Ideology is Holding Back Aging Research

We can all agree that priorities in research for a longer, healthier human life span are far from rational.  Among the distorting influences are

  • Leap-frogging ahead to medical research in a field where the basic science is not yet fully understood.
  • Inertia from a research infrastructure that has been built on the wrong priorities.  Both people applying for grants and people evaluating those applications are stuck in an old paradigm.
  • Investment capital seeks profits in short-term, low risk projects
  • Misunderstanding of the basic nature of aging—a misunderstanding which also has capitalist roots.

Last month, an article in Nature Biotech surveyed the firms that are involved in longevity research, their resources and their strategies.


Until recently, research in aging medicine has been Balkanized into study of atherosclerosis, cancer, Alzheimer’s disease, Parkinson’s, and various smaller projects to study the diseases that affect older people.  The idea that we might be able to address all these diseases in one fell swoop if we can alter the fundamental biology of aging is not new, but it has been slow to take hold, and even now, research priorities remain lopsided.  Basic research in the biology of aging is absurdly under-funded, when compared to budgets for research on particular diseases.  The National Cancer Inst alone has a $5 billion budget, and Big Pharma is investing billions of their own in new chemotherapy agents that may or may not be marginally more effective than the old.  Meanwhile, the basic science of aging is studied on a budget estimated to be less than $1 billion.  Within that budget for the pure science of aging, I would propose that there are also substantially distorted priorities.

An article in Nature Biotech last month surveyed the private biotech investments in anti-aging technology.  We should all pause to celebrate the fact that this field finally has credibility, and is attracting substantial funding.  But, in my view, the funding is largely misdirected, and a few projects that I think would be good bets for a major leap in life extension have yet to be funded at all.

Researchers on aging are slowly pivoting from treating aging as a disease or indication to considering it a collection of age-related diseases.

This is the good news.  There is an enormous streamlining available when we turn from treating diseases separately to treating the root cause of aging.  But there is still a lot of ideology that says, “it can’t be that easy.”  This is the bad news.

[Linda] Partridge says “theoretical and practical insights have led to the conclusion that aging is likely to be a highly polygenic trait”. Contributing to aging is a protean list of processes, among them, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.

Partridge’s theory is taken from George Williams’s seminal paper of 1957.  He writes in response to Medawar’s program of isolating the root causes of aging in a small number of physiological processes:

Any such small number of primary physiological factors is a logical impossibility if the assumptions made in the present study are valid. This conclusion banishes the “fountain of youth” to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace’s “superman” have already been placed by other theoretical considerations. Such conclusions are always disappointing, but they have the desirable consequence of channeling research in directions that are likely to be fruitful.  [Williams, 1957]

But this perfectly reasonable conjecture of Williams was proven to be dead wrong in the 1990s, as single genes were discovered that offered dramatic life extension in worms.  There are now dozens of such genes known, and many of them are genes that need to be disabled, not new genes that need to be added to the genome.  In other words, there are powerful, known pro-aging mechanisms that make promising targets for pharmaceutical intervention.  Throwing a monkey wrench into an existing metabolic pathway is what Big Pharma knows best how to do (e.g., seratonin re-uptake inhibitors, beta blockers, COX2 inhibitors).  What we need is an inhibitor of pro-aging genes.

Rapamycin seems to be the first candidate in this category, and it is being appropriately explored, as reported in this space last week.

Here’s a caveat: The easiest path to life extension is through caloric restriction mimetics.  In other words, trick the body into thinking it has less food than it is really eating.  Some of the early genetic modifications in worms worked in this way.  DAF-2 was an early discovery, doubling life span of worms in Kenyon’s lab when it was partially disabled [1993].  The catch is that lab worms are champions of adjustable life span.  They are exquisitely adapted to be able to survive months at a time with no food at all, but to die within a few days once they have plenty to eat.  Larger animals also live longer when they eat less, but the effect is much smaller.  My guess is that CR potentially adds 5-10 years to human life span–nothing to sneeze at, but not the big, dramatic gains we might hope for in the long run.  If we find a really, really good caloric restriction mimetic, we might hope to capture most of that 5-10 years.

This is the low-hanging fruit being chased by the lion’s share of private investment in anti-aging medicine today.  No doubt, it will be achieved in short order (though it may be decades before we know which strategy works best, because longevity data in humans takes a long time to compile.)

Neglected is the potential for much greater gains that go beyond the potential of CR mimetics.

Let’s go back to Partridge’s “protean list” of complicated processes that have to be addressed:

  1. telomere attrition — This is a primary aging clock, cause of many downstream effects.
  2. epigenetic alterations — Gene expression changes with age.  When we are in our teens, gene expression is modified to halt growth and initiate puberty.  When we get old, a similar process leads to a gene expression profile that gradually destroys the body on an accelerating schedule.
  3. genomic instability — This is DNA damage, and by far the greatest source comes from short telomeres.  Telomeres cap the ends of a chromosome and keep it from unraveling.  When the telomere is too short, the chromosome becomes unstable.  So this may be traceable to #1. => See comment below by Bowles for another mode of genomic instability, this one controlled by epigenetic markers.
  4. loss of proteostasis — This refers to protein mis-folding, which is observed in Alzheimer’s Disease among other diseases of old age.  But proteins are being created and folded and re-cycled all the time.  Part of the reason that mis-folded proteins accumulate with age is simply that the body’s repair mechanisms are slowing down.  Another part is (my guess) that genes that take care of this function are being down-regulated–in other words, we might trace this problem to #2 as primary cause.
  5. deregulated nutrient-sensing — This is loss of response to insulin, related to “metabolic syndrome.”  I believe this happens under epigenetic control.
  6. mitochondrial dysfunction — This is the “free radical theory” or “mitochondrial free radical theory”, still invoked despite all the evidence against it.  It’s true that we have fewer mitochondria as we age, and that the mitochondria process energy less efficiently.  But the activity and the reproduction of mitochondria are under control of the cell nucleus, hence this, too, will prove to be a symptom and not a root cause of aging.
  7. cellular senescence — barely distinguishable from #1, telomere attrition.
  8. stem cell exhaustion — primarily caused by telomere attrition.
  9. altered intercellular communication — hormone signals through the blood are under epigenetic control.

Thus the “protean list” of nine complications derive largely from two ultimate sources: telomere loss and epigenetic reprogramming.  These should be our primary targets for anti-aging research.

* A Cell article this week from Elizabeth Blackburn’s UCSF lab suggests that activating telomerase may have rejuvenating benefits over and above its role in extending telomeres.

Companies investing in anti-aging research

The following table is taken from the same article: 

Table 1 Companies commercializing longevity
Company (year founded, location)FocusFounders (affiliation)Seminal publication
Alkahest (2014)Translating parabiosis, transfusing young blood into Alzheimer’s patientsKaroly Nikolich, Tony Wyss- CorayVilleda 2014
Calico (California Life Company, 2013)Research and development into the biology of life span with undisclosed amount of Google funding.Arthur Levinson, Cynthia Kenyon, David Botstein, Hal Barron
CohBar (2009, Pasadena, CA, USA)Develops mitochondria-derived peptides with pleiotropic effects in age-related conditions (diabetes, cardiovascular disease, Alzheimer’s disease)Pinchas Cohen (University of Southern California), Nir Barzilai (Albert Einstein), John Amatruda (formerly with Merck), David SinclairMuzumdar, 2009
Elysium Health (2014)Consumer health productsLeonard Guarente (MIT)Mouchiroud 2013
Human Longevity Inc (2014)Combining human genomics, infor­matics, stem cell advances to solve diseases of agingCraig Venter, Robert Hariri, Peter Diamandis
L-Nutra (2008)Fasting mimicking and enhancing dietsValter Longo (USC)Parrella 2013
Metrobiotech (2008)Compounds that raise NAD+ levelsDavid Sinclair (Harvard)Gomes 2013
Navitor Pharmaceuticals (2014)Selective regulation of M-TORC1, raised $23.5 million in series A round of fundingDavid Sabatini (MIT/ Harvard)Dibble 2013
Proteostasis Therapeutics (2008)Therapeutics that modulate protein folding and homeostasis; preclinical programs in cystic fibrosis, neurode­generative diseases $45M raisedAndrew Dillin (UC Berkeley) and Jeffrey Kelly (Scripps Research Institute)Cohen 2009

 

None of these is investigating epigenetic reprogramming, probably because it is too early for commercial investment–no one knows how to do it yet.  The only company based on telomerase activation is Sierra Sciences, which is below the part of the chart I reproduced, companies listed as in financial straits.  The only company with research based on a changing profile of circulating blood factors is the first, Alkahest.

The two wild cards are Craig Venter’s Human Longevity, Inc and Google’s CALICO.  Both are well funded, and neither has offered details about their research programs.  Last year, Venter hired the man who headed Google Translate, signaling a brute force approach, based on theoretical agnosticism: Sequence a million human genomes.  Look for patterns, e.g., what do the genomes of people who don’t get Alzheimer’s Disease have in common.  In my opinion, this is a cumbersome approach, inspired by successes in information processing, rather than knowledge of biology.  As I said, I think aging is controlled by epigenetics, and the largest gains will be made when we learn to re-program the epigenetic profile of an old person to make it look more like a young person.

CALICO, then, is crucial.  Their direction is not yet determined, and will be shaped by Kenyon’s vision and beliefs.  Kenyon has ambition and a wide-open imagination, and she is open to ideas about programmed aging.  We can hope that her extensive experience with worms informs but does not limit her vision.

 

Foundation funding

Historically, Ellison Foundation has been one of the most reliable sources of big bucks for innovative research, with about $400 million in aging-related grants since 1997.  But last year, Ellison pulled out of anti-aging research.  The Life Extension Foundation (LEF.org) has, by its own accounting, funded research totaling $140 million over three decades.  They have been independent of the bureaucratic thinking of the National Institutes, but they have their own biases, favoring natural remedies that can be sold without FDA approval.  SENS Foundation, with an annual budget of $4.5M, has grown from the singular vision of Aubrey de Grey, and has all the ambition and also the limitations of Aubrey’s paradigm.  To their credit, SENS is looking seriously at long-term projects that show potential for major gains in life span.  But, at least from my perspective, they are neglecting the most promising avenues, because Aubrey does not believe it is possible that aging might  be controlled by biochemical signaling.  The “engineering” approach to fixing what goes wrong is a long, hard road.  Peter Thiel has offered the greatest outside support for SENS, and Thiel has also made grants to other anti-aging initiatives.

 

Historical distortion of aging science by evolutionary theory

 In the long run, the greatest damage has been done indirectly, by capitalist ideology that has infiltrated the culture of evolutionary science.  From the beginning, Darwin’s theory was hijacked by “social Darwinism” which twisted the theory to create justification for hereditary class privilege in British society.  “Fitness” was elided with “financial success”.  “Natural selection” became a sanction from Natural Law for income inequality.

In the first half of the 20th Century, Darwin’s theory was re-cast as a modern science, with quantitative measures, equations, and predictions.  The work was spearheaded by R.A. Fisher, who happened to be both a prodigious genius in statistical theory, and also an elitist/eugenicist.  The version of evolutionary theory that was bequeathed to us was further caricatured by Richard Dawkins as the Selfish Gene.  In this version of evolution, the emphasis is on individual competition to the exclusion of cooperation.  There is little room for self-sacrifice, and such obviously communal adaptations as sexual reproduction have become inscrutable mysteries.

This kind of theoretical foundation has made the biological community blind to clear and manifest signs that aging is an epigenetic program, akin to growth and deveopment.  When you are a teenager, genes are turned on that cause secretions of sex hormones, and reproductive function is awakened.  When you are in your 60s and after, another set of hormones is switched on epigenetically, and the body becomes hyper-inflamed, auto-immune, insulin resistant and self-destructive.  Most biologists look at these changes and they figure that the body must know what it is doing, that there must be a redeeming positive benefit for these changes, and it would be dangerous to second-guess the body’s wisdom.  But the truth is that these late-life epigenetic changes have little benefit, and their predominant purpose is to destroy the body on an accelerating time scale.

Most researchers are busy asking themselves what goes wrong.  Neglected is the process plain and clear, where the body is being destroyed by “what goes right”.

It follows that the greatest opportunities for radical anti-aging are to characterize the chemical signals that control aging, and to adjust the signaling environment of an old body to make it more like a young body.

To some extent, this can be accomplished simply by lengthening telomeres, which have a substantial epigenetic reach of their own (TPE).  There are knowledgable advocates in the field who think lengthening telomeres is the most important thing we can do.  It is certainly the most accessible path, and should be a high near-term research priority.

 

My candidate for basic research:
Study the Epigenetic Clock that Controls Development as well as Aging

Biological science today does not know how the onset of puberty is timed.  We know that epigenetic changes are triggered at an appropriate age, and a few key sex hormones initiate the onset of fertility.  What we don’t know is how the body detects that the time has come for this to happen, whether there is an internal clock mechanism, and if so, how it works.  To me, this would be one of the most valuable studies in basic science, and I believe that when the epigenetic/developmental clock is understood, the results will carry over directly to understanding of the aging clock.  And if we can reset the aging clock, it’s a whole new ballgame.

32 thoughts on “Ideology is Holding Back Aging Research

  1. Nice blog…. thought I would add an idea that I’ve been pondering for many years…
    genomic instability can also be caused by the loss of methyl groups that are on the 5mC’s attached to the DNA….
    the 5mC’s not only can suppress gene transcription..
    .they also prevent DNA cleavage by restriction enzymes…
    Not sure if josh has studied those yet but I learned they always cleave at palindromic sequences
    like GTTACTGCCCGTCATTG
    but if the cytosines are methylated as 5mC’s the restriction enzymes cannot cleave…

    so if the DNA loses a lot of it’s 5mC at many places with age
    then possibly a lot more cleavage can occur which can lead to crossovers (DNA swapping places)
    and dislocations (chunks of genes ending up somewhere else like on the wrong chromosome)
    these types of genomic instability often lead to cancer and other problems

    also a demethylated genome sine it is more easily cleaved can also be more likely to undergo apoptosis rather than mitosis
    a apoptosis works primarily by snipping up the dna into little pieces.

    Just some food for thought

  2. Wyss-Coray’s Alkahest was based on the paper by Villeda in 2014. But my paper detailing heterochronic plasma exchange – what Alkahest seems to believe it possesses, gave the outlines of the procedure in 2013 – and Tom Rando knew about it because we communicated about it – (and said he didn’t think I’d get anywhere with that programmed aging stuff) before the paper.
    So this is just the case of the big guy (Stanford) stomping the little guy? I don’t think so.
    What’s more important is understanding aging – and I think I do, it’s simple when you don’t place the blinders of stochastic aging on. Forget about the ‘why’s and ‘wherefore’s and just know aging and death are important characteristics of life – and that at its basis a living organism isn’t simply a collection of macromolecules – but a four-dimensional construct. Just as we can wangle intricate three dimensional forms from one dimensional sequences of amino acids, four dimensional structures build and collapse based on the interactions of molecules through informational networks organized in time and space.
    In the simplest of living things (debatable – but I think perhaps ultimate parasites) the bacteriophage T4 transcription starts at one end of its single molecule, linear DNA genome producing the early transcripts – the enzymes that destroys the bacterial DNA so that only its own DNA survives to direct all further activity – and the transcription proceeds to the other end of the molecule – each subsequent transcription implementing the construction of viral proteins and viral DNA and finally – when transcription reaches the far end of the DNA, the enzyme T4 lysozyme is produced, destroying the bacterial cell wall and allow the two hundred or so viruses contained therein to escape. My point is that we are in many ways programmed in such a way – not so strictly as T4 – much more ad lib – more like a video game than a play – but with a beginning a middle and an end.
    The immortal jellyfish – Turritopsis can go back to level 1 (the polyp) once it’s reached the end of level 2 (the medusa) – and I believe that we can too. Of course we’re a bit more complex that Turritopsis – but that may just mean that we have a variety of ‘chapters’ or ‘levels’ we can return to for different purposes. Sounds crazy I know – but follows the evidence.

    • Tweak the blood to restore a youthful state and much of the rest will hopefully follow once the body remembers how to be younger.

      Lets hope we can get your HPE Plasma study underway soon Harold. I think it is time to go public with it and seek funding and grants so we can get your theory put to the test.

  3. The idea that there are one or two fundamental drivers of aging is eminently reasonable. Evolution cannot proceed without death, so it follows that species with preprogrammed death have an evolutionary advantage. We should expect that preprogrammed death developed at the very earliest stages of life on Earth and that the mechanism(s) are strongly preserved in our genome. Of course, evolution fills every niche, so there must also be various factors that modify the fundamental causes of death in marginal ways, for example, the ability to delay aging during a famine. The fundamental secret presumably lies in the most ancient aspects of our nature.

  4. I’ve read an article written by you Josh from September where you cover CRISPR and I could notice optimism when you wrote it. And yet, I don’t see same optimism in this article and you don’t mention CRISPR. Did something change in the mean time regarding your views on CRISPR and it’s potential?

    https://www.youtube.com/watch?v=AiCvqnUIe04
    David Sinclair (as from minute 17 of the video) talks about altering epigenom by using CRISPR technology. He mentioned few months ago that they are doing research regarding epigenetic changes and that first results looks promising. Until they publish something we can only guess what that might be…

    Good thing is that many scientist agree that decade of epigenetics is just starting.
    Just last example:
    http://med.stanford.edu/news/all-news/2015/02/project-maps-human-epigenome-discovers-immune-system-role.html

    I am glad to see that my disbelief and confusion when I use to read about “junk” DNA was justified…

    • Yes – I agree that CRISPR is the most promising approach to epigenetic reprogramming that we have at present. But I hasten to add that CRISPR is just beginning to be tested as an epigenetic tool, that previously it has been used primarily to splice DNA, i.e., to make genetic and not epigenetic changes. Another project is to characterize the gene expression differences between young and old, which surely must vary from cell to cell, from tissue to tissue. Then CRISPR (or something else) will have to be adapted in a tissue-specific intervention. All this seems do-able, but it’s not going to happen tomorrow.

  5. Actually puberty can be delayed in humans. It is used in children who have gender identity issues, to delay the onset of puberty until they can decide whether they want to go through gender reassignment or not. Puberty can be delayed by years, although I don’t know if it could be delayed indefinitely (it is generally delayed by as little as possible, while psychological evaluations are conducted, because it also delays growth and other physical developments).

    It would be interesting to look into that, and especially to know whether this delaying has any effect on the setting of old age and longevity. Although they may have other issues tied to their gender identity that lessens their lifespans, making the study difficult (and the sample size relatively small).

    However, if the same can be replicated with mice, there would be less ethical challenge in testing for theories: Can their puberty be delayed indefinitely? Does it affect the onset of old age? Does it affect lifespan? Note that because it would affect growth/size it would have to be checked carefully for confounding factors (like CR).

    It would also be interesting to know if people (mostly women) who use hormone replacement therapy at menopause (the human bio-identical one, not with horse hormones) live longer, or less, or the same.

  6. I think the first place to look is the blood, wryss-Corey is on the right path. I believe the body can be fooled into a more youthful state and the means to test this are available and already approved for safety.

    Telomeres can change length through exercise and diet albeit a small amount so we know they can be changed. Dr blau at Stanford also recently used a technique to lengthen them using htert on skin cells. I know of a biotech that uses gene therapy to do the same.

    I suspect if you can introduce young blood factors to an older person there would be robust rejuvenation as seen in mice. It is also possible those factors could influence telomere length too as part of a return to a younger environment.

    We don’t know all the different factors in young and old blood but we don’t need to in order to test proof of concept. Plasma would give us the pathway to testing this and rejuvenation would be easy enough to see.

    • Thank you, and I agree.
      Can you tell me more about “a biotech that uses gene therapy” to lengthen telomeres? I was aware that this was done in mice in labs of Maria Blasco, but I didn’t know there was a commercial service for humans.

      • They are using an AAV delvery system with hTERT and are planning to test it combined with GDF-11 and another therapy. I will find out more and let you know.

  7. Josh, don’t know if my prior post was received, so I will try again.

    To my knowledge, and I am almost certain, there is no “commercial service for humans” offering [telomerase] gene therapy to lengthen telomeres. That being said, Michael B. Fossel is giving a lecture at the April Age Mgt Medicine Group conference, titled “Resetting DNA,” that dovetails pretty closely to many of the points you make above. Here is the Lecture description:

    “Aging is an active, dynamic process – rather than a passive accrual of damage – driven by predictable patterns of epigenetic change within cells. The change in gene expression results in decreased DNA repair, protein pool turnover, ATP/ROS ratio, lipid membrane efficacy, and a gamut of changes which define cell senescence. Such intracellular (and intercellular) changes result in predictable tissue and organ dysfunction, including vascular endothelial and microglial cell failure, with secondary clinical pathology, including arteriosclerotic and Alzheimer’s diseases. While clinical interventions can be based on specific genes, the panoply of epigenetic changes are modulated by a loss of relative telomere lengths. Research consistently shows that relengthening of the telomeres results in cellular, tissue, and organismal benefits both in vitro and in vivo. Such data includes human trials of oral telomerase activators and telomere relengthening in animals in vivo, but a more effective intervention may be to use tailored plasmid delivery of active telomerase genes in human subjects. Such trials are now planned.”

    Also, the AMMG Bio for Dr. Fossel ends with the statement: “He is currently working to bring telomerase to human trials for Alzheimer’s disease.”

    Some of us have planted our stakes in the field of small molecule telomerase activators, plus addressing the other major causes of telomere shortening, but as you point out in your description of Linda Partridge’s protean list of “The [9] Hallmarks of Aging” [Cell 2013], telomeres and/or telomerase are at the center of many if not most of them, as well as the associated “Interventions that Might Extend Human Healthspan” presented by the authors (which include Maria Blasco.)

    David B. Cross, Founder & President, Telomere Biosciences, LLC.

  8. To your point that: “There is an enormous streamlining available when we turn from treating diseases separately to treating the root cause of aging,” again, the accumulated research in Telomere Science strongly supports that view, specifically that short telomeres and/or lack of telomerase activity:

    1. Are now demonstrated to be a causal factor in at least the following degenerative diseases:
    –Type 2 Diabetes: [KL Rudolph AGING 2010; M Armanios PLoS ONE 2011; EH Blackurn/M Armanios Nature Reviews: Genetics 2012]
    –Rheumatoid Arthritis: [Weyand/Gorozny Nature Reviews Rheumatology 2009]
    –Coronary Heart Disease: [P Welleit et.al. BMJ 2014]; Coronary Artery Disease [V Codd, et.al. Nature Genetics 2013]
    –HIV’s progression to AIDS: [XG Yu Blood 2008]
    –Idiopathic Pulmonary Fibrosis [EH Blackurn/M Armanios Nature Reviews: Genetics 2012; M Armanios Proc Natl Acad Sci 2008]
    –And while perhaps not yet at the level of demonstrating a causal relationship, there is increasing strong research evidence of a key role played by telomeres & telomerase in Alzheimer’s Disease [e.g., Spilsbury, et.al J Neurosc 2015] and Immune function including Immunosenescence [esp. RB Effros w many studies]

    2. And that in addition, telomere length and telomerase activity are demonstrated to be vital to:
    –a. Adult Stem Cell health, regenerative capacity, and functional lifespan–inc. HSCs, MSCs, Neural Stem Cells, and Endothelial Cells, which per a recent Vanderbilt study 08/14: “Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue.”

    As stated by Maria Blasco: “Short telomeres are causal of disease because when they are below a certain length they are damaging for the cells. The stem cells of our tissues do not regenerate and then we have aging of the tissues. These findings suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. Telomere maintenance appears to be essential for the prolonged persistence of stem cell function.” [Blasco: Nat Chem Biol 2007, FEBS Lett 2010, J Neurosc 2009; KL Rudolph: Exp Geront 2009, Biochimie 90 2008; Jaskelioff/DePinho: Nature 2010]

    And per Eliz. Blackburn & Mary Armanios (J. Hopkins): “Short telomeres cause haematopoietic stem cell failure.” [EH Blackurn/M Armanios Nature Reviews: Genetics 2012]

    –b. Mitochondrial health & function [see among others: Sahin/DePinho: Nature 2011, Nature 2010]

    I believe the above very strongly supports your point that “telomere loss”…”should be [one of] our primary targets for anti-aging research.”

    David B. Cross, Founder & President, Telomere Biosciences, LLC.

    • No commeracially available service at this time is correct but the technology is out there. Dr Blau at Stanford recently increased telomeres in skin cells in -vivo using htert and I know of at least one other group apparently close to testing using a gene therapy utilizing Htert.

      I do agree with you about telomeres being a priority and its up there with blood factors and restoration of a younger environment.

  9. While speaking of telomerase activation, there is an interesting interview with Dr. Michael Fossel in “Smart Publications”.

    As I try to read almost anything he publishes, in this case I couldn’t figure out when this interview was published. I wish was “old”, since he mention that “I think that you’ll see the first human trials within ten years” and on the other hand I wish is “new” as he mention “insertion of a new hTERT gene into the cells of human ” and that “it’s the process we’re most able to perform right now technically.”

    The interview is here:

    Countdown to Telomerase Therapy: An Interview with Dr. Michael Fossel

    By David Jay Brown

    http://www.smart-publications.com/interviews/mavericks-of-medicine/dr-michael-fossel

    He is describing the three ways he thinks we can reset the gene expression.

    Would be nice if Josh can get in touch with Dr. Michael Fossel and ask couple things and post them back in his blog, so at least some things are clarified.

    Also, a greater idea, would be nice to create an international fund to support these scientists that really wants to bring into humans age reversal.
    People can make donations to this fund and support people like Michael Fossel, Harold Katcher, Bill Andrews, etc.

    So we can see age reversal implemented in humans (and pets too!) in couple years, rather than decades.

    Isn’t any organization out there that can take on this?

    • Adrian we are currently trying to get Harold’s HPE study underway. He has been involved in discussions on the Gerontology Research Group mailing list about his ideas and there has been some interesting discussion.

      I ham working with various people trying to get some funding for his project so watch this space!

      • I noticed Michael fossell is pushing ahead with a plasmid deliver system for telomere rejuvenation. This brings the list of projects to do that even more.

        Now I would like to see telomere rejuvenation therapy combined with plasma therapy to restore youthful function. I am wondering if the two combined could tip the balance and reset the system?

  10. Here, if I am not mistaken, the major push is to rejuvenate cells in situ.
    Without knowing much about the details I would be afraid that randomly inducing hTert in somatic cells could be very risky because it could easily lead to malignancy.
    I have always been thinking on a different paradigm. Create a few, healthy, young IPSC cells in a dish, expand them, test them with stressors (radiation, chemicals).
    Differentiate them into adult stem cells, then implant. We know this should work in case of HSC, because its been routine clinical practice to repopulate bone marrow. With a little luck it should work for other cell lines.
    Isnt there anyone out there working on such treatment?
    And IPSC inplantation is actually further ahead then htert induction. There is already a human trial ongoing in Japan with IPSCs.
    Also I read – but forgot where – about a company that is planning to produce erythrocites from IPSCs in the US.

    • Does telomerase cause cancer? I have written an article on this subject, and I am convinced it is a red herring. There are “theoretical reasons” to believe that telomerase must cause cancer. If life could be extended so easily, why wouldn’t the body be doing so itself, without our intervention. There are always tradeoffs.

      But this theory is wrong, and in practice, longer telomeres lead to lower cancer rates.

      • Well, my main point is not about cancer risk – though I found this article, which states induced hTert causes immortalization and hyperplasia if not outright cancer
        https://www.med.upenn.edu/gastro/nci/documents/Telomeraseinducesimmortalizationofhumanesophagealkera.pdf
        – but the approach itself from an engineer’s point of view.
        According to this article
        http://www.nature.com/bjc/journal/v96/n7/full/6603671a.html
        telomerase is upregulated in stem cells, more so in progenitors and not present in somatic cells.
        hTert seems to be part of a delicate developmental program and if I could, I would bet it is also regulated by epigenetics or blood factors.
        Now if we take a shotgun – because I believe any in vivo genetic manipulation is highly probabilistic – and start upregulate or insert hTert in random cell populations we may not get what we wish for. Its like overwriting the binary of an executable without understanding it.
        Thats why I advocate using the natural process all the way: create youthful stem and progenitor cells and implant them.
        Actually I just found a paper where it is mentioned as a distinct potential in IPSC cells.
        http://hmg.oxfordjournals.org/content/early/2013/08/19/hmg.ddt379.full

        • Thanks.
          I agree about the potential of stem cell therapy, but with the proviso that adding new, rejuvenated stem cells can’t eliminate the damage done by existing senescent stem cells, which secrete inflammatory cytokines, poisoning nearby tissues and signaling the body as a whole to increase inflammation. It may be that eliminating cells with short telomeres is just as important as maintaining a reservoir of cells with long telomeres.

          And I’ll read the articles you cite on telomerase and cancer.
          – Josh

          • The problem with this is young rejuvenated stem cells are influenced by their environment and according to Irina Conboy it seems if you implant them into an aged environment they do not do well.

            The Stem Cell niche has to be rejuvenated to a younger phenotrype in order for it to work otherwise new stem cells get supressed, or thats how I understood her Beyond Parabiosis video. They have tried to seed organs with young stem cells before and ran into this issue.

  11. Calorie Restriction is not the only means for which a reasonable argument can be made that there is a 5 to 10 year BioHack possible for humans.

    — There are at least 3 Human Survival studies showing that the key measurable variable of another means can reasonably be considered a 5 to 10 year BioHack.
    — There are hundreds of studies demonstrating that the key measurable indicator (Heart Rate Variability, HRV) of this means is correlated with Morbidity and Mortality.
    — The Mechanism by which Higher HRV explains the demonstrated 5 to 10 year advantage in humans has been extensively explored in at least 100 animal studies.
    — That Mechanism, the Cholinergic Antiinflammatory Pathway, is known and is mostly about NF-kB inhibition at the moment just before it performs Cytokine Transcription, Especially in the Spleen…
    — The leading student of that mechanism, Dr. Kevin Tracey, hold a 2009 Honorary Doctorate from the Karolinska Institute.
    — I believe that the CAIP and/or the Spleen is implicated in the health/life benefits associated with Parabiosis studies, Meditation triggering of Telomerase, and Baati’s C60-OO mice experiment.

    — A plausible case can be made that the Cholinergic Antiinflammatory Pathway is implicated in Rejuvenating Parabiosis studies…
    ->> The CAIP has important nerve endings in the Spleen and blood in mammals passes through the spleen every 2 to 10 minutes, depending on the species.
    ->> NF-kB is inhibited in the Spleen via the CAIP and that inhibition has been shown to inhibit Cytokine expression in drawn ex-vivo whole blood.
    ->> Parabiosis appears to be rejuvenating in mice.
    ->> And Higher/Lower HRV is profoundly correlated with Longevity, Morbidity, and Mortality, respectively.

    — A plausible case can be made that the CAIP is implicated in the Epel Mindful Meditation Telomerase increase studies…
    ->> Fredrickson and Epel have both shown that Meditation increases HRV
    ->> Hence, implicating acetylcholine expression
    ->> hence, the CAIP must have been triggered
    ->> hence, NF-kB inhibition in the Spleen

    — A plausible case can be made that the anti-inflammatory functions of the Spleen are important for understanding the longevity effects of the Baati C60-OO study.
    ->> Figure 2 from the Baati study showed that C60 crystals were engulfed by Spleen Macrophages
    ->> Table 2 showed that C60 weight in the Spleen diminished little if at all over a period of 8 days.
    ->> My speculation… NF-kB was inhibited by some means in the Spleen macrophages responsible for blood filtering.

    Here’s a link to 8 slides that show graphic figures of some key evidence…
    https://docs.google.com/presentation/d/1LpZvpSRziiCTNJIP-xjy1pQqanLXT6WqCdvgIRJ8gig/

    More about the Spleen in my next blog comment…

    Thanks for the blog Josh.
    HDW

  12. Josh,

    very good post. Very clear view on the state of the research on anti-aging.

    I guess, currently the best option is spare money support from affluent people.
    It’s really great to have google involved. However, given human nature, I’m sure when the first clear achievment is shown, insane amounts of funds will come to join the party, but that can take too long.

    Best.

  13. @HDW or Steve I have mentioned NF-kB as a possible target for down-regulation and it is something that could be done via gene therapy. Have been asked to forward supporting paperwork to their science team which they will have a look at and see if it could be a combo with TERT therapy.

    Related to this Bioviva has applied for funding from Longecity and will also be running a crowdfunder via the new Lifespan.io platform which launches in August. Look out for Bioviva interview on Singularity soon too!

    @Santiago rich people funding such things would be nice but I think the first steps might have to come from regular people crowdfunding disruptive science. Lifespan.io is hoping to promote life extension science projects like this where the general public can get far more involved than ever before and help support the work. I think the first pass life extension therapies will come from private enterprise and kickstarting this will likely have to come from people like us.

    • Hi Steve H…

      I have cross posted something close to the very high level literature summary about NF-kB and Telomerase that I posted a few days ago at LongeCity (http://goo.gl/MsFEgh).

      — At that link, I include links from 2014-2015 studies that don’t appear in the post I made at Josh’s blog…
      — My informed hunch at this point is that HMBG1 is the more specific molecular link between NF-kB and Telomerase related processes.

      • Great stuff let’s hope longecity agree to the tert project. It will be going ahead in August as a fund raiser on lifespan.io hopefully if its accepted in unison with longecity if they agree. If we can raise enough it means a good pilot test with lots of good data.

  14. Far from rational? How so? Cause it would dramatically reduce healthcare costs? Or because it would eliminate many age related illnesses and hit the people who profit by sickness and death?

    It’s always telling that Coca Cola spends more annually on researching new flavors than all the funding given for longevity and life extension research.

    Less and less people are naive or ignorant enough to believe in magic. Excuse me, God. Who’s invention is based around old peoples and civilizations fear of death and need to be controlled. Nobody likes the idea of simply not existing but the truth sometimes hurts. We can collectively do something (which I believe is wholly within our ability) or we can continue throwing money away at illnesses which would be cut by huge swaths if not removed all together if we could stay young longer.

    I am confident that as the old timers die off and lose policy making positions and the humorous bible thumping crowd begins to open their eyes, we will head in that direction in the very near future. What’s discerning is that ancient peoples were more concerned and active in this ironically enough, and it may not come in time for me.

    Wake up people! It’s a real shame I’m not rich or I would have long been putting my money where my mouth is.

    Google calico gave me tremendous hope and pride until I see them offering prizes for things like heart disease as opposed to what they originally touted.

    Coming from a cancer survivor – wanting to see less go to what is almost synonymous with dying, and more go to curing 7 billion instead of thousands – is telling.

  15. “Thus the “protean list” of nine complications derive largely from two ultimate sources: telomere loss and epigenetic reprogramming. These should be our primary targets for anti-aging research.”

    A theory of aging must accommodate the striking increase in (mean) lifespan due to rapamycin. Telomere loss and epigenetic reprogramming seem to be better explanations for the limitations of extension of maximum lifespan.

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