical research? The big message from medicine in the 20th Century is that the body has robust healing power, and if we can harness that, to turn on the latent healing, remove obstacles so the body can do what it is designed to do–that is the essence of good medicine. Restoring the body’s natural healing. That’s taken us far, and it’s the right paradigm for infectious disease, for trauma, for everything that afflicts us when we’re young. But it’s not going to work for the diseases of old age. We’ve focused on seeing how the body has been derailed and helping it get back on track. But with aging, the body is already on track–it’s on track to destroy itself. This is why natural medicine, holistic medicine if you will, will not work for the diseases of old age. Once you realize that the body is programmed for a finite lifespan, for deliberate self-destruction, it changes the picture. Inflammation is a good example. Inflammation is a protective mechanism. That’s its original purpose. But late in life, inflammation turns on the body and destroys perfectly good cells. Autoimmunity is another example. The immune system is essential for our lives, but as we get older, autoimmunity becomes a problem. Arthritis is an autoimmune disease. We’ve learned that dementia and Parkinson’s are also deeply connected to autoimmunity. Apoptosis is a third example, programmed cell death. Again, we need it. When a cell is in the wrong place at the wrong time or when it is diseased, the cell is programmed to eliminate itself. But as we get older, perfectly good cells, nerve and muscle cells are committing suicide. These are the mechanisms of programmed death that collectively constitute aging. Getting the body back on track is the medicine we’re used to. It’s natural medicine, the medicine of the 20th Century, and it works great when we’re young. But for the diseases of old age, we will need to interfere with the program. We will want to thwart the body’s self-destruction. I’m knocking on doors, shaking people and telling them that this is what we need to realize. In the anti-aging community today, there is a deep divide between those who look at aging as damage that accumulates over time despite the body’s best efforts to protect itself. Our job, then, is to assess the damage at the cellular level and come up with ways to repair these damaged cells. The other half of the community–my half–says that aging is controlled at a systemic level by signal molecules in the blood. It’s true that cells suffer damage, but they’re damaged because they’re getting signals that tell the cells to shut off their repair mechanisms. Of course, we could figure out how to repair the damage. But this may take many decades of research to figure out all the different things that need repair and how to fix them. Once we realize that all this damage is happening under the regulation of signal molecules, a shortcut suggests itself. If we can understand the signaling system well enough to intervene there, we can tell the body in its own biochemical language to repair itself. Our job is to rebalance the signal molecules at their youthful state so the body thinks it’s young and takes up these repairs is it did so well in its prime. This is the royal road to anti-aging medicine, a great shortcut.

IP : I’m a big fan of the history of regenerative biology. There’s a fascinating body of work from the 1940s-60s, when they were transplanting cells from old bodies to young, taking off a right hand and sewing it on the left. We learned that putting young cells into an older environment doesn’t usually show any benefit. But when the old cells are exposed to a young environment, they move toward being youjng again. This concept of the higher-level signals controlling things at level of whole tissues is going to be extremely important. I completely agree with you on that. Talk a little about DataBETA. What stage is it at, and how can people get involved.

JJM : DataBETA is the Database for Epigenetic Evaluation of Treatments for Aging. We have a natural experiment out there. Millions of people trying to extend their life expectancy using a variety of strategies–medications, diets, exercise, in different combinations. If this were ten years ago, we’d ask, How can we know what is working? We’ll have to wait decades for enough people to die that we can count them and know which groups are succeeding in lowering their mortality risk. All that is changed with the Horvath clock. The Horvath clock looks at gene expression, one particular mechanism of gene expression called methylation. It may not be the most important epigenetic mechanism, but is the one we have the best handle on. We know how to assess methylation, to map it quickly and cheaply. So Horvath developed a clock based on methylation patterns on DNA that change consistently with age. If you look at certain methylation markers, you can tell within a couple of years how old a person is. In some cases, the methylation clock turns out to be a better indication of how long a person is going to live than the chronological age–which was the original calibration for the methylation clock. You can make a strong case that these methylation clocks are a true measure of your body’s metabolic age, and if you succeed in setting back the methylation clock, it is a sign that you’ve actually made the body younger. If you slow the progression of the methylation markers, you’ve probably slowed down the aging process itself. This is an opportunity for a revolution in anti-aging research. At last we can know what works without having to wait decades, but maybe just a year or two to see changes in people’s epigenetic markers. The idea for DataBETA is to recruit 5,000 people with 5,000 different strategies, recruiting for great diversity. Measure methylation ages at the beginning, middle, and end of a two-year period. See which are aging faster, which are aging slower. Is there a sub-population that is aging backward, getting younger over the course of the study? Look for the people who are doing best, and then look for commonalities. What combination of strategies characterize the people who are most successful at slowing or turning back the clock? The easy part is going to be collecting data, and the hard part will be making sense of it. Maybe there will be a signal buried in the noise, and my hope is that we will be able to use statistical methods to disentangle all these interacting effects. If we can find a common theme among the people who are most successful in slowing or reversing aging, then we’ll have an idea what combination of strategies is likely to work.

IP : I don’t know how many biohackers and how many amateurs are out there trying to find what works, but it seems like an untapped population to gather data from.

JJM : News from just the last week: For several months, I’ve been looking for university partners to actually run the study. I need people with experience running a trial. I need an Institutional Review Board to make this kosher. Just last week I was up at McGill (in Montreal) and met Moshe Szyf, who was a pioneer in studying methylation markers on DNA, starting 30 years ago. He is a world-class expert in the statistics of methylation patterns. He loved my project, and he wants to take it under his wing at McGill. So I now have the partner I need to move forward. We will need another couple of months to get necessary permissions and to set up a secure online database, but I’m hoping that by the end of the year we will begin accepting people into the program.

IP : Excellent! You’ve got to have good partners and the right connections to get the job done in this increasingly connected world, and it sounds like you’re doing it.

I read your bio, and you’re involved in so many other things in the Philadelphia area where we both live. I mentioned that you teach yoga, you’re actively involved in meditation, you are an amateur musician on piano and French horn with Olney Symphony, you’re an environmentalist, you were president of the Coalition for a Tobacco-free Pennsylvania. Many other things that are extremely important in aging include our mental health, the environment around us. Talk a little about the importance of all these things in your personal anti-aging protocol.

JJM : There are so many people who know one aspect of me. They think of me as the neighborhood yoga teacher, where I’ve been teaching one class a week for 40 years. They don’t know that I’m an astrophysicist. There are people who know me from the amateur music community who have no idea of my work in evolution. I’m known in the election integrity community for using statistics to root out election theft. I’m grateful that you’ve looked up all these other parts of me. It’s a privilege to live the way I live. I don’t have a lot of money, but the thing it’s most important for me to buy with what I have is freedom to pursue the activities and ideas and the ways of giving back that mean the most to me. I live a life of service to the community where I live, service to the scientific community, service to a political community as well.

One activity you didn’t mention is that I am an editor at OpEdNews, which is a people’s forum on current affairs, debunking the lies that are routinely fed to us by the news media we trust most–the lies of the New York Times and CNN and National Public Radio. I try to call them out, and I rely on a broad knowledge of science to counter the political propaganda, not just of the Republicans but the Democrats, too. It’s a great privilege to live the way that I live, to be independent of a boss or of an institution. Sometimes people pay me for what I do, but often I’m doing it because it’s what I’m interested in, what I believe in. I would hope that we might all live this way. But I recognize that the economy is being controlled so that very few people have that option today. People have to think about paying the rent and keeping food on the table, and they have little energy for anything else. It doesn’t have to be that way.

IP : I agree with you in a major way.

JJM : The other half of what you asked, what does this have to do with aging? When you think about anti-aging interventions, you imagine a pill or a medical treatment. Or maybe you think, if I really starve myself–if I’m willing to be hungry all the time, I can live a long time. Twenty years ago, the book came out The 120-Year Diet, which was about caloric restriction in humans. We now know that this works much better in short-lived species than in long-lived humans. We can double the worm’s lifespan with CR, and the mouse might live 40% longer. But in humans, we’ll be happy with an extra 5 years–maybe 10 years if you compare the strictest caloric restriction to the obesity brought on by the Standard American Diet. We’re not gong to live 120 years just by starving ourselves? What is the most powerful thing we can do to extend our life expectancies? It’s to live in a way that’s socially connected. To have loving relationships with our families. To be engaged in our communities. To have service relationships, and to be needed. To be a leader. People who have these things in their lives can expect to live 10 to 15 extra years, compared to the depressed and the lonely who are probably the predominant majority in this country. This is the largest increment in life expectancy that we know how to control, far larger than anything you can get from pills. And it’s good news because it says that the most fulfilling way to live is also the healthiest in the long haul.

IP : That’s an extremely wonderful message, especially in 2019 when, as connected as we may all be electronically, we experience a lot of distance from one another in a human sense. Josh, one final question that I like to ask my guests: Who is the person in history you most would have liked to have met. If you could ride my hypothetical time machine and visit for awhile, who would you sit down with? An astrophysicist? An evolutionary biologist? Who would be most rewarding for you to meet?

JJM : I had a bunch of people over just last Friday night reading the Tao Te Ching of Lao Tzu. This is the bible of Daoism, and I’ve been absorbing the message of the master Lao Tzu, about whom very little is known, where he lived and even if he was one person or a composite of several. The book dates from 2500 years ago, around the time of Confucius and Socrates and Zoroaster and the Buddha. This was an amazing age when all over the world, there was a simultaneous flourishing of wisdom among communities that had no contact with each other. The one that speaks to me the best is Lao Tzu. Tao Te Ching means literally, Moral Text, and you think, What are the rules for good living? What are the 10 Commandments of Daoism? But that’s not what the book is about. It say, Yes, there’s good and there’s evil in the world, but it’s not your place to take sides. Don’t try to fight for the good to defeat the evil. There’s no need for that. The Dao of the world is taking care of that. The Tao Te Ching counsels you to become a natural person, in touch with your instincts, with the part of you that is the Dao. Then you don’t worry about what to do, don’t struggle with decisions. You don’t look back and lament, “If I had only done such and so.”  But if you’re motivated in each moment by connection with the Dao that leads you into harmony with the way the world is unfolding. How different this is from a life of trying to figure out the difference between right and wrong.

When I was growing up, I was the smartest kid to come out of my high school in a generation. I thought, “I am my brain.” I had no idea there was anything valuable in me besides the extraordinary brain I’ve been given. It’s been a lifelong lesson for me that the brain is a great servant but a poor master. If I got to meet one person from the past, it would be Lao Tzu.

IP : Josh, it’s been a great pleasure to hear your story and the way your mind works. It’s completely fascinating. You truly bring together a convergent expertise in an area that requires synergy and combinatorial thinking.

Methylation Clocks and True Biological Age

The good news is that the DataBETA project has found a home.  After several months of seeking a university partner, I am thrilled to be working with Moshe Szyf’s lab at McGill School of Medicine.  DataBETA is a broad survey of things people do to try to extend life expectancy, combined with evaluation of these strategies (and their interactions!) using the latest epigenetic clocks.  Szyf was a true pioneer of epigenetic science, back in an era when epigenetics was not yet on any of our radar screens. No one has more experience extracting information from methylation data.


DataBETA is just the kind of study that is newly possible, now that methylation clocks have come of age. Studies of anti-aging interventions had been impractical in the past, because as long as the study depends on people dying of old age, it is going to take decades and cost $ tens of millions. Using methylation clocks to evaluate biological age shortcuts that process, potentially slashing the time by a factor of 10 and the cost by a factor of 100.  But it depends critically on the assumption that the methylation clocks remain true predictors of disease and death when unnatural interventions are imposed. Is methylation an indicator, a passive marker of age? Or do changing methylation patterns cause aging?

Two types of methylation changes with age

Everyone agrees that methylation changes with age are the most accurate measure we have, by far, of a person’s chronological age—and beyond this, the GrimAge clock and PhenoAge clock are actually better indications of a person’s life expectancy and future morbidity than his chronological age.

Everyone agrees that methylation is a program under the body’s control. Epigenetic signals control gene expression, and gene expression is central to every aspect of the body’s metabolism, every stage of life history. Sure, there is a loss of focus in methylation patterns with age, sometimes called “epigenetic drift”.  But there is also clearly directed change, and it is on the directed changes that methylation clocks are based.

But there are two interpretations of what this means. (1) There is the theory that aging is fundamentally an epigenetic program. Senescence and death proceed on an evolutionarily-determined time schedule, just as growth and development unfold via epigenetic programming at an earlier stage in life. Several prominent articles were written even before the first Horvath clock proposing this ideas [ref, ref], and I have been a proponent of this view from early on [ref]. If you think this way, then methylation changes are a root cause of aging, and restoring the body to a younger epigenetic state is likely to make the body younger.

(2) The other view, based on an evolutionary paradigm of purely individual selection, denies that programmed self-destruciton is a biological possibility. Since there is a program in late-life epigenetic changes, it must be a response and not a cause of aging. Aging is damage to the body at the molecular and cellular level. In response to this threat, the body is ramping up its repair and defense mechanisms, and this accounts for consistency of the methylation clock. In this view, setting back the methylation pattern to a younger state would be counter-productive. To do so is to shut off the body’s repair mechanisms and to shorten life expectancy.

So, if you believe (1) then setting back the bodys methylation clock leads to longer life, but if you believe (2) then setting back the bodys methylation clock leads to shorter life.

I think there is good reason to support the first interpretation (1). Epigenetics is fundamentally about gene expression. If you drill down to specific changes in gene expression with age, you find that glutathione, CoQ10=ubiquinone, SOD and other antioxidant defenses are actually dialed down in late life when we need them more. You find that inflammatory cytokines like NFκB are ramped up, worsening the chronic inflammation that is our prominent enemy with age.  You find that protective hormones like pregnenolone are shut off, while damaging hormones like LH and FSH are sky high in women when, past menopause, they have no use for them. There is a method in this madness, and the method appears to be self-destruction.

Until this year, I have been very comfortable with this argument, and comfortable promoting the DataBETA study, which is founded in the premise that setting back the methylation clock is our best indicator of enhanced life expectancy. The thing that made me start to question was the story of Lu and Horvath’s GrimAge clock, which I blogged about back in March. 

The GrimAge clock is the best predictor of mortality and morbidity currently available, and it was built not directly on a purely statistical analysis of direct associations with m&m, but based on indirect associations with such things as inflammatory markers and smoking history. (This is a really interesting story, and I suggest you go back and read the March entry if you have not already. The story has been told in this way nowhere else.)

(Please be patient, I’m getting to the point.) Years of smoking leave an imprint on the body’s methylation patterns, and this imprint (but not the smoking history itself) is part of the GrimAge clock. I asked myself, How does smoking shorten life expectancy? I have always assumed that smoking damages the lungs, damages the arteries, damages the body’s chemistry. Smoking shortens lifespan not through instructions imprinted in the epigenetic program, but quite directly through damaging the body’s tissues. Therefore, the epigenetic shadow of smoker-years that contributes to the GrimAge clock is not likely to be programmed aging of type (1), but rather programmed protection, type (2).

For me, this realization marked a crisis. I have begun to worry that setting back the methylation clock does not always contribute positively to life expectancy. The canonical example is that if we erased the body’s protective response to the damage incurred by smoking, we would not expect the smoker to live longer.

The bottom line

I now believe there are two types of methylation changes with age. I remain convinced that type (1) predominates, and that setting these markers to a younger state is a healthy thing to do, and that it offers genuine rejuvenation. But there are also some type (2) changes with age—how common they are, I do not know—and we want to be careful not to set these back to a younger, less protected state. 

The methylation clocks promise a new era in medical research on aging, an era in which we can know what works without waiting decades to detect mortality differences between test and control groups. But it is only type (1) methylation changes that can be used in this way. So it is an urgent research priority to distinguish between these two types of directed changes.

This is a difficult problem, because the obvious research method would be to follow many people with many different methylation patterns for many decades—exactly the slow and costly process that the methylation clocks were going to help us avoid. My first hunch is that we might find a shortcut experimenting with cell cultures. Using CRISPR, we can induce methylation changes one-at-a-time in cell lines and then assess changes in the transcriptome, and with known metabolic chemistry, make an educated guess whether these changes are likely to be beneficial or the opposite. As stated, this probably will not work because methylation on CpGs tends to work not via individual sites but on islands that are typically ~1,000 base pairs in length. Perhaps changes in the transcriptome can be detected when we intervene to methylate or demethylate an entire CpG island.

Perhaps there is a better way. I invite suggestions from people who know more biology than I know for experimental ways to distinguish type (1) from type (2) methylation changes with age.

Scaling the Alzheimer’s Cure

This edition of Aging Matters is stolen from Rhonda Patrick’s interview of Dale Bredesen. That hour is so packed with actionable information and theoretical background that I found myself going through it slowly to understand and digest it. The result was an appreciation for the breadth of vision embodied in Bredesen’s comprehensive program to combat Alzheimer’s Disease, and also discovery of some gaps in which the story appears incoherent.

For my own health and to learn more, I’ve personally signed up for the RECODE program as a patient. After the video analysis I talk about my experience.


The RECODE program in a nutshell
from Deborah Gordon video

  1. Diet
  2. Lifestyle
  3. Hormone re-balancing
  4. Supplements
  1. Diet: Low grains, low glycemic, high fats, quasi-ketogenic, anti-inflammatory. Intermittent fasting (e.g., 13 hours overnight fast every day). Eggs are good. Cilanthro is detoxifying. Ketones are good for the brain. Medium-chain triglycerides (MCTs) are a good shortcut to ketogenesis.
  2. Lifestyle: Exercise 30-60 min each day, the more the better. Weights and interval training are particularly good. Sleep 8 hours each night. Challenge the mind with active learning and problem-solving.
  3. Hormones: Estradiol, testosterone (DHEA), Pregnenolone, Thyroid hormones, Progesterone (but not progestins)
  4. Anti-diabetic supplements: Magnesium, Chromium, Berberine, Vinegar, Cinnamon
    Nootropic supplements: Ashwagandha, Gotu kola, Curcumin, Bacopa, NR, Mg Threonate
    Lion’s Mane, ALCAR=Carnitine, Citicoline, DHA=Omega 3, PQQ,

Blood targets:

  • Homocysteine <7 (!)
  • Vit B12 >500
  • CRP <1
  • HbA1C <5.5
  • Insulin < 5
  • Vit D >50, up to 100
  • Zn/Cu >1 and Zn >100

Also from the Deborah Gordon video: The APOε4 allele is the biggest genetic risk factor for AD. It was the ancestral form of the gene, from early hominid history. In European populations, only 15% of genes are ε4, but there are tribes in Nigeria where the APOε4 gene still predominates and, paradoxically, they have low rates of AD, even lower than Nigerians who don’t have the APOε4 allele. (Maybe it’s something they ate.)

A simple blood test or 23andMe can tell you if you have the APOε4 risk factor, but many people don’t want to know. Bredesen’s program offers differential treatment for APOε4 patients, and can greatly reduce the excess risk if started early.


Notes from Rhonda Patrick’s interview with Dale Bredesen

AD is the 3rd leading cause of death in America, after cardiovascular disease and cancer, and it is rising as the population ages and as better treatments become available for the other two. 5.2 million Americans have been diagnosed with AD, and a substantial fraction remains undiagnosed.

Diagnostic markers of AD are tau tangles and amyloid-β placques in the brain. Amyloid-β is a protein byproduct that aggregates into clumps about the size of a nerve cell. Tau is another protein that clogs microtubules, preventing chemical transmissions. Curiously, most AD patients have these markers, but some people have the markers without dementia symptoms, and others have dementia without the markers.

Plaques are pink, Tau tangles black

Spinal fluid taps can be assayed for presence of Amyloid-β, and this is the most sensitive test we have for AD, with an accuracy of 90%

A-β is both a neurotoxin and a neuro-protector, in different contexts. So the theory is that A-β is produced by the brain in response to insults. A-β can neutralize toxic metals and can kill invading microbes. Some people’s brains produce A-β and it successfully protects them, while others are producing A-β though their brains are overwhelmed. One difference seems to be inflammation. Inflammation in combination with A-β creates a strong dementia risk.

Sirtuins and NFκB are mutually inhibitory. The body flips between a pro-inflammatory state (NFκB) and anti-inflammatory (sirtuins), and age almost always tips the balance toward more inflammation (NFκB).

Microglia are environmental brain cells, not neurons, but important to brain function. They are activated in two forms, called M1 and M2

There’s an ideal ratio of M1:M2 = inflammation:resolution = 2.5 

The amount of A-β in the brain comes from a balance between A-β production during glial metabolism and A-β elimination through phagocytosis. That is to say, A-β is constantly being consumed and eliminated by a class of white blood cells. A blood test by George Bernard has shown that almost everyone diagnosed with AD is not eliminating enough A-β via phagocytosis.

Maresins and resolvins are members of a group of cell signaling molecules called SPMs or “specialized pro-resolving mediators.” Many SPMs are metabolites of omega-3 fatty acids and have been proposed to be responsible for the anti-inflammatory benefits of omega-3 in the diet. Patrick says that in her own research she has found that people who are APOε4 positive benefit from fish in the diet, but not from omega-3 supplements. Bredesen speculates that this might be true generally, and that there are anti-oxidants in fish flesh that we haven’t yet catalogued.

How RECODE Works

Bredesen has identified 36 risk factors for AD, and different patients suffer from different combinations of these. The factors break down into just six categories:

Type 1 AD is primarily caused by Inflammation.

The inflammation may come from a variety of causes, for example

  • leaky gut (which also contributes to arthritis)
  • P gingivalis (a periodontal infection that can spread to the brain)
  • Borrelia burgdorferi is the Lyme bacillus
  • Mold and other fungi in the environment

Type 2 AD is atrophic

Some of the nutrients or hormones necessary for nerve growth and synaptic connection are missing. Examples include

  • Estradiol
  • Vitamin D
  • Progesterone
  • Testosterone
  • Pregnenolone
  • Thyroid hormones

In a healthy brain, there is a balance between learning and forgetting, of growing new synapses and recycling old ones. We can think of Type 1 as too much destruction of synapses, and Type 2 as failure to grow new synapses.

Type 1.5 AD is glycotoxicity=too much sugar

Diabetes has two components: depressed response to insulin (insulin resistance) and excess sugar in the blood (because the insulin signal is not being heeded). The excess blood sugar causes Type 1 symptoms, while the insulin resistance causes Type 2 symptoms. There is both too little creation of new neural connections and also too much loss of existing neural connections. Type 1.5 really means a combination of Type 1 and Type 2, and it is associated with metabolic syndrome or diabetes.

Edward Goetzl of UCSF has shown that AD is characterized by insulin resistance in brain neurons even when the rest of the body is not insulin resistant.

Sugars can bind to proteins, gumming them up, creating Advanced Glycation Endproducts, or AGEs. When this happens because of sugar levels that are too high, it’s called glycotoxicity. Hemoglobin A1c is glycated hemoglobin, and it is commonly measured blood tests to assess the extent to which glycation is a problem more generally.

Note: Symptoms for all Types 1, 1.5, and 2 are memory loss, particularly short-term memory.

If your fasting insulin is >4.5 or your A1c >5.5 or your fasting glucose >93, you have insulin resistance, which is the most common, most important, and most treatable condition leading to AD.

“Ketoflex 12/3” is a mnemonic for Bredesen’s basic diet program: (1) mild ketosis, ongoing (2) flexible vegetarian diet, treating meat as a condiment (3) 12 hours of fasting every night, beginning 3 hours before bedtime.

Vegetarian is fine. If adding meat, it should be grass-fed beef or free-range fowl. If fish, the best fish are Salmon, Mackerel, Anchovies, Sardines, Herring (mnemonic: “SMASH”) to maximize omega-3s and minimize mercury.

Beta hydroxybutyrate (BHB) When the body is fasting or deprived of carbohydrates, it switches over to ketones for fuel. BHB is one of the ketones the body burns, and it also signals the body to alter gene expression in a beneficial way.

Bredesen recommends 70% of calories from fat. This is really on the edge of an extreme keto diet, best achieved with a nut-based diet supplemented by salad oil.

% calories from fat
Walnuts 83%
Sesame Tahini 77%
Avocado 77%
Chocolate unsweetened 74%
Peanuts 72%
Almonds 72%
Sunflower seeds 72%
Egg 64%
Tofu 57%
Chicken drumstick 53%
Salmon 49%
Milk, whole 47%
Ground Beef 44%
High-fat yoghurt 31%
Kale 30%
Brown Rice 15%
Broccoli 8%
Whole Wheat 5%
Oranges 4%
Lentils 3%
Apples 0%

The chart gives you a rough idea of what Keto-flex looks like in practice.  Salads with oily dressing are a good staple, since the greens provide fiber and phytonutrients but few calories, and most of the calories are from the oil in the dressing. Nuts are a tasty protein source that keeps the fat intake high. Fruits are bad news. If you eat an apple (0% of calories from fat), you have to expiate the sin with 1½ Tablespoons of salad oil.

It takes a few weeks to switch over from a sugar-burning metabolism to a ketone-burning metabolism. If you try to do it too quickly, you end up with the “keto flu”, headaches, nausea and low energy.

MCT=Medium-chain triglycerides, such as coconut oil, are the best oils for inducing ketosis. They are good for APOε4 negative people, but with APOε4 positive they pose a long-term risk of “bad cholesterol” in the blood. APOε4 positive people should jump-start a ketogenic diet with MCTs, then switch to olive, sunflower, or walnut oil.

During fasting, the body clears out waste outside cells (glymphatic system) and digests waste within cells (autophagy). For people who are APOε4 negative, 12-14 hours fasting each day is sufficient, APOε4 positive 15-16 hours is better.

Type 3 AD is cortical/toxicity

Derives from toxic build-up, heavy metals, pesticides, environmental toxins. Type 3 tends to present with high ratio of copper to zinc in the blood (generally a bad thing) and low triglycerides (generally a good thing).

Copper and zinc compete in the body, and many factors contribute to an excess of copper in modern Western environments (copper water pipes, low stomach acidity). This is one more reason not to take PPIs for common gastric distress or GERD*.

* PPIs include Prilosec and Nexium. Never take PPIs. If you must take PPIs, get off them after a few weeks.  This advice is from Mitteldorf, not from Bredesen.

Zinc is a component of many enzymes and hormones in the body, and contributes to neurogenesis and to a healthy immune system. Low zinc is also a risk factor for type 2 diabetes. High copper:zinc ratio increases inflammation. There are many good reasons to keep your zinc levels high, from male sexual function to enhanced immune response.

Note: Presenting symptoms for Type 3 are more often problems with disorientation, calculations, visual perception, reasoning and word-finding. Type 3 is more common in younger patients, in females, and in people without the APOε4 allele.

Look up more information about Type 3 under Posterior Cortical Atrophy (PCA).

Damp or water-damaged buildings can lead to toxic mold exposure. Aflatoxin is common in our diet.  It comes from grains or nuts that have been improperly stored, and especially from peanuts. Different people can have very different sensititivies to aflatoxin.

Mold contributes to both inflammation and toxicity. You can test your home for mold spores, or test your urine for mold toxins in the body.

Type 4 AD is vascular

The causes and risk factors are the same as for cardiovascular disease, but arterial blockage can affect the brain as well as the heart.  Multiple small strokes lead to loss of function in specific brain areas, inducing idiopathic forms of dementia.

Type 5 AD Traumatic

The same kinds of cognitive symptoms can derive from trauma to the brain, most often from a car accident or sports injury.

 

From the Discussion between Patrick and Bredesen

Herpes virus is a risk factor for AD, possibly because of its inflammatory effect.

Saunas are protective against AD. This is because of heat shock protein, but also because sweating helps the body to eliminate heavy metals. Wash immediately after sweating with a non-oily soap to assure that the toxins are not re-absorbed.

Homocysteine is a risk factor for faster brain atrophy and worsening cognitive decline. The old standard was <13, but Bredesen likes to see <7. How to lower your homocysteine? Eat raw vegetables, take folate supplements = vitamin B9. Caffeine, metformin, and niacin=vitamin B3 can all raise homocysteine levels. The MTHFR gene variant increases homocysteine levels. The amino acid methionine tends to raise homocysteine, but (the chemical relationship) there is no evidence that supplementing with SAMe increases homocysteine.  Betaine is a supplement that decreases homocysteine directly.  (Betaine also increases stomach acid, so it’s appropriate for some stomachs and not others.)

 

RECODE in My Experience

For a new drug or a specific diagnostic test, translation from the laboratory to the field is straightforward. What Bredesen has is something else.  It is a program of diagnostics, leading (through expert analysis and personal counseling) to an individualized program tailored to the patient. Though in principle it should be scalable, it’s a system that resists mass production. This year, Bredesen has partnered with Apollo Health to train a diaspora of specialized doctors, and begin to offer his program for Alzheimer’s nationwide. The program is called RECODE, for REversal of COgnitive DEcline.

Last fall, I enrolled in the RECODE program to learn more about it, and to help formulate an Alzheimer’s prevention program for myself (age then=69). I was frustrated by the unresponsiveness of the Apollo team. They seemed well-intentioned, but overwhelmed by expansion that was faster than they could keep up with. This summer, I tried again, and I also enrolled Ben (85), a relative who has recently moved with his wife to a Continuing Care facility because of early stage AD.

I found that the dysfunctional system had become functional, and that there is now a network of doctors trained in RECODE, including several near my home in Philadelphia. My personal experience has been good. Dr Reina Marino, who worked with me, was attentive and knowledgable and patient with the technical details that I imagine I was the only patient to ask about. In the months that she has been practicing RECODE, she has already seen some patients significantly improved, though no dramatic recoveries to report yet. She hinted that some patients didn’t follow through with the multi-faceted protocols for changes in life syle, diet, and environment. Indeed, I was disappointed to learn that Ben decided that his memory was “not that bad”, and he couldn’t be bothered with the program. On the other end, Dr Marino has been too busy to follow through with me.  My sample of one may or may not indicate that individualized medicine is time-consuming and expensive. On the subject of “expensive”, Medicare won’t pay for RECODE treatment, and my Medicare Advantage plan only covers a small part of the cost.

The RECODE web site for patients is not as friendly as it ought to be. I’m a computer professional, and I still had to get a RECODE staff person on the phone to tell me what needed to be filled out before I could download my test results and find a practitioner. The interface should be re-designed as soon as is practical to be navigated easily by older people who may be uncomfortable with computer systems.

Two more causes for concern

Ben scored 11 out of 30 on the standard MOCA paper-and-pencil test for cognitive impairment. That’s low even for an Alzheimer’s patient (though, to speak with him, one might have the impression that he was functioning at a high level). I was surprised to see that Ben’s blood test scores were better than mine in most areas. Comparing our two test results, it was not at all obvious why Ben should be impaired while I am not. If these tests are designed to pinpoint an individual cause for individual symptoms, then it seemed to me that they did not distinguish well between Ben’s condition and mine.

Link to my personal RECODE report

The initial report scores patients in five areas:

  • Toxicity–mercury, lead, arsenic, mold, pesticides, toxins that build up in the body
  • Glycotoxicity–accumulated damage from too much sugar in the blood
  • Trophic loss–micronutrients and minerals insufficient in the bloodstream
  • Inflammation–from leaky gut or chornic disease burden or autoimmunity or just aging
  • Vasculature–stiff or clogged arteries depriving the brain of sufficient oxygen

In four of these areas, Ben’s score was better than mine (meaning lower risk); only in glycotoxicity did I do a bit better than Ben. The risks are individually ranked for each patient, and both Ben and I were found to be at highest risk for toxicity, associated with Type 3 AD. But Ben’s toxicity was well below my own.

“This is not a one-size-fits-all program. Everyone’s version of RECODE is personalized, based on their test results.”

This has been a hallmark of the Bredesen protocol from the beginning, based on the premise that AD has very different causes in different individuals. It is, of course, the most difficult thing to achieve while the program is moving from the laboratory into the health care system. Differential diagnosis depends on, first, a computer algorithm, and then, the human intelligence of a doctor or other practitioner who has been trained by the RECODE core team.

Despite our very different profiles and different diagnoses (Type 3 for me, Type 1.5 for Ben), the first three steps in our computer-generated recommendations were identical. The section labeled “Your Suggested Plan” was identical for Ben and myself. The greatest risk factor identified for both of us was toxicity, yet the #1 recommendation for both of us was the keto-flex diet. This is congruent with the paradigm promoted by Mayo Clinic and elsewhere that AD is a kind of “type 3 diabetes”. Bredesen endorses this as one piece of a more complex story, so I had hoped for a more nuanced prescription from RECODE.

Reducing homocysteine was the #2 recommendation for both Ben and myself. The medical establishment recommends keeping homocysteine levels under 15, but Bredesen wants us to cut that in half. I have read the section on homocysteine from Bredesen’s book, and it is not clear whether homocysteine is important because of its direct neurotoxicity or because it is a marker of inflammation. After my RECODE interview, I left the Marcus Institute for Integrative Health with a bottle of a supplement formula designed to lower my homocysteine levels by direct and indirect action. Principal ingredients are B vitamins, N-Acetyl Cysteine (NAC) and (this one was new to me) betaine-HCl=trimethyl glycine (TMG). TMG reacts directly with homocysteine, pulling it out of the bloodstream. Are we fooling ourselves if we pull homocysteine out of the blood without reducing inflammation? David Quig says that betaine works great in the liver, but it doesn’t affect homocysteine levels on the other side of the blood-brain barrier. A better alternative for the brain is 5-methyl tetrahydrofolate, a fancier folate supplement than the common and cheap synthetic folic acid. (Note also that folic acid is toxic to people with the MTHFR allele.)

The bottom line

Last year, Bredesen published an account of replicated success in 100 patients that was, if anything, more impressive than the original. Under his close supervision, the Bredesen lab is able to reverse AD with a rate of success well beyond any treatments in the past. The Bredesen system depends on individualized diagnosis and individualized treatment plans, so scaling his methodology for wide application presents daunting challenges.

1st Age Reversal Results—Is it HGH or Something Else?

Yesterday, the TRIIM study was described in science news headlines around the world, though, through a glitch, the original research paper is not yet on the Aging Cell web site. (You saw it first here.) I refer you to the writeup in Nature’s News section for a full summary of the paper, and in this column I will add my personal framing, and what I know about the study from private connection to its authors and one of the subjects. The big news is setback of the epigenetic clock, by several methylation measures. Instead of getting a year older during the trial, nine subjects got a year younger, on average, based on the version of the Horvath methylation clock that best predicts lifespan. The study had been originally designed to regrow the thymus. (Loss of thymus function has been linked to the collapse of the immune system that occurs typically before age 70.)  Imaging showed that the functional part of the thymus expanded over the course of the trial, and blood tests confirmed improved immune function. The treatment included 

  • human growth hormone (HGH)
  • Metformin
  • Vitamin D
  • Zinc
  • DHEA

It is my belief that the age of our bodies is controlled by several biological clocks. (Greg Fahy, who conceived and conducted the TRIIM study, shares this perspective.) Candidates for clocks include 

  1. Thymic involution
  2. Methylation profile
  3. Timekeeper in the hypothalamus
  4. Telomere length
  5. Perhaps some changing homeostatic state of signal molecules and transcription factors circulating in the blood

This story is about #1 and #2.  To be explicit, I’m saying that the body doesn’t wear out with age, but rather aging is a continuation of the timed growth and development program into a phase of late-life self-destruction. Just as growth and development are under epigenetic control. 

Thymic involution

The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink, simultaneously losing its functional tissue and filling with useless fat. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives. A healthy immune system is important for fighting infection and for eliminating cancer cells before they become tumors. Immune aging may be related to systemic aging in other ways. (Of course, aging affects the immune system, but it also seems that the immune system may be a driving force in other aspects of aging.)

The thymus shrinks and degrades throughout adult life.

Thus, a rejuvenated thymus might have generalized anti-aging benefits. I first learned this story from Greg Fahy, PhD, chief scientific officer at 21st Century Medicine. and, indeed, he was the first to think of thymic involution as an aging clock, and remains the most enthusiastic and most knowledgable expert on the relationship of the thymus to aging.  Twenty years ago, Fahy experimented on himself, and found evidence that he was able to reverse decline of his thymus with HGH=human growth hormone. Ever since, he has wanted to conduct a clinical trial to see if his N=1 result could be replicated.

Methylation aging

Already seven years ago, several of us were speculating [Johnson; Mitteldorf; Rando] that aging is controlled by an epigenetic clock. Epigenetics is gene expression, which changes from moment to moment, from tissue to tissue, and also from young age to old. There are many modes of epigentic control, but the one best studied and easiest to measure is methylation of the cytosine C’s that appear in repetitive islands (C-G-C-G-C-G-C) in our DNA. (Cytosine is the C in ATCG, the four nucleic acids that form the DNA backbone.) Also at this time, Steve Horvath published the first paper using methylation to measure age; Horvath has led in this fast-moving field ever since. I’ve written [here, here, here, and here] about aging clocks based on methylation. The most important things to know are 

  • The methylation state of a person’s DNA is the most accurate known measure of his biological age. The latest methylation clocks can predict morbidity and mortality even better than chronolotical age.
  • I am among the biologists (still a minority but growing in acceptance) that believe methylation is a prime driver of aging. In other words, changing the methylation state of the body’s cells to a more youthful profile will actually make the body younger.

The TRIIM Study

In 2015, Fahy finally had funding and regulatory approval to replicate his one-man trial in a still-tiny sample of ten men, aged 51-65. That it took so long is an indictment of everything about the way aging research is funded in this country; and not just agingall medical research is prioritized according to projected profits rather than projected health benefits. The protocol included frequent and extensive testing of many aspects of age-related health.  Treatment consisted of

  • Human growth hormone (HGH), 0.015mg/Kg body weight, adjusted individually according to metabolic response. HGH doesn’t survive digestion, so it is self-injected with a tiny needle in the belly 
  • Metformin, 500mg daily
  • Vitamin D, 3000 IU daily (5 times RDA)
  • Zinc, 50mg daily (5 times RDA)
  • DHEA, 50mg

The hypothesis was that HGH would stimulate regrowth in the thymus.  Zinc and vitamin D were added because they are known to enhance immune function.  Metformin, a standard diabetes drug, was added because HGH can cause insulin resistance, a pro-diabetic effect.  DHEA is a proto-hormone from which all sex hormones and steroid hormones can be made in the body; and blood levels of DHEA decline steadily with age. DHEA is linked to both better immune function and expression of IGF1. The TRIIM paper says that DHEA was added to help counteract any tendency toward insulin resistance, but according to Examine.com, DHEA does not affect the insulin metabolism.

DHEA levels decline with age. (figure fr Spice Williams-Crosby)

As the study was planned, the primary endpoint was to be thymus size, and so, at considerable expense, MRI images of the thymus were planned up to 5 times during the 12-month study period. Various blood tests were planned to track other metabolic changes, especially to assure that subjects were not being exposed to increased risk of cancer or diabetes. HGH is weakly linked to cancer risk and more strongly to insulin resistance.

Results

Subjects felt a kick from the daily HGH and some reported temporary weight loss and endurance improvement; but the increase in energy was associated with anxiety and insomnia for some. There was no sustained effect on youthful feeling or appearance.

MRI imaging confirmed that, though the thymus wasnt increasing in size, the functional matrix of the thymus was indeed regrowing at the expense of the fatty, atrophied portion in 8 of the 9 subjects. Several blood tests indicated better immune function.

  • C-reactive protein, a marker of inflammation, decreased.
  • The ratio of lymphocytes to moncytes is an emerging measure of resistance to cancer, and TRIIM subjects showed a decrease in monocytes.
  • Portion of the T cells that wer PD-1 positive went down. PD-1 is a means by which cancer cells shield themselves from the immune system.

This level of success might have led to a modestly encouraging publication, but fortuitously, Fahy made contact with Horvath toward the end of the study, and Horvath volunteered to analyze changes in the subjects’ methylation. (TRIIM had preserved some blood samples from each of the patients at each time point, so this could be done retrospectively.) The result demonstrated a decrease in methylation age, consistent enough to be visible in a sample of only 9 subjects. This was the first time that a treatment in humans led to a setback of the epigenetic clock.

There was no reason a priori to  imagine that HGH would affect methylation age, either directly or through its effect on the thymus. If anything, theorists (including Fahy) imagined that the thymus and DNA methylation functioned as indepdent aging clocks.

Fahy reached out to Steve Horvath, who responded with enthusiasm.  Horvath did the methylation analysis and the careful statistics that could draw significant conclusions from a marginal effect in a small sample.

Methylation testing procedure: white blood cells are run through a kit that measures methylation at 850,000 sites in the DNA. Then computer programs are used to extract an age from some small subset of a few hundred sites. Once you have done the lab work, the difficult and expensive part is over. Calculating several different methylation ages is as simple as running the appropriate software package.

  • At the start of the test, the average epigenetic age of the group was already well below average chronological age. This is presumably because the subjects tended to be highly-motivated anti-aging enthusiasts. Whatever they were doing before the TRIIM study was already working well. By the Levine Clock, they were 17 years (!) younger than their chronological age, and by the GrimAge clock they were 2 years younger.
  • A year of extra chronological age would be expected to add one year to the methylation ages, but instead all methylation clocks registered an average decrease in age.
  • The so-called Grim Age clock, new this year from the Horvath lab, is the best available measure of life expectancy. By the Grim Age clock, subjects became a year younger while their chronological age was a year older.
  • For most of the clocks, the big drop in epigenetic age came during the last three months of the trial (months 9 to 12), raising the possibility that there is a latency period, and a longer trial might produce a bigger drop in epigenetic age.
  • After the trial was over, months 12-18, there was a marginal tendency for epigenetic age to “catch up” with chronological age, a loss of the benefit during the test period. The Grim Age clock, arguably the best indicator, did not regress, but held firm at 18 months.

Summary of methylation data from the Aging Cell article. Click to enlarge.

The Bottom Line

There is no known mechanism whereby HGH is expected to affect the methylation profile. This is not to say that it does not do so, but it is just as viable to think that the combination of vitamin D and Zn is affecting methylation age.

High blood levels of vitamin D and zinc are known to be correlated with lower all-cause mortality and longer life expectancy. Metformin is being investigated in its own right as an anti-aging drug. DHEA has been promoted as an anti-aging supplement for decades, though existing studies indicate DHEA does not increase lifespan in mice. The principal effect of HGH is to increase the hormone IGF1, and DHEA also does this, far more cheaply and over-the-counter, but to a much smaller extent.

HGH is both expensive and theoretically suspect for long-term use. Elevated levels of IGF1 are known to decrease lifespan in rodents; dwarf mice and dwarf humans without IGF1 receptors live longer, healthier lives [ref].  Readers looking to make immediate changes to their personal stack based on the results of this experiment might try the four cheap and proven ingredients, leaving out the HGH for now.

The results are tantalizing, and will certainly motivate follow-up studies, despite the fact that there is no patentable element to the TRIIM protocol. There are five ingredients in the cocktail, all credible, and the interactions among the five are completely unstudied. This first TRIIM study presents good reason to believe that there are anti-aging synergies among some of these ingredients, and it should be an immediate priority to study which among the five are synergizing.



Important, though unrelated news:

Cell phone carriers the world over have plans to roll out 5G technology in the next few years. There is growing evidence that existing 4G technology increases cancer risk, and can cause acute symptoms in sensitive individuals. Lab tests indicate that higher frequency radio waves are a more serious threat. 5G operates in a frequency range ~10 times higher than 4G, and because of absorption in the environment, signals have to be stronger.

(This is not ionizing radiation that can directly break chemical bonds. The biological activity of radio waves is not well understood, but there is a theory that it acts by opening calcium gates in cell membranes, which are a primary mechanism of nerve firing, among other ubiquitous metabolic functions.)

There has been no health testing of 5G frequencies, or if the telecomm companies have performed tests, they haven’t published results. We should be demanding extensive animal and human tests before the technology goes into service.

This weekend, a series of videos about health effects of 5G has been opened at The 5G Summit.

Rejuvenation at the Cell Level

Cell biologists are within striking distance of “partial reprogramming”.  Already, technology has arrived to turn an old cell into a young cell in a Petri dish, and researchers (Turn.bio) are looking intensely for ways to safely rejuvenate cells within a living body. Is this the breakthrough that we in the human rejuvenation movement have been waiting for, or is it a sideshow? 

Partial Reprogramming

In nature, aging is part of a one-way street.  A germ cell becomes a stem cell becomes a differentiated cell, and then the differentiated cell grows old.   

In the course of nature, cells change their epigenetic state from left to right.  Nature must have a mechanism for resetting the cellular aging clock, going all the way back to the left. If this didn’t exist, then all cells would be on a one-way path to extinction.  At some point in the life cycle, nature needs to take a mature cell and turn it into a germ cell (sperm or egg). But, in the process, epigenetic programming is wiped clean. Two things happen simultaneously: memory of the cell’s functional differentiation is lost, so it becomes again a pluripotent stem cell; and the age of the cell is reset to zero.  

It never happens in nature that the cell’s epigenetic age is reset to zero, without also erasing the cell’s functional identity.  Nature has no need for this process. But for cellular rejuvenation, this is what we would like to be able to do. If all the cells in your bones became young again, you might lose the calcification and brittleness of old bones and regain the springy resilience of a 10-year-old.  But if all the cells in your bones became stem cells, your bones would lose their structural integrity and your body would collapse like a mass of jelly.

In theory, we might learn enough about hundreds of epigenetic changes that take place with age, and use CRISPR or analogous process to reset each one of them individually.  This would be cellular rejuvenation “by hand”. If we are really, really lucky, then this Herculean biochemical task might be avoided by some accidental pathway by which the cell resets these hundreds of epigenetic markers on command.  But we have no reason to expect that a mechanism exists to do this, because in the normal course of a life cycle, nature has no need for it.

Thirteen years ago, Yamanaka [2006] found that differentiated cells (specifically skin cells) could be induced to revert to stem cells by exposing them to just 4 proteins, which have come to be known by their initials as OSKM, the Yamanaka Factors.  This was akin to what nature does, resetting the cellular age and erasing the cell’s function.  Then, three years ago, a study from Juan Carlos Belmonte at the Salk Institute gave us hope that de-aging a cell might be possible without loss of its identity.  They used the same OSKM, but exposed the cells for just a few days, then turned off the exposure. They reported that the cells were made younger without erasing their function. Mice with the rejuvenated cells lived longer.  This was a proof of principle, but there were big caveats. First, they worked with progeria mice, genetically programmed to age unnaturally fast. Second, the mice were genetically prepared with OSKM grafted into their DNA, and pre-coded with a chemical switch so that OSKM could be turned on and off at will by injecting the mice with doxycycline.  For mice that are not genetically modified before birth (or for normal people), delivery of OSKM to individual cells and timing that delivery poses a substantial challenge.

Then, in a preprint posted to BioRxiv just this spring, Vittorio Sebastiano and his Stanford group took another step forward.  They added two more ingredients to the Yamanaka recipe (OSKMLN) and succeeded in rejuvenating human fibroblasts in cell culture, as reported by the methylation age of the cells.  This experiment had neither of the two limitations of the Belmonte group, and it was human cells rather than mouse — three steps forward.  But it was done in vitro only — one big step backward.

Turn.bio is a biotech startup that is seeking to develop and capitalize on the technology.  Steve Hill of the Life Extension Advocacy Foundation (LEAF) interviewed Sebastiano about his discovery and the path forward.  Hill provides more background in this article.  Over at FightAging!, Reason reviewed the subject.

Is epigenetic reprogramming a driver of aging, or a response to cellular damage?

Hill asked Sebastiano this question, and he hedged in his response:

My personal opinion is that I can’t really decide whether the epigenetic changes are the cause or the consequence. I cannot decide what theory is right in the sense that some people suggest it’s a developmental program of aging and some people say it’s a consequence of damage accumulating. What I really care about, at the end of the day, is that, regardless, epigenetic changes explain aging. The epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell. 

— Vittorio Sebastiano

The logic in this answer is incoherent.  I suspect that Sebastiano is not confused, but he knows what he has to say to keep his funding flowing, and to keep from being distracted by philosophical arguments.  There is a prejudice in the field that he has chosen to skirt, rather than confront it head-on. Look at his last sentence, “The epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell.”  He recognizes that altering the epigenetic program is going to make the cell younger, but he avoids saying that the body has arranged the epigenetics to make the cell older.

Aging as an epigenetic program

The core truth here is that alteration of gene expression is the way the body functions.  Gene expression is different from cell to cell, from tissue to tissue. The way the body changes its strategies from minute to minute and also from decade to decade–also gene expression. Epigenetics = gene expression is the heart of the way the body’s metabolism and the core of the developmental program by which we grow arms and legs and bones and muscles.  It is also the core of the aging program, but you can run afoul of funders, decision-makers, journal editors and other gatekeepers if you say so. Better not to say so.

We know the cells of nearly every tissue are epigenetically reprogrammed as we get older.  Is the purpose of this reprogramming to resist the damage, which is the primary cause of aging? (standard theory)  Or are the epigenetic changes implemented as a self-destructive program for the express purpose of weakening and then killing the body? (programmed aging theory, to which I subscribe)   

This is no abstract question for theorists–it has fundamental implications for practical anti-aging research.  If the epigenetic changes are there to resist aging as best the body knows how, then we shouldn’t be tampering with them. But if the epigenetic changes exist only to create damage and stymie the cell’s repair mechanisms, then restoring the epigenetic program of the cell to a younger state looks like a promising anti-aging strategy.

Reason on Cancer

The response at FightAging! to Sebastiano’s experiments with cellular rejuvenation starts with a presumption that this kind of intervention must raise the risk of cancer.  Where does this presumption come from? His thinking is based on general principles of evolutionary theory. Theory says that the body is trying to live as long as possible, and if the body has made the decision to permit cells to senesce, it must be from a self-interested calculation that it is better to allow certain but slow death in the guise of cellular senescence than it is to risk the possibility of near-term death from cancer.

I believe the evolutionary theory is wrong, and if so, there is no a priori reason to think that cellular rejuvenation will increase cancer risk.  In fact, we might hope that cancer risk decreases, as the body’s immune system is restored to a younger state and systemic inflammation is quelled.  (Of course, we will still want to experiment with animals and then humans to assure ourselves that the treatment does not increase cancer risk.) 

I have staked my professional career on the theory that aging is programmed self-destruction, that the body is not trying to live as long as possible, but rather is aiming for a predictable lifespan, and if we thwart that program, we won’t have hell to pay.*  

 

Clear logic of programmed aging

Aging is an epigenetic program, honed by natural selection for the sake of the community over the individual.  The one-line proof is that genes regulating aging have been preserved in the genome since we were descended from single-celled ancestors 1 billion years ago.  A longer version is in this blog five years ago, and the 300-page version is in my book.

Once you accept that aging is programmed, it follows that aging must be coordinated system-wide.  We can look for one or several clock mechanisms, and for signals that transmit the age-state of the body through (almost certainly) the blood plasma.  The quickest path to rejuvenation technology is not “repair of damage” — a daunting challenge of bioengineering — but only a modification of the signaling environment, or, perhaps, direct manipulation of the body’s aging clocks.

Cellular Rejuvenation: The Path Ahead

When the treatment matures, what will be our strategy for the body as a whole?  Is there a central clock (perhaps in the hypothalamus, a neuroendocrine region of the brain) where the treatment must be targeted, after which the rejuvenation signal will be transmitted to the body without further intervention?  Or would we have to reprogram every cell in the body?  

What about inflammation?  Presumably, systemic inflammation is controlled by signal molecules that will revert to youthful levels after reprogramming.

What about arterial plaques?  Will they be cleared up by a rejuvenated metabolism?  Same question for beta amyloid in the brain?

What about oxidative damage?  Would the body know how to pick up the ball that it dropped when we were much younger?  What about cross-linking? Accumulation of lipfuscin?

At times like these, I’m shaken awake to realize how little I really know about the aging metabolism, and the signal transduction that drives it.

————-

 

Perspective

For me, this is a case where the technology has gotten ahead of the science.  

The big picture is that from the 1950s, evolutionary biologists have handed the medical researcher a mistaken framework.  Medical researchers have done their best to ignore the theory and forge ahead with a practical program that addresses the changes that are observed to take place with aging.  This agnosticism is a lot better than sticking dogmatically to a flawed theory.

But we could do so much better — we will do so much better — when we embrace the correct theory.  A clear theoretical framework will be extremely helpful in guiding lab experiments toward the most important questions.

Here’s what I mean, specifically:  Evolutionary theory offers the clear message: the body cannot have organized programs of self-destruction.  This implies that aging is a disorganized process. It must be damage. It must be random and it must be local.  It makes sense to learn about the cellular biology of aging, and develop ways to heal the aging cell. Aging will be remediated from the bottom up.

But the theory is wrong.  In fact, aging is coordinated systemically. It is a top-down process, directed by signal molecule in the blood.  The most efficient way to remediate aging is to study the signaling mechanism, to understand it well enough that we can alter the signaling environment, telling the body that it is young.  We don’t have to repair damage in every damn cell in the body. All we have to do is to re-adjust the levels of hormones and transcription factors that circulate in the blood to youthful levels.

Once we think this way, it is obvious where the focus of our research ought to be.  

  • We need to understand how the system is coordinated.  It is not yet known whether the clock that controls aging is in a specific location, probably the hypothalamus deep in the center of the brain, or whether the clock operates as a consensus among many distributed sites (e.g., telomere lengths and methylation states in many tissues).  In this latter picture, the transcription factors that circulate in the blood and dictate epigenetic state are generated throughout the body, contributed by every cell in every tissue.
  • Even more important, we need to catalog the thousands of signal molecules in the blood, proportions of which change with age.  It is likely that some of these are more important than others, and if these few are reset to youthful proportions, the rest will follow.  How many? Is there a manageable list of signal molecules that can be re-balanced in the bloodstream, and it will reprogram all the rest? Or must we manipulate hundreds of separate hormone levels in order to turn back the aging clock?  The answer is yet unknown. A related question: How long must the blood levels of these compounds be artificially maintained before the body is reprogrammed to a youthful state, and the intervention is no longer necessary? We might imagine people lined up for a once-every-decade trip to the rejuvenation clinic with an IV drip for two days.  But if the treatment has to be sustained for months at a time, it will be prohibitively expensive, uncomfortable, and disruptive.  

Here’s an example that comes from this kind of thinking — an experiment we might start with: Take a sample of blood plasma from an artery going into the brain of a young mouse (or human), and catalog the proteins and RNAs.  Do the same with the blood plasma emerging from the brain. “Subtract” the two profiles with a computer comparison to see which elements are changed.  Any significant differences might tentatively be imputed to the hypothetical hypothalamic clock. Repeat the two measurements and the differencing with an old mouse.  The difference of the differences is a good first guess as to what molecules in the blood control aging.

Back to Cellular Rejuvenation and Partial Reprogramming

Cellular rejuvenation may turn out to be a crucial technology for us to master, or it may be something we don’t have to understand in detail, because the body does this by itself once we rebalance the signal molecules in the blood.  Or — a third possibility — it may be that cellular rejuvenation in the hypothalamus is sufficient to reset the body’s global aging clock.  We could be addressing these questions experimentally.

Money in Aging Research, Part II

Part II : A Survey of For-profit Research Centers

How much money is going into aging research? The information is not so easy to come by.  This interview estimated that companies working on medical solutions to aging have a market cap of $300 billion as of 2018.  I’m guessing this number is rather too optimistic. This Business Insider article counted $850 million in venture capital funding in 2018.  That’s million with an m–a lowball estimate, it seems.  It’s safe to say the answer lies somewhere in the vast ocean between these distant shores.

I have not found comprehensive data on startups in anti-aging medicine, so this survey is incomplete and biased according to my own familiarity with the companies and their programs.  And the more important disclaimer: I have strong ideas about what the end of aging will look like, and this has colored the view I present of each company below. If you know of companies that you think should be on this list, please make suggestions in the Comments below.

Partial List:

Mature drugs

Geron is ancient by present standards, founded in Silicon Valley in 1990 by Michael West, who was already an advocate of telomerase therapies.  They are long established, with market cap of $260 million but only 15 full-time employees. Clearly, their mission is research rather than production. Over the years, they have turned their telomerase expertise into drugs that block telomerase, useful as a cancer treatment, since most tumors cannot continue to grow without telomerase.GRN163L (Imetelstat), is a drug under development that targets telomerase.  They apparently made the decision years ago, when they sold the IP for their best telomerase promoter to Noel Patton that telomerase was too dangerous to let out of the cage.  I wonder if even now they realize that was a mistake.

Elysium Health is Len Guarente’s company selling a formula of NR and pterostilbene.  Pterostilbene is a “better resveratrol”. Interest in both resveratrol and the NADH pathway grew out of Guarente’s long-time study of sirtuins.  I believe that modest health benefits have been established from this approach, but NADH is so well studied that if there were dramatic results, we would have seen them by now.  And NR treatment is not without risks.

Telomere therapies

Sierra Sciences (Bill Andrews) is focused on small molecules that promote expression of telomerase, lengthening telomeres and preventing cell senescence.  Screening hundreds of thousands of chemicals in vitro for telomerase activity, they came up with TAM 818, which is now for sale in New Zealand as a skin cream.  In an unrelated approach, they are offering a clinical trial (in a South Pacific island where regulatory agencies permit) using gene therapy to add copies of telomerase.  My personal opinion: Several years ago, I believed that telomere shortening was an aging clock of primary importance, but then a large Danish study demonstrated that the scatter in telomere length is greater than the consistent drift toward shorter telomeres with age.  I still think elongation of the shortest telomeres is an anti-aging strategy, but no longer regard it as centrally important.

Telocyte (Michael Fossel) is experimenting with telomere elongation to prevent Alzheimer’s disease and even to restore neurological function.  Fossel understood aging and had the vision to appreciate the role of telomere erosion more than 20 years ago, and I have the highest respect for him, but from what I know, AD as a target seems to be mismatched to the biology of telomeres.  Telocyte has recently announced a strategic partnership with Maria Blasco, a Spanish researcher whose lab has produced most of the biggest milestones in telomerase therapy.

Gene therapy

Rejuvenate Bio The Harvard laboratory of George Church was early in recognizing the potential for CRISPR technology to bring gene therapy into mainstream medicine.  Rejuvenate Bio is offering a gene therapy program to dogs who are at genetic risk for mitral valve disease, a congenital heart disorder. It’s cheaper than human trials, with less liability when something goes wrong, and it’s a viable lab for gaining experience and honing technique. [Writeup at FightAging!]

Stem cell therapy

Stem cells are among the most promising technologies we have for regenerative  medicine.  I’m surprised not to find more companies doing basic research, but there are lots of companies bringing the present (hit-and-miss) state of the art to patients.  Advanced Cell Technologies, a leader in the field, is now a part of Astella Therapeutics. Apceth Biopharma delivers stem cell technologies in the health marketplace but doesn’t seem to do much research.  Pluristem Therapeutics and Brainstorm Cell claim to have active research programs.  I have found no companies focused on the potential of stem cell therapies for extending lifespan.

Clinics and personalized medicine

AHNP (Apollo) acquired MPI, which was Dale Bredesen’s vehicle for bringing his Alzheimer’s protocol to the medical public.  I give AHNP special mention because I believe that Bredesen’s program is not only the first credible treatment for bringing brains back from AD; further, I think that Bredesen’s Alzheimer’s preventative program doubles as a comprehensive program to slow aging.  With individualized programs based on a battery of diagnostic tools, it’s a new model for how to do preventive medicine. I believe the program has transformative potential, but translation to the clinic has led to growing pains at AHNP. They can’t train new staff fast enough, and they’ve fallen behind explosive demand from new patients. Their software interface is buggy and there’s a backlog of requests for personal support, but they’re aware of the problems and building capacity as fast as they can.

Leucadia Theraputics has a diagnostic and treatment model for Alzheimer’s Disease based on drainage of amyloids from the brain, and physical blockage of the drainage pathway.

L-Nutra is Valter Longo’s company, offering programmed, packaged meals that provide some of the benefits of fasting with less of the hunger and deprivation.

Data Mining

Human Longevity is mining hospital records and genomic data to look for correlations. They offer testing and counseling to customers, then base their study on their customer base.

ASDERA is Knut Wittkowski’s small but important New York think tank.  Like other math geek operationss, they are using computers to mine data for patterns that lead to new drugs.  But unlike the others, they are not relying on the black box approach of neural networks. Wittkowski is an old-school statistician, familiar with an arsenal of classical statistical tests, choosing with judgment and expertise applied to the caseat hand.  Both approaches are computationally intensive. The difference is whether computations are guided by expertise and experience or by an algorithm that directs its own search toward a human-defined goal. Think of it as Artificial Intelligence vs Human intelligence, if you like.  Supervised learning vs a purely algorithmic search. Time will tell which approach yields more leads to actual treatments. I’m rooting as usual for the underdog, the classical against the avant garde.  Neural networks may yield a prescription, but you don’t know if it’s a fragile artifact of the particular data you used or a robust new truth about biochemistry, and the computer can’t tell you what it’s thinking.  With more human participation in the process comes more understanding of where the result comes from and (at least) a guess as to what it probably means.

 Acturx is another data mining project, headed by Edouard Debonneuil.  Debonneuil’s background is in actuarial science for insurance companies, and he is mining insurance records of millions of patients.  By correlating prescription records with health outcomes, they look for unknown benefits from known drugs.

Senolytics

Everon Biosciences was founded in 2010 by Andre Gudkov, with awareness of programmed aging built into their strategy. Gudkov believes that endogenous DNA damage in somatic cells is a primary clock driving diverse aging phenotypes.  A prominent kind of DNA damage is the duplication of regions of DNA that contain no genes (retrotransposons, including LINEs and SINEs).  NRT1 is a drug in development that inhibits the enzyme that makes the copies.  Another locus of research is senescent cells as emitters of signals that drive inflammaging.   But while other companies are racing to find agents that selectively kill senescent cells (leaving normal cells undamaged), Everon has focused on the innate immune system, including neutrophils and macrophages.  Their hypothesis is that the innate immune system takes care of senescent cells when we are young, but the system has a fixed lifetime capacity, and once its limit is reached, senescent cells accumulate and the vicious cycle of increased inflammation begins.  EBS3899 is a molecule they are testing for its ability to sensitize macrophages to senescent cells, and it seems to work better in vitro than in vivo.

Unity Biotechnology works on one molecule at a time, exploring their potential to relieve arthritis or degeneration of the eye or age-related disease in lungs, liver, kidneys and the CNS.  UBX0101 is their arthritis drug, in trials.  Other drugs at earlier stages of development target senescent cells and cognitive decline.

Oisin Biotechnologies is searching senolytic drugs, joining a crowded race to minimize toxicity to normal cells while efficiently eliminating senescent cells.

Biomarkers and Age Clocks

Spring Discovery and InSilico Medicine. In order to study anti-aging interventions, we need to evaluate them, and the traditional measure — waiting for experimental subjects to die — is too slow. This is the reason the Horvath clocks are so important.  His algorithms based solely on methylation profiles are the best measures of human biological age we have so far. Spring and InSilico are both trying to improve on that, combining other measures along with methylation, and using neural network analysis — the black box of AI — to look for patterns that evade human brains. These two companies are unrelated and working on opposite coasts, but if there’s a difference between their goals or methods, I have yet to understand what it might be.  [ScienceBlog article on InSilico]

Signal Molecules in Blood Plasma

[Background in my blog from 2 years ago.]

Jesse Karmazin’s Ambrosia  was an ambitious start-up, turned to object lesson in hazards of the fast track.  The basic premise is sound — that blood factors from the young are able to set back the clock of the older animal (or person) in whom they are introduced.  But which blood factors? And how much is needed? And how many treatments would be needed before the body would set its own clock back, and start producing the youthful factors by itself?  Karmazin’s plan was to ask these questions with clinical trials funded by his subjects, people willing to pay thousands of dollars for two transfused pints of blood from a young person. This past winter, the FDA stopped him in his tracks.

Tony Wyss-Coray’s Alkahest has taken the same promising premise and followed with more care toward a promising future.  In the early 2000s, Wyss-Coray was one of the Stanford pioneers of parabiosis. Originally, Alkahest seemed to be headed in the same direction as Ambrosia, offering small quantities of young blood to wealthy clients afflicted with Alzheimer’s.  But now they’ve made some important discoveries about the active ingredients that give young blood its rejuvenating power. They are well aware that it’s all about dosage–that some plasma components need to be downregulated and some upregulated to turn old blood to young (and perhaps turn old bodies to young…).  They’ve coined the term “chronokines”, key proteins that increase or decrease with age, and they’ve identified a few of these and launched clinical trials for macular degeneration and, Parkinson’s, and dementia. I’m impressed. My only suggestion is that they should be alert to the possibility that the interaction among these chronokines might be non-linear and, perhaps, surprisingly complex.

Other approaches

Google CALICO is well funded, but their relevance to progress in the field is hard to assess.  We might guess that their research direction follows the intersts of Cynthia Kenyon and David Botstein, i.e., understanding the genetic contributors to aging in worms and yeast cells.  They are partnering with Harvard’s Broad Institute and California’s Buck Institute in basic research.  They are in it for the long haul, building biochemical knowledge from the ground up. If someone doesn’t get there first, we may be very glad for their industry in another 10 years.

Google has also invested in shorter-term drug development through Verily Life Sciences, with partnerships that include GlaxoSmithKline. Personal note: I see a danger here, in which the company that we trust to direct us to the best information sources is allied with an industry that has done so much to promote its products with disinformation about health.

Lyceum is Michael Rose’s effort to commercialize research he’s done on the genetics of aging in fruitflies.  The web site claims a systems approach, which sounds right to me, but no details are offered at this early stage.

resTORbio is developing variants of rapamycin, which is perhaps the most credible anti-aging drug commercially available.  Rapamycin is not patentable, the main reason we see more research on variants and less on rapamycin itself.

CHAI = California Healthy Aging Initiative
Game-changer on the horizon

Activists in California are gathering support for a ballot initiative to provide $12B in state funding for anti-aging research over the next 12 years.  CA is one of the states in which the people can create legislation directly with their votes; and in 2004, this process was used to appropriate $4B for stem cell research.  Promoters of CHAI are trying to build on this precedent. But they face a dilemma. Gathering signatures and educating the public is an expensive proposition. They will need a broad coalition of research interests in the field to get their measure off the ground.  But of course, these organizations will want to write the text in such a way as to direct future funding to themselves. The grass-roots activists who are energizing this initiative believe that adding incrementally to institutions that are already well-funded is less likely to generate disruptive technologies than many small grants to individuals and start-ups with idiosyncratic theories of aging.  I like the idea of supporting small people with big ideas, perhaps because I are one.  This is a science still in its exploratory phase, where we do not have a definite idea what will work, and there are competing theoretical frameworks to guide us.  Once the proof-of-concept is complete, it’s appropriate to pursue the “D” part of “R&D”, and for that, industrial-scale research is the most efficient course.

My perspective on the state of research

I believe that aging is regulated under epigenetic control, but that the biochemical language of epigenetics is complicated, and it will be a slow road indeed if we persist in studying one intervention at a time.  The time is right for open science, open communications, interdiciplinary collaboration, and the testing of treatments in sets of 2 and 3 and 4. (If we study only treatments in isolation, we miss the boat; but if we try to study 5-way and 12-way interactions, the number of combinations will overwhelm our neural networks–both silicon and wetware.)

I continue to promote DataBETA because I think that it is a methodology for exploring the landscape from a perspective of radical empiricism, and point us in new directions.  DataBETA is looking for a university partner with experience in large-scale trials and otherwise is funded and ready to launch.

Our knowledge of biochemistry comes mostly from a reductionist framework.  We understand cellular systems better than we understand organs and tissues. We understand least of all the global signaling and interactions by which the body coordinates its growth, its homeostasis and (I believe) its aging.  The primitive state of systems biology counsels an empirical approach.

Im glad to see money and talent pouring into aging research, and it’s refreshing to see how much of it goes to people without theoretical preconceptions.  But many of the engineers and computer geeks coming into aging science are experienced in a world where problems can be split into manageable parts—divide and conquer.  My guess is that aging will be refractory to this approach, and will yield in the end to a multi-pronged but holistic therapy.

I gave up on the stock market years ago, the pride of the mathematician laid low by the surprises of the real world; but if I were a gambling man, I’d bet on Bredesen/Apollo.  There’s a solid core of biochemistry under a mountain of clinical data, and sparked to life with a bit of inspired guesswork.  They are modest (or prudent) enough to claim ‘only’ to have cured Alzheimer’s, but I would be eager to see methylation tests that relate their protocol to the best aging clock we’ve got.

Money in Aging Research, Part I

Part I : The Business Culture of Science

Since 2000, there has been a 20-fold increase* in research funding for anti-aging medicine.  Wow! That’s a good thing. But let’s keep our eyes on the ball. There is danger that this welcome infusion of capital may be biasing research priorities toward those that are most likely to be profitable, and maybe even diverting the best researchers from the radical thinking that will change our understanding of biology.


Whoever discovers an effective age-reversal treatment is destined to become a multi-billionaire!

At first blush, this statement seems obvious, but that doesn’t mean it’s true.  There are many historical examples of people who gave enormous gifts to the world, but struggled in their lifetimes for recognition and even for a livelihood.  Schubert, Poe, and van Gogh are artists who died poor, while people after them reaped billions from their work. Inventors who never profited from their inventions include Johannes Gutenberg and Nikola Tesla, Jagadish Chandra Bose, and Antonio Meucci (who?).  Reginald Fessenden invented radio a generation before Marconi.  Rosalind Franklin got no credit for being the person whose diffraction data and analysis was stolen by Watson and Crick for their Nobel research on the double helix.  

More to the point, there have been great discoveries that had no commercial value, or even negative commercial value.  Linus Pauling spent the last years of his life documenting the anti-cancer action of intravenous vitamin C. To this day, vitamin C is under-utilized and under-studied precisely because it is so cheap that no one can get rich from it.  I believe that aspirin and metformin may be two of the most potent life extention drugs that we currently know about, but we can’t be sure, because they are both long out of patent, and no private company can justify the investment to study them.

Rumors abound about cancer cures and energy technologies that are being suppressed because they would derail two of the most profitable businesses in the history of capitalism.  I don’t dismiss such claims out of hand.

If there were a drug that could increase average human lifespan by 15 years (with side-effects that were wholly salutary), there would be a dozen companies tinkering with it, adding a methyl group here or a double bond there, looking for a variant that might boost lifespan by 18 or 23 years.  In fact, there is about a 15-year advantage for people who are in a loving relationship, have deep community ties, assume responsibility for leadership, make lots of money, enjoy frequent sex, and remain close to young family members; in comparison, the typical middle-aged American is lonely, alienated, struggling financially, and sub-clinically depressed, with a life expectancy 15 years shorter than it could be.  The most effective things you can do to increase your statistical life expectancy are psycho-social, but who is conducting research into optimizing the life-extending benefits of community and relationship?

Diet, exercise, saunas, and fasting are life extension strategies that are promising and under-researched because there is no clear path to mega-profits.

 

What I believe

I am convinced that the primary basis of aging is an epigenetic program.  Systems that repair and protect our cells and tissues are gradually shut down, and destructive systems including inflammation and apoptosis are ramped up at late ages. Gene expression changes, modified systemically by transcription factors that circulate in the blood.  I believe that these blood factors are the holy grail of aging research. Control over aging will come when we learn enough about the basic language of epigenetics to reprogram gene expression with our interventions.

The difficulty is that there are dozens of known epigenetic mechanisms, of which only a few have been studied in detail.  A few years ago, it was understood that modifying non-coding regions of DNA could affect the transcription of nearby genes (cis epigenetic signals), but now we know that transcription of genes far away from the modification can also be affected (trans signals).

There is yet more complexity: most hormones and regulatory molecules have secondary roles that affect transcription.  Imagine an ecosystem of signal molecules that maintains itself homeostatically, but also changes with age. Sixty years ago, we learned that the genetic code is as simple as it can logically be; every codon three base pairs on a DNA strand is uniquely transcribed to one amino acid, and a protein is built by chaining these together in order.  Today we are learning that epigenetics is about as complex as it can be. So in my paradigm, basic research in epigenetics is an essential foundation for anti-aging medicine. If we are lucky, a dozen synergizing interventions will do enough reprogramming to re-set the aging clock. Perhaps there is even a region of the brain that is a common source for the molecules that induce age-related change.  If we are unlucky, it may require re-balancing blood levels of hundreds of different substances.

I am optimistic that this can be done, but it will require collaboration on a broad scale.  The process is unlikely to end with a single patent-holder who can rake in $ billions. The secrecy and the balkanization of corporate research is slowing progress.

 

Biases in Corporate Aging Research

For the last five years, Google CALICO has been the 800-pound gorilla in the room.  Of course, we welcome their funding, the legitimacy they lend, and their collective brainpower to our field.  But they don’t play by academic rules. They are not following the open-source / free-to-the-public model that has been so successful for Google in software.  They trend secretive and are not collaborating with university experts outside their walls.

CALICO isn’t announcing its philosophy or paradigm, but we might guess from its lineage that their methodology is rooted in data mining and artificial intelligence.  Other companies that have announced publicly that they are taking this approach include Unity Biotech, InSilico Medicine and Spring Discovery.  They have in common a data-intensive approach founded in theoretical agnosticism.

Machine learning has been used successfully to create algorithms that translate languages, that drive cars, and that recognize faces.  The best thing you can say about this approach to anti-aging medicine is that it is free of the theoretical biases that have plagued aging research through the decades.  The worst thing you can say about it is that it misses a fundamental difference between organisms and machines.

Machines are designed by human logical minds, and each part is engineered to perform a single function and do it optimally.  Organisms are evolved by a process that depends on results only and involves no logical thought. We have found empirically that in biology, parts tend to serve multiple purposes.  Causes and effects are entwined in tangled feedback loops. Hormones and other proteins are likely to serve multiple, overlapping functions, some of which are metabolic and some of which are regulatory.

With a homeostatic physical system, you can tweak it to the right and it will bounce back to the left some fraction of the distance, so that the net effect is to move to the right but with less than your original amplitude.  With a homeostatic biological system, you can tweak it to the right and it may bounce back and end up further to the left. The canonical example of this is hormesis, which is so counter-intuitive that it took experimental scientists two decades to establish its legitimacy among biological theorists.

The Challenge of Using AI to Modify Aging

Machine learning algorithms work by finding optimal paths toward a well-defined goal.  The machine learning paradigm needs a clearly-defined goal as a prerequisite. In the previous triumphs of machine learning listed above, the goal was well-defined before the process was begun.

Application of machine learning to anti-aging will require a quantified measure of biological age.  This is what has held up the field in the past. We can measure lifespans in worms in a few weeks, but to measure lifespans in humans takes decades.  Aging research needs feedback that is faster than this.

Just in the last year, there are epigenetic clocks based on methylation that predict future mortality and morbidity far better than any other metabolic test.  The bottleneck now is the availability of methylation data that is correlated to anti-aging interventions. That is why I have promoted the DataBETA project to collect methylation data from a diverse set of early-adopters of anti-aging interventions.

Using theory-free computer algorithms to search for anti-aging interventions is better than going about it with the wrong theory, but it’s not as effective as starting with the right theory.

 

This is larger than aging medicine

The culture of business has had a profound impact on science in general, not just aging science.  A hundred years ago, people who pursued science were motivated by pure curiosity and intellectual ambition, because there was little reward to be had.  Today, science is a career for something approching 10 million people worldwide.  Then, science was pursued by dogged individuals.  Now, science is managed by bureaucracies.

More patents have been issued since 2000 than all of history before. It’s often said that the number of working scientists is 10 times greater than all the scientists who have ever performed research in the past, but the actual figure is more than 100 times.

Credit: Future of Life https://futureoflife.org/2015/11/05/90-of-all-the-scientists-that-ever-lived-are-alive-today/

The advance in scientific data reflects this increase, and more.  To the extent that scientific productivity can be quantified, the productivity per scientist has increased as the number of scientists has advanced exponentially.

What we don’t have is exponentially more understanding.  It’s enlightening to compare the first half of the Twentieth Century with the second.  The first half** brought us revolutions in understanding:

  • Milliken made the electron real as Rutherford pointed to the structure of the atom
  • Planck told us the world is quantized
  • Einstein taught us to think in terms of a fabric of space-time, molded by matter-energy
  • Heisenberg and Schrodinger taught us that the quantum world is fundamentally interconnected and indeterminate
  • Godel surprised us with a demonstration that there are limits to mathematical certainty
  • Hubble discovered that there are hundreds of billions of galaxies beyond our own, and that they’re flying away from us, the further the faster
  • Lewis, Born, and Pauling gave us a science of chemical bonds based in quantum physics
  • Alpher and Gamow proposed the hot Big Bang universe
  • Franklin, Crick and Watson discovered the biochemical basis of genetics

What do we have in the second half of the century to compare? I’d put three things in the same league as the above list, and they are all observations for which a theoretical framework remains elusive:

  • Penzias and Wilson stumbled on the 3 degree microwave background, promoting Big Bang cosmology to the status of a quantitative science (1965)
  • Observations of distant galaxies proved that the expansion of the universe is accelerating; dark matter and dark energy were introduced as the least radical modification to established cosmology (1997)
  • Epigenetics came into its own in the 21st century, as it was discovered that big variations in gene expression are more important for the direction of life than small variations in gene sequence.

With so many more scientists, why aen’t we seeing new and powerfully synthetic theories?  It’s just not plausible that no one as smart as Newton or Euler or Darwin or Planck is alive today.  Then, are the “easy” problems all solved, and the remaining problems in science so much harder? Certainly that’s true to some extent.  But there is a larger part of the story, and it is the canalization of scientific thought. Scientists today are paid to be efficient. There is a model of productivity borrowed from industry that is completely inappropriate to science.

We are all agreed that your theory is crazy. The question that divides us is whether it is crazy enough to have a chance of being correct.                       — Niels Bohr (to Wolfgang Pauli)

Through the culture of business, science has become conservative, which is to say dogmatic.  It is more difficult than it used to be to throw out a theory that doesn’t work. Almost everyone is working to push outward in the directions that science has already advanced, but almost no one is digging at the roots, or exploring fundamentally new directions.  Almost everyone is engaged in the safe science of incremental advance and almost no one is taking the big risks.  Tenure is granted to fewer science faculty members, and they are getting tenure at later ages.  Career uncertainty makes scientists risk-averse.

With so much at stake, science is being managed by committees and bureaucracies.  They judge on the basis of conventional wisdom and measurable results.  Business by nature is risk-averse.  But in the long run, science can only advance when we scrap the idea of predictable returns on investment and accept a very high failure rate.


Part II next week: survey of biotech companies doing research in anti-aging medicine.

———————
* 20-fold increase is my estimate, a soft number.  I’ve been unable to identify hard statistics, and of course the very definition of “anti-aging” is changing as the idea that all diseases of old age can be delayed has come into general acceptance.

** I’ve taken the license to include two discoveries from 1952 in the first half of the century.

Eat Glutathione

Every supplement has its downside.  Metformin and rapamycin are the best candidates among fully-developed products, and metformin can dissipate the benefits of exercise, while rapamycin can suppress immune response and raise insulin resistance.  NAD enhancers can affect epigenetic methylation and damage the liver.  I’ve written about the adverse effects of anti-oxidants, which are the most highly publicized treatments for aging.  But glutathione (GSH) is one anti-oxidant for which I’ve read multiple benefits, and I’ve never seen a negative word. As far as I know, the more glutathione you have, the healthier you can expect to be.  


Glutathione is akin to a miniature protein with just 3 amino acids (glutamate, cysteine, and glycine).  Our bodies manufacture glutathione regularly from the three constituent amino acids, but we make less of it when we are older, and need it more.  (In my book, this is an example of programmed aging, the body deliberately turning to self-destruction, but you don’t have to believe in programmed aging.

Glutathione

It was originally discovered as a recyclable anti-oxidant.  The most active and toxic ROS are reduced to the less toxic form, hydrogen peroxide, H2O2, and it is the job of glutathione to take care of the H2O2. The active (reduced) form is abbreviated GSH, and the ‘second-hand’ form, ready to be recharged, is GSSG.  Glutothione reductase is the enzyme that does the honors of restoring GSSG to GSH. Glutathione antioxidant activity depends on an enzyme containing the trace element selenium, which is available in a quirky variety of foods (brazil nuts, mushrooms) and in trace mineral supplements.

As the number of supplements I take has multiplied over the years, I have begun to randomize my intake, selecting from a shelf full of pills each morning based on whim as much as anything.  Through this transition, N-Acetyl Cysteine (NAC) is the one supplement that I keep handy and continue to take several times each day. NAC is a precursor and recharger of glutathione. After researching the present article, I’ve added raw glutathione to my pill shelf, for reasons you’ll read below.

Image result for n-acetyl cysteine

N-Acetyl Cysteine

Cancer is a counter-indication (?)

H2O2 is not just a toxic byproduct; it is also a signaling molecule with multiple functions, including self-destruction of the cell.  GSH can lessen the propensity for apoptosis (cell suicide). This is generally a good thing in anyone over 50, but you might think twice about it if you’re actively battling cancer.

 

Not just an ordinary anti-oxidant

In addition to anti-oxidant activity, GSH is now known to have many other roles, including DNA repair, protein synthesis, and chemical signaling.  It is not obvious that the health benefits of GSH come from its role as anti-oxidant.

In the liver and kidneys, GSH binds to a broad variety of toxins and carcinogens, helping to neutralize them while they are being eliminated.  There are several common genetic variants that affect the hormones that assist in this process, glutathione S-transferases, or GSTs. People with GSTM-1 variants are more susceptible to most cancers, asbestos, lead and mercury poisoning, etc. The herb silymarin (milk thistle) increases the presence of glutathione selectively boosts glutathioneIn the liver. Hospital ERs use NAC for emergency detox, and in my personal experience a relative’s life was recently saved and liver damage avoided with intravenous NAC.

 

Animal evidence

Supplementation with NAC has been found to increase lifespan in several animal models, most important in male mice

(Female mice in this study with or without NAC live as long as male mice with supplementation.)

 

Human evidence

To my knowledge, there is no direct evidence in humans regarding lifespan or mortality benefits of NAC or glutathione.

Glutathione is produced within each cell, and cells produce less of it in older humans.   This is the reason glutathione levels decline as we age, about 40% between ages 30 and 70.  Not only do older people have less glutathione, but levels tend to be lowest in people with chronic disease of any sort [ref].

NAC can extend the capacity of muscles to resist fatigue, both in rodents and in humans [ref].  This is probably related to recharging glutathione in and around mitochondria as they expend energy.  Glutathione is especially useful in the energy metabolism, and there is evidence it is continually pumped into mitochondria.

 

Eating glutathione?

I have believed for a long while that GSH doesn’t survive stomach acid, and it’s worthless to take it orally.  This was based on the idea that GSH is a miniature protein, and the peptide bonds that hold proteins together are efficiently broken in the stomach.  Hence the time-honored way to get more GSH is to take NAC, which is a precursor which the body uses to make GSH.

I’ve learned there are several things wrong with this story.

  • Oral GSH is more bioavailable than I had thought.
  • NAC only can lead to more glutathione if the body is flush with the other two amino acids, glutamate and glycine.  For people who take NAC, glycine commonly becomes the bottleneck, so it helps to supplement with glycine as well.
  • NAC often doesn’t increase total glutathione, but “recharges” the GSSG form back to GSH.  So NAC can increase available glutathione up to a limit, but may not be sufficient to restore youthful levels in those of us who are past our youth.  Alpha lipoic acid also helps to regenerate GSH, and so supplementing with ALA also tends to increase GSH levels.
  • Liposomal and sub-lingual versions of glutathione are supposed to be more bio-available, but there’s not much data to support this, and the data seems to show only marginal improvement in bioavailability–not enough to justify the big difference in price.

 

Raw and Liposomal

Oral glutathione (raw) 250mg/day increased levels in red blood cells by about 30% over 6 months.   Increasing to 1000mg/day didn’t do significantly better [ref].  

Liposomal delivery is the encapsulation of the payload (glutathione) in microscopic droplets of vegetable oil, which protects the glutathione through digestion, and helps it pass through cell membranes.

I could only find a shorter-term study of liposomal glutathione [ref], and results were only marginally better than with raw glutathione.

In this study, a genetic defect that impairs glutathione efficiency is associated with low HDL and high trigycerides in the blood, which are two of the most telling indicators of cardiovascular disease.  In this study, people who come into the ER with heart attacks tend to have much lower glutathione than a control population that doesn’t have heart attacks.

 

The Bottom Line

Glutathione serves multiple protective functions.  The body manufactures less of it as we age.  There is good indirect evidence from several angles that glutathione is an anti-aging supplement.  In recent years, it has become clear that it can be taken orally with good effect.

Glutathione GSH is constantly being used as an antioxidant, after which it becomes GSSG, which needs to be recycled to GSH.  NAC helps in the recycling, so more glutathione is available in its active form. The action is short-term and doesn’t increase the total amount of glutathione.  Taking glutathione orally has a long-term benefit, increasing the total amount of glutathione in blood and in cells. Liposomal glutathione may be more readily absorbed than the simple glutathione pills, but it is so much more expensive that it’s hard to justify.  There is independent evidence for NAC as an anti-aging supplement in rodents. 

Chris Masterjohn has posted a review which seems to ask all the right questions, and I have taken much of my analysis from him.