Anti-Aging Medicine: Two Paths Diverge

…and sorry I was I could not travel both.

  • Aging is an accumulation of damage.  If we want to return the body to a more youthful state, we’re going to have to repair that damage.
  • The body never forgets how to be young.  Given the appropriate signaling environment, the body will restore itself to a youthful state.

The future of medicine is the future of anti-aging medicine.  I don’t think anyone seriously disputes this.  Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic.  We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier.  To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans.  Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present.  Pills (e.g. metformin, berberine) may offer some of the benefits of CR without the hunger, and an “exercise pill” has been proposed.

The next step is to actually reverse aging, to restore the body to a more youthful state.  Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms.  I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue.  The other school says that once the toothpaste is out of the tube, it’s not going back in.  We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.


“Everything degrades over time–it’s basic physics”

This is just wrong, but it’s so prevalent (among gerontologists and the great unwashed masses alike) that I’ll refute it yet again:  There is no physical necessity for aging.  Analogies to wearing out and to chemical corrosion are flawed and misguided.  The body may accumulate more damage than it repairs; but it may also repair more damage than it accumulates.  The choice is made by the metabolism (as programmed by evolution), not by physics.

  • The Second Law of Thermodynamics is specifically about closed systems, meaning systems that don’t interact with the outside world.  But living beings are evolved to take in order from food or sunlight and dump entropy back into the environment.  All of life is an end run around the Second Law.
  • Still, some people say the “end run” has to come to an end some time.  How can repair be “perfect”?  Well, it doesn’t have to be perfect. There is nothing perfect about a 20-year-old body, and it is the body’s metabolic choice whether to build itself ever stronger, more resilient and less vulnerable to disease, or allow it to decay, or (in between) to maintain a constant level of youthful robustness indefinitely.
  • …and indeed, some animals and many plants do go on getting stronger and larger, with lower and lower mortality risk, year after year after year.  This is called negative senescence, a fancy word for aging backwards.  Most trees do it, as well as lobsters, clams, some turtles, and possibly sharks and whales.
  • If physics demanded that living organisms always degrade then growth and development would be impossible.

Evolutionary biologists almost all appreciate this—aging is a problem for evolution, not for physics.  Though many of the symptoms of old age may look like accumulated damage, there is no necessity for the damage to accumulate; the body is making a choice to repair the damage only partially, as opposed to rebuilding better-than-new, which is perfectly possible, both physically and biologically.

More detail is in my blog post from 2014.  Here is an academic paper on the subject.

“If the body could rejuvenate itself, it would already have done so.”

This is also a common view, and harder to dispel.  I think it is just as wrong as the one above, but full disclosure compells me to admit that I’m still in a minority on this question.

Since the 1960s, Nature has become an object of reverence, especially among the secular quarter in Western culture, people who are skeptical of religious dogmas.  The myth is that evolution has worked for millions of years to perfect the individual, and that human intervention is more likely than not to trip over the law of unintended consequences.  Biochemistry is not only highly optimized, it is also highly intricate and every biochemical plays multiple roles.  

Like most myths, this one carries some truth.  A lot of Western medicine treats symptoms, not causes, and has questionable value in the long run.  Human attempts to “manage” nature have been fraught with rude surprises.  And a natural diet of vegetables and fruits is a much better starting place for healthy nutrition than is a diet of processed food.

But “natural medicine” can never reverse aging.  The problem is that we are not just evolved to be strong and fertile individual competitors, but we are also evolved to be part of a stable ecosystem.  Aging was bequeathed to us by evolution, not for our sake as individuals, but as a way to stabilize ecosystems.  Individuals need to die on a schedule that is internally determined because if we left the matter of death to the world outside, then starvation would be the principal cause of death, and starvation tends to take everyone down at the same time.  This is called “extinction”.  The population can’t afford to eat whatever is available and die only when the food runs out, because then everyone would die at once.  The population would swing wildly up and down.  Evolution has taken pains to protect our species from extinction, just as surely as she has taken pains to make us individually tough and resilient and fertile.

When it comes to aging, we can’t assume that “we tinker with evolution’s product at our peril, because evolution has already done her best to make us live as long as possible.”  In fact, the body’s repair mechanisms slow down as we get older (just as we need them most).  The immune system goes haywire, failing to attack pathogens but turning on the self (arthritis, diabetes).  Healthy nerve and muscle cells commit suicide (Loss of nerve cells is part of Alzheimer’s Disease; loss of muscle is called sarcropenia, a universal wasting disease.)  

As we get older, the balance of signals in our blood changes in some ways that are random and some that are predetermined.  All the predetermined changes are detrimental; signals in the blood raise the level of inflammation, which is the most significant root cause of all the diseases of old age.

The idea that aging was programmed into us for the sake of the ecosystem isn’t just an abstract theory; the theory was devised to explain the reality that the aging body both shuts down repair mechanisms and turns on active self-destruction, in a way that looks quite deliberate.  All the principal mechanisms of aging have been preserved over the vast stretch of evolutionary time. 


Examples of the Rebuilding Approach

Prosthetic limbs, artificial knees and hips are nothing new, but they do keep getting better.  Computer technology promises artificial limbs that can interface with existing nerves so that amputees can learn to control them.  When lenses in the eyes become clouded by cataracts, surgery to replace the lens with plastic have become routine.  Artificial eyes are now conceivable, and there are crude working models.  Mechanical hearts would be most useful, but the technology has been the subject of an intensive bioengineering program since 1969, while mortality rates remain stubbornly high.

Tissue engineers are working on techniques to grow organs on scaffolds.  Tracheas and bladders have already been implanted successfully in humans.  

Despite impressive technological advances, the challenge facing this approach is formidable.  Things that go wrong as we age include clogged arteries, inelastic skin, and weak, degraded muscles.  These parts are not easily replaced.  Brain aging presents the ultimate challenge.  No one wants a prosthetic brain.  (Maybe I’m wrong about this.)

Aubrey de Grey and his SENS Foundation have prominently championed the repair-and-replace approach to geriatric medicine.  The current research program of the SENS Foundation (from their web site) includes

      • Engineering new mitochondrial genes
      • Fighting cancer by shutting down the cancer cell’s ability to maintain telomeres
      • Convincing the body’s immune system to attack amyloid plaques
      • De-fanging or eliminating senescent cells
      • Enhancing lipofuscin clearance
      • Engineering a new thymus
      • Epimutations in single aging cells
      • Finding amyloid in the heart
      • Quantifying extracellular crosslinks
      • Rejuvenating risk/benefit analysis
      • Rejuvenating the microenvironment
      • Repopulating the Gut
      • Scaling up glucosepane research

Four of the thirteen may be regarded as signaling approaches; the rest are conceived as building understanding and a technology of control at the molecular level that SENS hopes will ultimately be the basis for engineering aging out of the human metabolism.


Examples of the Signaling Approach


A growing number of anti-aging researchers are betting on the idea that we don’t need to repair everything that goes wrong with aging because the body can repair itself, if only we can rejuvenate the signaling environment.

FOXN1 rejuvenates the thymus

The slow disappearance (“involution”) of the thymus over a lifetime has been implicated in the age-related decline of the immune system.  The rebuilding approach seeks to replace the aged thymus with tissue engineering [ref, ref]; in contrast, the signaling approach seeks to stimulate the body to regrow the thymus on its own.  Of course, this is the easier approach, if it works.  Greg Fahy has reported success with growth hormone.  Several labs have recently reported hopeful signs that a signal protein called FOXN1 might be a specific trigger for regrowth of the thymus [ref, ref].



Last week, a press release from David Schubert’s group in the Salk Laboratories in La Jolla made headlines for J147, a compound they have focused on more intently.  The world was introduced to J147 with a 2011 article in the high-profile journal PLOS One, which didn’t receive as much attention as it deserved.  There is a new article in the subsidy journal Aging that is getting more attention that it deserves.

The most notable thing about J147 is that it is a promising result from a new methodology for drug development.  Schubert’s lab began with curcumin, the active neuroprotective and anti-inflammatory component of turmeric.  Chemists synthesized and isolated hundreds of chemical cousins of curcumin, which were screened in cell cultures for neuroprotective activity at lower and lower doses.  

In the end, the molecule J147 doesn’t look much like curcumin.



Both molecules have two aromatic rings.  The curcumin molecule is mirror symmetric, which J147 is not.  And J147 contains fluorine, which no natural biomolecules do.  (Among popular drugs Prozac and Lipitor contain fluorine.)

The best ones were tested in rodents.  J147 improved memory in young mice and old.  In a mouse strain genetically engineered to be vulnerable something close to human Alzheimer’s disease, daily doses of J147 were able to delay onset of memory loss.  Even after the mice suffered memory loss, J147 was able to reverse it [ref from 2013]

The reason the new paper made more of a splash than the old was that it was framed in terms of general anti-aging benefits, rather than neuroprotection or memory improvement.  The new paper reports that mice on a lifelong regimen of J147 show generalized abatement of markers of aging as they grow older.  The work is promising, but it was all done with SAMP8 mice, genetically engineered to contract a version of Alzheimer’s disease, which usually kills them before they are a year old.  J147 has not yet been assayed for life extending potential in normal mice.  

J147 is presently available in tiny quantities for a prodigious price.


ALK5 Inhibitors

Mike and Irina Conboy working at UCBerkeley have identified ALK5 as a pro-aging signal, and report success in rejuvenating tissues and whole mice with a molecule engineered to block the ALK5 pathway.  Their recent paper may be viewed as a manifesto for the signaling approach to anti-aging medicine.  It begins:

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

This sentence is dense with meaning that is worth deconstructing.

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches,

The traditional view is that cells suffer damage with age.  Stem cells know they are old because of shorter telomeres.  They accumulate lipofuscin, and their DNA mutates over time.  Of course, aged stem cells cannot be as effective as young stem cells.  But the claim here is that the cells themselves are fine.  They are responding to signal molecules in the blood that tell them to lay down on the job.

elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus,

The bad actor is fingered and, what is more, its source is traced to the hippocampus—a region of the brain known for neuroendocrine signaling, and implicated in other time-cyclic processes.

analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

The Conboys had previously found that TGF-β signaling was responsible for inhibiting muscle growth in aged mice.

The article goes on to describe the receptor for TGF-β, one step downstream, that is responsible for the negative consequences of TGF-β signaling.  The receptor is called ALK5, and there are known molecules that can clog ALK5, blocking the signal pathway that has inhibited new growth in old bodies. “Very interestingly, both neurogenesis [new nerve cells] and myogenesis [new muscle tissue] were significantly enhanced in the aged mice treated with ALK5 inhibitor, compared to the animals receiving control buffer.”

ALK5 inhibitors are also available from lab supply houses, even more dear than J147.  But, to be fair, the molecule is more difficult to synthesize and the dosage is probably smaller.  (In fact, we have only theory to guide us for human dosages, since both these molecules have yet to be tested in humans.)


The Bottom Line

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible.  How could human engineering improve on processes that Nature has been perfecting for a billion years?  Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run.  

But a funny thing happened along the way.  There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body’s (biochemical) language in order to say, “Have at it!”  A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the “selfish gene” is in need of an overhaul.   But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing.  They are pursuing a signaling approach because  it works.


34 thoughts on “Anti-Aging Medicine: Two Paths Diverge

  1. As you know Josh, the real beginning of my scientific life (yes, I’ve had publications before and pretty popular ones too), began with the Conboys’ paper about the systemic milieu controlling aging.
    Yes the J147 story couldn’t help but get my attention – my only caution is what the Baker study (removing senescent cells from mice) showed in terms of the difference between ‘models’ of aging, and real aging. Then my guess is J147 would affect the ‘clock’ most associated with AD – so that might be inflammation leading to everything else, or actually the clock setting back (how????) so that inflammation is delayed.
    The more we see, the more we realize that aging is reversible – that functions thought gone are still there, if silent. We know they can be re-awakened by rejuvenation (and many techniques have given rise to it), so we know it’s not their loss that results in aging – it’s the deliberate ‘refusal’ to turn down the production of harmful factors (inflammatory factors, amyloidogenic proteins), and to turn up repair and maintenance activities when they’re needed.

    • I disagree with you that Glucosephane crossinlinks are a signalling problem. There is no evidence whatsoever to support the idea that an improved signalling environment will cleave Glucosephane. If the body could remove it fast enough it would, but it does not. We have crosslinks forming from an early age so the body whilst it might slow the accumulation better when younger it still builds up.

      I suspect the answer to aging lies not in other path or the other but more than likely a combination of restoring the signalling environment as proposed by Conboys as well as removing waste that the body cannot process fast enough or at all.

  2. Hi Josh

    I’ve been reading your blog for a while and just want to say thank you for all the very interesting information and thoughts.

    I’m not from a biology background (i’m a video game developer/software engineer), but I have to say after reading many evidence such as the research on rejuvenation from parabiosis, it’s very hard to dismiss your theory of programmed aging.

    Having said that, in practical I’m not sure if the two anti-aging medicine strategies are necessarily mutually-exclusive? I mean, even if our genes are programmed to slowly turn off the repair mechanisms, the accumulated damage is still the consequence, therefore fixing damage should still be possible to delay, stop or even reverse aging? (even though it may be much harder than the signaling approach) Why we can’t try both at the same time?

      • Calibration of the signalling environment may be harder than repairing the root cause of the problem. Like I said previously aging is probably a combination of loss of signalling environment combined with accumulation of waste which cannot be removed. I believe we will probably find controlling aging requires both approaches.

        SENS approach aims to restore signalling environment be tackling directly the source of the dysfunction rather than the traditional approach of trying to mess about with metabolism much further downstream.

        The Conboy approach attempts to calibrate the signalling environment much further upstream nearer the dysfunction so could prove useful in restoring homeostasis.

        I think a mixture of both approaches is likely required and TGF-beta levels is a big player in that. Glucosephane also significantly increase TGF-beta levels in tissue and the conboy work indirectly shows what would happen if that was cleaved, the stem cells resume normal function and are in fact not damaged as SENS suggests.

        Like I said the two paths or camps are not mutually exclusive and there is plenty of crossover.

  3. I wonder what regulates tgfb1.
    Also in the COnboy paper the expression of TGFb1 was much less upregulated in old tissue than it was seen on the staining. Maybe something breaks down tgfb1 in young cell normally?

  4. Another great posting, Josh!
    I interact often with the folks at SENS Research Labs, and was astounded recently to realize that they have dug in their heals in the wear-and-tear camp, using a little artful language to explain how contrary evidence still fits. In youth, I tended to jump to extremes, but today less so. My bet is that the answer is somewhere in between, with “programmed negligent suicide” being the overwhelming perp. May we live long enough to see!

    I take issue with one statement, though. “All of life is an end run around the Second Law.” It appears to be quite the contrary; life is a fulfillment of the Second Law. From ancient single cells to humans, life is a mechanism for converting complex molecules into simple ones. Objectively speaking, even our greatest skyscrapers are built first and foremost to allow us to consume more (i.e., to convert yet more complex molecules into simple ones). Giving credit where it is due, this unique and compelling interpretation of why life exists in an apparently mindless universe was first put forward by my old, lost friend, Donnel Sain.

    • Thanks, Walter. I agree that “programmed negligent suicide” is a good description for most of the mechanisms of aging we know about.

      The idea that life is a some super-efficient machine for generating entropy is currently in vogue. My co-author, Dorion Sagan has written about it. And last year there was science news from Jeremy England, a physicist at MIT who claimed to formalize the theory.

      But I must say, I just don’t see it. To me, the salient thing about life is that we living things extract free energy from the environment in order to maintain homeostasis within ourselves, and to reproduce. Of course, entropy is generated in the process—but that doesn’t distinguish life from non-life. All chemical processes generate entropy. Life generates entropy rather “inefficiently” if you think about it that way, because so much useful work and constructive chemical information is extracted in the process. A fire is a much faster, more efficient way of turning complex organic molecules into CO2 and H2O.

  5. Enough of this blind men and elephant business. Seriously. Stop it. Both you and Aubrey are trying to say that “aging” is one thing or the other, when “aging” is not even one process at all.

    Glucosepane cross-links- which screw up your collagen and give you hypertension and wrinkles- are so obviously not programmed that it’s painful to see them glossed over here.

    Also, “programmed” and “signaling environment” do not mean the same thing.

    Isn’t it obvious by this point that it’s chickens and eggs? Damage accumulation leads to poor actions by cells leads to damage accumulation leads to…

    Seriously. Again. Enough with this God damned slapfight.

    • Thanks for your concern.

      Aubrey and I have deep respect for one another, and we continue to argue about it in print and in person because we both agree that there’s a lot at stake. If aging can be reversed with hormonal signals, it will be a shortcut that cuts many years from the path to practical anti-aging medicine. But if this can’t work, then it’s a waste of resources to be supporting research in this direction.

      • Glucosepane cross-links increase TGF-beta and they are not programmed. I know people who worked on the original Yale Glucosepane work to create it in a lab and it occurs as a results of glycation in the blood. It is an example of waste accumulation which the body is unable to break down (or not fast enough by cycling the ECM).

        Signalling environment is clearly vital to stem cell mobility and cell function and keeping that environment running smoothly is the key to aging. However some things the body cannot deal with and it is those things like Glucosephane and Lipofuscin and amyloids that must be dealt with in order to restore that environment. The body knows what to do once that signalling is restored and this has been shown by the conboys etc….

        • That is just not correct. Everything in the body is programmed, although sometimes the programming is indirect. The cross-linking that you mention is a product of time and, therefore, you might claim it is not related to programmed aging, but the truth is that it is indirectly related. The tissues that are subject to such cross-links, for example, the eye lens and skin ICM, are long-lived tissues. The half-life of skin collagen, for example, is 15 years.

          The collagen in young skin has much higher levels of both collagenase based breakdown and collagen deposition/remodeling than older skin. In other words, the natural process by which collagenase (higher in young skin) destroys collagen also gets rid of cross-links. The natural process by which new collagen is manufactured and laid down is also much higher in younger skin. Once the old collagen is gone and the new laid down, the new collagen has no cross links to worry about. It will take another 15 years or so before it gets filled with nasty cross-links.

          In short, the steady decline in the intensity of both creative and destructive progress, as we age, even with regard to things like glucosephane cross-linking, is programmed aging.

          • I have to say, I agree. An AGE-breaker might be useful in the old, but the reason they persist in the body is reduced turnover of the matrix – young cells would solve this problem on their own just by the increased rate of breakdown/replacement.

  6. Yes all this kefuffle about J147 and Metformin and AKL5 all good stuff. But until we understand the underlying biology of human aging not just this receptor or that signaling molecule or this mitonchondtial dumpster will we really be able to make a difference to the lifespan of Homo Sapiens. To understand biology we have to observe biology in high resolution and in a spatio-temporal dynamic fashion. We have to elucidate the real significant biological differences between old cells and young cells and then screen for methods or molecules that recreate the youthful phenotype. After all you take two aging genomes (Mum and Dad) and combine them and create a brand new genome (Baby) all the time so it is possible to reverse aging we just haven’t figured it out yet

    • We do not need to understand everything to the Nth degree in order to do something about it or with it. We did not understand electricity for decades though we used it.

      The majority of aging can be divided into waste accumulation and signalling environment problems. We know what these are and in some cases how to deal with them.


    The good news is that editing genes is now becoming possible using gene therapy.

    Methods of gene therapy “The following forms of gene therapy can be envisioned: 1. the introduction of a gene at an undefined place in the genome, when a functional genetic factor is missing (gene insertion)
    2. selective replacement of an abnormal gene an own or foreign normal gene (gene-substitution) 3. selective reverse mutation of an abnormal gene into its original state or destruction of an abnormal gene (gene modification) 4. influencing the regulation of a specific gene With the current available methods of genetic engineering it is possible to do…[only] gene addition.”

  8. Very insightful article! I agree the body can theoretically rejuvenate itself. It would probably require a nuanced approach to actually reverse aging, and dependent on life stage. By life stage I’m defining it in 3 phases of 1) growth/ childhood, 2) maturity, and 3) preservation/ old age. In old age, for example, I’d put the focus on agents or treatments that facilitate repair processes with some signaling support. In maturity – using a more balanced approach between bodily repair and gradually revving up signaling closer to that seen in early adulthood.
    Overlaying the strategy to repair accumulated damage and restoring signaling, I like Dr. Ames’ triage theory which states “If you’ re even modestly deficient in one of the essential micronutrients, your body has to “ration” them in terms of priority. Under this scenario, the body will always direct nutrients toward short-term health and reproductive capability—and away from regulation and repair of cellular DNA and proteins that increase longevity. This means that while your body may be providing nutritional support in an effort to sustain system-wide physiological function and reproduction, at the cellular level, the process of decay and death is accelerating.”
    So far this approach has been working for me in practice to significantly slow aging (I’m in my early 40’s and look like I’m in my late 20’s). But these are good topics to add to my research to reverse aging. I’m especially interested in Josh’s article on C60 … sounds promising.

  9. Hi Josh!
    First of all congrats for your insightful, interesting and always enriching science blog. I share your idea that many age-related processes are mediated by your genes as we get older. Maybe if we could mimic the hormone signals of a young body, we would be able to rejuvenate an old one. Recently I read a study which was performed on mice (sorry, don’t have the link any more). They basically sewed two mice, an old one and a young one, to each other so that they would share their circulating blood. The old mouse’s brain rejuvenated to the same state as the young one’s. I do not know about the other bodily function though as the study’s focus was on the brain. Later they did a similar experiment using only the blood plasma of a young mouse, injecting it to the old mouse with a similar rejuvenating effect. Then, on the other hand, I think that many age- related processes can be attenuated by dowregulating mTor activity, at the same time as upregulating the FOXO transcription factors by inhibiting IGF-1 signalling. In fact metformin, curcumin, astaxanthin and many anti-aging drugs act upon mTor inhibtion. CR too upregulates FOXO transcription factors and inhibits mTor activity. All those drugs mimic in certain way CR. By upregulating the FOXOs and inhibiting mTor, the body is also able to reduce inflammation and increases autophagy which is also important in order to maintain a healthy body.

  10. Further to Mike Powell’s comments: “Erasing the past. Studer’s lab routinely takes patients’ skin biopsies, reprograms the cells into iPSCs, and then differentiates these into a cell type of interest. They noted that it is possible to ascertain the age of the original skin cells—whether from a 5-year-old or 99-year-old patient—but that after going through reprogramming, the iPSC-derived, now-differentiated cells had lost the memory of their age. “This is amazing and means that aspects of aging appear to be reversible.” But because the lab wanted to study cell types from patients with degenerative diseases, it was important to establish a way to put back the age information into the reprogrammed cells. In 2013, Justine Miller, then a graduate student in the lab, added a gene responsible for Hutchinson-Gilford progeria syndrome, a rare premature-aging disorder, and showed that the technique could age the differentiated cells that had undergone reprogramming. “We think about recipes of how to make a cell type, but now we can also think about programming an age into a cell,” says Studer. “It’s fascinating how to potentially manipulate this, to speed up or slow time, and potentially prevent age-related diseases.” from

    • W O W
      I am glad I am taking time to read through all the comments – I think this is one of the most important findings ever. I would really love to know more about how they determine that that iPS cells have their age reset – does this mean that methylation state and telomeric length are also restored?

      This could mean that a powerful age-reversing strategy could be available RIGHT NOW via stem cell therapy using iPSC (though prohibitively expensive). Think about it- this hits 4 of the main targets of anti-aging – DNA methylation state, telomere length, senescent cells, and signals in the blood.
      1) Studies have already shown stem cell therapy has a senolytic effect – triggering removal of senescent cells. This should remove some bad actors, lower inflammation, and help improve blood plasma profile.
      2) New cells being produced by the heterochronic stem cells would be younger – having longer telomeres and younger methylation state, continually moving the average cell age younger as cells turn over.

  11. Glucosephane crosslinks also create significant amounts of TGF-b and contribute to the loss of signaling environment.

    Loss of signaling environment is the largely a consequence of the rising TGF-β/pSmad3, when that signalling environment is improved ala conboys we see cells improve and return to function. The signalling changes the “program” the cell runs on in a sense but that does not imply aging is programmed only that cells follow programs.

    What is the root cause of this rising TGF-β/pSmad3 in the hippocampus? Is it glycation jamming up the system and boosting TGF-β/pSmad3 production?

  12. Question is, if a supplement like L-carnosine (which has been shown to inhibit the formation of AGE) will have a cascade effect on the formation of TGF-b and thereby to some extent preserve the signalling environment?

  13. Yes it may well slow the accumulation rate much the same as Metformin does by acting as a sacrificial agent in the bloodstream. So by that measure if it slows down the rate of tissue glycation then it would also slow down TGF-b increasing all the stem cell decline/loss of signalling that brings.

    Advanced glycation end products are not the full story but they seem to be a very large piece of the aging puzzle given how much dysfunction they cause.

  14. “… there is no necessity for the damage to accumulate; the body is making a choice to repair the damage only partially, as opposed to rebuilding better-than-new, which is perfectly possible, both physically and biologically.”
    – Repairing or rebuilding better than new implies that cell is intelligent enough to always recognize the damage. How? When template strand contains a mutation which thus becomes invisible for proofreading machinery, what will prompt it to replace a wrong nucleotide? When promoter is hypo- or hyper-methylated, what will notify the cell that this particular setting is incorrect? I think that some of your statements are not entirely correct from biological standpoint.

    • Somatic mutations are inevitable, it’s true, but they have nothing to do with aging. This was demonstrated in a study by Cal Harley, back in the late 1980s if my memory serves me. The connection to aging is an appealing idea that keeps coming up, but there is no experimental evidence for it.

    What the Future Holds for J147 (1146963-51-0)

    There is still a long road before J147 (1146963-51-0) will be available to treat most Alzheimer’s patients. First the drug must complete the rigorous clinical trial phase. Once the clinical trials have been peer reviewed, the process for FDA approval will begin.

    Researchers are mindful of the urgent need for a meaningful treatment for Alzheimer’s disease, but they are also committed to not rushing the science. So far, all of the results for J147 are extremely positive and no other Alzheimer’s drug has ever looked this good this far into the process.

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