Aging in the news this week

In the press this week

  1. High-profile, misleading “proof” that aging is inevitable
  2. Disappointing results from Alkahest trials
  3. NewYorker article on exercise in a pill
  4. Splicing factors rescue senescent cells

  1. Mathematical proof that aging is inevitable

The headlines in the secondary scientific press said

Humans living forever is ‘impossible’ according to science

It’s mathematically impossible to beat aging, scientists say

Aging is Inevitable: Math shows Humans can never be Immortal

Mathematical models of aging are my specialty, but I’m not foolish enough to believe in the models.  I’m skilled and experienced at modeling so that I can adjust the assumptions to make a model do anything I want it to do.  I’ve seen time and again how tiny parameter changes can lead to opposite conclusions.  

Mathematical models can prove something is possible.  “Nature might arrange things in this way…”  But math models can never prove something is impossible.  Nature always has the option of arranging things in a way that’s different from the assumptions in your model.

In fact, the paper purports to be a general proof that aging is inevitable in all multicelled life.  But there are a few animals and many plants that don’t age.  Long periods of negative actuarial senescence (during which the probability of death goes down and down for years at a time) are common in trees, molluscs, and sea animals that keep growing without a characteristic, limiting size.  Turritopsis and Silphidae are capable of regressing to larval stage when starved and beginning life anew with a full life expectancy in front of them.  Annette Baudisch has made a career studying and documenting “negative senescence”.  So the idea that aging is some kind of mathematical certainty has about as much credibility as the authoritative declaration in Scientific American that flight by a heavier-than-air craft was impossible (1904 – more than a year after the Wright Brothers’ first flight).

The paper that appeared last week in PNAS is based on the premise that there is a kind of Darwinian competition among cells in the body.  Cells reproduce and mutate within the life of an organism.  In their model, somatic evolution–genetic change over time among cells in the same body–must navigate a course between Scylla and Charibdis.  The result is that mutations must accumulate, leading either to dysfunctional cells, too weak to do their job, or to cancer cells that have lost their allegience to the body and go on

They call this “aging,” but in fact somatic mutations do not contribute significantly to aging [ref].  Rather, in humans, the causes of aging include runaway inflammation, loss of insulin sensitivity, and thymic involution.  (In my view, most of these changes are driven in turn by programmatic epigenetic changes in gene expression.)  They redefine the term “senescent cells” to mean “cells that lose vigor due to cellular damage”, and then look for somatic mutations that cause the loss of vigor; but in general usage the term usually applies to cells that have critically short telomeres, or have otherwise entered a senescent state through epigenetic changes.  

The bottom line is that Masel and Nelson demonstrate a process that theoretically must kill us in the end, but their proof is silent about how long “in the end” might be, and they offer no evidence that the process they describe has to do with aging as humans (or other animals or plants) experience it.  Whatever “in the end” might mean, it must certainly be longer than 80,000 years, because that is the age of the Pando Grove which, last time I checked, qualifies as a multicelled life form.

Scylla and Charibdis

 

Blowing my stack (forgive me)

No one wants to think that death was handed to us with malice aforethought by evolution/nature/the gods.  In African myth, death was an accident caused by the laziness of a canine messenger of the gods.  In Judeo-Christian tradition, man would have been immortal if only Adam had not tasted the forbidden fruit.  William D Hamilton, one of the most insightful and best-grounded thinkers in evolutionary biology, proved that aging was an inevitable result of natural selection in 1966; forty years on, Baudisch and Vaupel used very similar reasoning to prove the exact opposite–that natural selection could never lead to aging [2004].  There are smart, famous people even today who argue that aging derives from the Second Law of Thermodynamics (Hayflick, of all people, is the man who discovered that cell lines run out of telomere).

We want to think that Nature is beneficient, that evolution has done her best by us and made us as strong and durable as possible.  If we get old and die, it must be because of something beyond evolution’s control.  But it’s just not true.  Natural selection first imposed aging on one-celled protozoans, and some of the same mechanisms that cause aging and programmed death in protozoans are active ingredients in human aging today (including telomere shortening and apoptosis).  Aging and programmed death have a long evolutionary history, and an ancient genetic basis.  We must conclude they exist for a purpose.

William Wordsworth asked, “Who shall regulate with truth the scale of intellectual ranks?”

Winston Churchill told us, “A lie gets halfway around the world before the truth has a chance to get its pants on.”

Arthur C. Clark said, “When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong.”  

Young Paul Nelson may be excused for getting carried away by his mathematics, but his mentor (and my former colleague) Joanna Masel ought to know that what they have done is irresponsible.  These memes have consequences.   Arguably, the small and under-funded community of anti-aging research is the most promising frontier of medical science today, offering a vision that may eclipse multi-billion dollar research programs in cardiovascular disease, cancer and Alzheimer’s disease.  Articles like theirs have power because the people who make funding decisions are not experts, they don’t like to be ridiculed, and they’re easily swayed by general sentiment in the research community = people who are already getting the funding.  

If we do not correct this impression, it is likely to discredit the most innovative and dynamic field of medical research today.

 

  1. Disappointing results from Stanford’s first trials of infusions of young blood

Alkahest is a for-profit spin-off from the Stanford lab of Tony Wyss-Coray, doing research with blood plasma from young animals infused into older animals.  I first wrote about the project two years ago.  The company leapt ahead of animal studies to try infusions of young plasma as a treatment for human Alzheimer’s patients.  Last week, Science Magazine reported on a pre-printed meeting abstract: no change in cognitive trajectory of patients who received the infusions.

The people I know best in the field of young plasma are Irina and Mike Conboy.  When I visited them last Spring, Irina told me she expected Wyss-Coray’s protocol couldn’t work.  The dosage is not sufficient, the duration of treatment is too short, and (according to the Conboys’ research) it is more important to remove pro-aging factors from old blood than it is to add the factors found in young blood.

Wyss-Coray took a chance, and I wouldn’t want to criticize his ambition.  But the research world being what it is, this high-profile failure is likely to set back funding for a promising research field.  Let’s do what we can to make sure that research by Wyss-Coray, the Conboys and Amy Wagers continues apace.

 

  1. New Yorker touts the Exercise Pill

An article in last week’s New Yorker began with a long encomium to the drug GW501516, developed by GlaxoSmithkline some 20 years ago, sold in the grey market as Cardarine or Endurobol.  Looking behind the headline led me to learn about  a family of transcription factors called PPAR.  They seem to be promising targets for life extension drugs that are just beginning to be explored.

“In mice, GW501516, either when combined with exercise or at higher doses by itself, induces some hallmarks of [exercise] adaptation such as mitochondrial biogenesis, fatty acid oxidation, an oxidative fiber-type switch and improved insulin sensitivity via AMP-activated protein kinase (AMPK)” [source]  

Sounds pretty good, doesn’t it?  But

“To its detriment however, tumorigenic effects of GW501516 have been reported and development was discontinued by Glaxo in Phase II clinical trials.”   

How serious is the risk of cancer?  Are there ways to separate the benefits from the hazards, either by combing with other drugs or by chemical modifications to the structure of GW501516?  Is there anyone with a lab who is seeking answers to these questions?  

Cardarine=GW501516

Personally, at age 68 the three main ways that I feel my age are (1) decreased flexibility in yoga postures, (2) decreased speed in running and swimming, and (3) I can’t remember what the third one is.  I have charted my steady progression.  Swimming and running times are 30-35% longer than when I was 40, and increasing year by year on an accelerating schedule.  Exercise is my personal biomarker for age.  For reasons of vanity and vitality as well, I eagerly seek pathways to improved performance.  I also think that the activities of GW501516 and other PPAR agonists suggest potential for life extension, though there seem to be no lifespan studies either in rodents or humans.
Much of my source for what follows comes from a new paper summarizing exercise-mimetic drug state of the art, and references therein.

PPAR stands for Peroxisome Proliferator-Activated Receptor.  Peroxisomes are organelles in every cell that specialize in breaking down fat into short chains that the mitochondria can burn.  Thirty years ago, PPARs were discovered in the context of making more peroxisomes, but we now know that their most important function is to increase insulin sensitivity and signal a switch from burning sugar to burning fat.

Stimulating PPAR-α lowers LDL cholesterol and blood triglycerides.

PPAR-γ is a transcription factor that controls creation of new mitochondria.  (Mitochondria are the source of cell energy, and as we age, we have fewer of them and they become less efficient, linked to all diseases of age. [from my blog last summer: Part 1, Part 2]  Stimulating PPAR-γ improves insulin sensitivity and atherosclerosis.  PGC-1α is a protein that turns on PPAR-γ, indirectly creating more mitochondria.  Activating PPAR-γ has been discussed as an anti-cancer strategy.

Stimulating PPAR-δ (the modus of GW501516) switches the body from a preference for burning sugar to burning fat.  Great for weight loss and also for endurance.  You can double the running endurance of mice with GW501516.  Presumably, it was rather effective in enhancing performance in human long-distance runners before it was banned in 2009.  In calorie-restricted mice and long-lived mutants,    PPAR-δ is overactive.  (I’ve seen PPAR-β referred to only as similar to PPAR-δ. Maybe they’re the same.)

Joe Cohen at Self-Hacked sings the praises of GW501516.  Comments on this blog claim that (1) the increased cancer risk in rats was at very high doses*, and (2) the mechanism in rats doesn’t apply to humans.  Other commenters also minimize the cancer risk, but don’t offer references, and they may well be trolls for the companies that profit from GW501516.

“Although peroxisome proliferators have carcinogenic consequences in the liver of rodents, epidemiological studies suggest that similar effects are unlikely to occur in humans.” [source, ref, ref, ref, ref, ref].  “A number of experimental observations suggest that there is a species difference between rodents and humans in the response to PPAR agonists.” [same source] The article goes on to say that PPAR agonists may be more likely to create cancers in rat livers than human livers because rat livers have 10 times the PPAR expression compared to humans. It may be that tumorogenesis comes from the function for which PPARs were named: multiplying the number of peroxisomes.  But we now know that PPARs promote new peroxisomes in rodents but not in humans.

Here’s what I’ve been able to find out about PPARs, GW501516 in particular, and cancer:

PPAR is upregulated in colon cancer cells.  This shows that cancer causes PPAR, but not that PPAR causes cancer. There are many articles like this one, comprising evidence that activation of PPAR-δ promotes growth of existing tumors of the colon. The evidence is indirect, and gives no suggestion of the magnitude of the risk in humans who have colorectal cancer, let alone whether it in implies a risk for people who don’t have colorectal cancer.

PPAR-δ increases expression of COX2, the opposite of what aspirin and NSAIDs do.  NSAIDs decrease risk of cancer, and this suggests both that PPAR-δ increases risk of cancer and that the effect may be offset with NSAIDs.

There are no studies in humans.  There are many websites selling Cardarine, from which I guess that at least several thousands of people have taken taken it since 2005.  I have seen no sales numbers or estimates of the number of self-experiments, let alone cancer statistics. I have been unable to locate any anecdotes about cancer.

This 2004 review preceded GW501516, and reaches no conclusion.  It does, however, state baldly that PPAR-γ (not δ) is generally anti-cancer and that PPAR-α (not δ) causes cancer in rats but not in humans.

I have been unable to find published reports of the origina Smithkline-Glaxo experiment with rats that led to concern about cancer and abandonment of GW501516.

SR9009 is an unrelated mitochondria-growing drug sometimes mentioned in the same articles as GW501516.  There are no studies suggesting that it is carcinogenic, but that may be because it is much newer and there are so few studies altogether.

I don’t know whether Cardarine is too dangerous for human use, or whether similar drugs can be developed that target PPR-delta more safely.  But I’m outraged that the decision to abandon research on Cardarine has been made by investors in a board room who have no concern for public health and consider only the corporate bottom line.  This is an example of the worst kind of collision between capitalism and medicine–a collision which claims millions of casualties each year in the US alone.

I can’t blame the suits in the board room for doing their job, marching to the tune of those who paid the piper.  But this is emblematic of a gross failure of our regulation system, the FDA, and the reliance on for-profit drug companies to decide on our nation’s research priorities.  We now have (presumably) thousands of people taking a drug which may have large benefits and may have large dangers.  Most of them are motivated by wanting to be more buff or more sexy, and they are paying little heed to long-term consequences.  And because FDA has washed its hands of responsibility, there is no one even keeping records or collecting data to learn from the massive experiment about long-term health effects of GW501516.

Cardarine (GW501516) is available from LC Labs ($2240/g), from Monster Labs ($45/g), and from IRC Bio ($108/g, cheaper in quantity)

 

  1. Splicing Factors rescue senescent cells

I must admit that RNA splicing factors weren’t on my radar until this week, but I find this new experiment pretty convincing.  Eva LaTorre and colleagues from University of Exeter (UK) claim that splicing factors, more than sirtuins, are the pathway by which resveratrol (and analogs) extend life.

Sections of DNA (genes) are transcribed into messenger RNA, which finds its way to ribosomes, where the mRNA is translated into protein molecules.  But there is an in between step (in eukaryotes, but not in bacteria).  The DNA contains not whole (contiguous) genes but pieces of genes that need to be spliced together to assemble instructions for a whole protein.  Large sections of the DNA, called introns, are not intended for coding, and they need to be spliced out.  And, in fact, the pieces can generally be spliced together in different ways to make different useful proteins.  The work of splicing is performed by molecular complexes called splicing factors.  This is a process to which I had not given much thought until reading this article, but apparently it is a crucial step in epigenetics.  Epigenetics, the process of turning genes on and off, seems to get more complex with each passing year.

Resveratrol was identified about 15 years ago as a compound that extends lifespan in many species (but perhaps not in mammals).  Resveratrol has many effects, but the primary mode of action has been thought to be through SIR2 (or SIRT1) or related compounds called sirtuins that are selective gene silencers.  But the LaTorre group set out to show that the anti-aging benefit was through splicing factors rather than sirtuins.  They synthesized variations on the resveratrol molecule and tested them until they found one that promotes slicing factors but has no effect on sirtuins.  

Using this resveratrol analog, they were able to turn senescent cells back into fully functioning cells, with restored telomeres and other epigenetic changes.  They demonstrated that this was accomplished through splicing factors, and without sirtuins.

All this was done in (human) cell cultures, and it the horizons are now open to see what effect such rejuvenation has at the whole body level.

_____________

* Of course, there is no established dosage for GW501516, but pills come in 10mg and 20mg typically, corresponding to ~0.1 to 0.3 mg/Kg.  The highest doses I’ve seen discussed in  humans are ~2mg/Kg daily, nominally the same as the rat dosage.

98 thoughts on “Aging in the news this week

    • PPARG is master regulator of adipogenesis promoting differentiation adipocytes.
      However PPARG good for mitochondria. So not good for weight loss. Want ARB that doesn’t have PPARG for weight loss

      • If one would want a less drugy way to increase PPAR-y expression L-carnitine would be a great option, the injectable form is widely used in bodubuilding.

    • And it IS weakly associated with bladder cancer, as PPARy is also associated with the invasiveness of bladder cancer cells.

      So strong PPAR agonists should be used with care – probably not for extended periods (years).

  1. Very interesting since age related DNA methylation is weakly correlated with expression profile, but I am not sure anyone checked the expression profiles for splicing variants.

  2. Progeria and Werners are both caused by incorrectly truncated proteins LMNA and WRN that show up in normally aging individuals at older ages…Can incorrectly truncated proteins come from incorrectly spliced RNA’s ? sounds reasonable this could be big!

    • Just finished your vit d book. Interesting stuff. It may interest you to know that there is a movement to Lower the minimal d blood level from 20ng to 12.5ng, despite the many illnesses related to low vit d , but the experts now believe that it’s all been overhyped. In a recent Harvard health blog Dr Joel Finkelstein, associate director of the osteoporosis center, was quoted as saying that if vit d is so important why does our skin tan in southern climates making it harder to absorb the stuff.
      So he apparently believes that we evolved to tan not to protect us from burning but rather to protect us from vit d!

      • One recent development suggests that vit.D reduces insoluble protein aggregates and extends life span in some animal models. For example:

        “Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1”

        In particular:

        “Vitamin D has been shown to extend lifespan in C. elegans (Messing et al., 2013). Moreover, short-term treatment with vitamin D reduces amyloid-β (Aβ) peptide aggregation and improves cognition in mouse models of AD (Durk et al., 2014). ”

        To me, this looks extremely interesting and I am surprised that experts do not seem to show interest in this work.

        • I totally agree and I think that most reasonable scientists now appreciate the importance of vitamin D, which I continue to believe should come from sun exposure if possible. The only real and legitimate argument is over the ideal blood level. I try to keep mine at 55ng-60ng/ml, but Jerry and others argue for 100ng, but I haven’t seen the data to convince me of that, while others think that 30-50ng is ideal.
          One thing for sure, if you’re getting a good amount of D, you’d better add in K2 and Mg since D will lower those levels and Ca will become a problem.
          One last point on this, I sometimes wonder about vit D and reverse causation, since some MS people have crazy low levels and have a hard time raising those levels. Almost as though the low D is causing the disease and the disease is lowering the D in a type of vicious circle.

          • Cannot we get enough amounts of vit K1/K2 from vegetable and dairy products? Interesting point that some diseases may cause chronically low vit. D. levels. Probably MD should systematically monitor vit D levels, at least for old people. I am not sure they currently do that.

      • Hi

        Tanning (melanin formation) does not completely block the UVB needed to manufacture Vitamin D. It only causes a darker skinned person to need to spend more time in the sun to synthesize Vitamin D.

        Many fair skinned people live in, or come from, areas that have more cloudy days. Cloudy days block more UVB and allow more UVA through the atmosphere. Darker skin people live in, or originated from, areas that typically have more sun.

        UVA goes deeper and damages collagen formation deep in skin, as well as the surface skin, hence the reason why lighter skinned (red hair, blue eyes) wrinkle more quickly than darker skinned people with more melanin.

        So perhaps the anti-skin damage effect is the purpose of tanning,(melanin) more than to block Vit. D, completely.

        The Melanin does prevent photoaging to a degree by blocking more UVB and UVA.

        Also, older people have more difficulty synthesizing Vitamin D from UVB expossure. Younger people do it more efficiently.

        People on certain medications or with certain diseases or disorders need to adjust dosage of D, either up or down.

        Also getting sunlight through the eyes, directly effects the brain and positively effects the Retina and functions of the Pineal gland, and functions of the Hypothalmus, and Pituitary gland.

        People now more than ever wear UV blocking eyeglasses, sunglasses or contacts which limits the exposure through the eyes, as well as wearing sun protection for the skin in general which limits UVB exposure.

        ————————–

        A study by Dr.’s Turner and Mainster of the University of Kansas School of Medicine, published in the British Journal of Opthamology in 2008 states that:

        “In addition to the healthy affect on your skin, sunlight also provides another positive benefit. The human eye contains photosensitive cells in its retina, with connections directly to the pituitary gland in the brain. Stimulation of these important cells comes from sunlight, in particular, the blue unseen spectrum.” …“these photoreceptors play a vital role in human physiology and health.” The effects are not only in the brain, but the whole body.
        ——————————————–

        Also, When the sun’s rays enter the Earth’s atmosphere at too much of an angle, the atmosphere blocks the UVB part of the rays, so your skin can not produce vitamin D, efficiently.

        These slanted rays happen during the early and later parts of the day and during most of the day during the winter season.

        That is likely why older people are more likely to die in January in less sunny parts of the world.

        Just some things to think about.

        • Hi
          About 5 years ago I spent some time with a group of Masai ‘s in Kenya and they of course spend an enormous amount of time in the sun. With mainly face and extremity exposure they were studied and found to have an average Vit D blood level of 45ng/ml.
          They are fit, active, and trim. What really struck me was their low fluid intake despite the scorching sun. They basically had 2 cups of coffee a day and that was about it. I couldn’t believe that they weren’t in renal failure but they have acclimated to this over the years I suppose in response to prolonged droughts.

          • Hi Paul:

            That is interesting information about the Maasai tribes.

            There are wild desert animals that can survive by sourcing water only from the other animals they eat or vegetation.

            Maybe the Maasai have adapted their bodies similarly.

            http://www.actforlibraries.org/animals-that-can-survive-without-water/

            From the link:

            “The sand gazelle has fascinated the scientific community

            The sand gazelle has undergone some dramatic adaptations to survive without water in the Sahara.

            ScienceDaily discussed recent study results which revealed that the sand gazelle has the capability to actually shrink its liver and heart when water is in short supply.

            By shrinking its oxygen-demanding organs, study researchers found, the sand gazelle breathes less, thereby reducing the amount of water lost to evaporation.

            This occurs not for just a short period of time, but for up to six months. Vegetation provides the primary source of both food and water sources for the sand gazelle.

            While there are several animals that are able to go without water for a period of time, some animals are able to survive without drinking water for extended periods of time.

            In fact, some animals have adapted to their habitat in such a manner that they are able to go nearly their entire lives without drinking free water. “

  3. Hi Josh, I’ve read the LaTorre paper in detail and I’m afraid I’m not convinced that these splicing factors have restored proliferative capability to senescent cells. The cells were grown in vitro until their doubling rate slowed below some arbitrary rate, not through being irradiated, and you can see from Fig 6b that 15% of the cells retained some proliferative capacity, as measured by the Ki67 protein. And after treatment 15% of the cells were no longer SA-galactoside positive, see Fig 6c. Coincidence? Almost certainly not. The authors admit as much in the discussion section: ‘Interpretation of data are also made more complicated by the observation that even a population of senescent cells derived from a single ‘young’culture is actually fairly heterogeneous, consisting of deeply senescent, newly senescent and pre-senescent cells.’

    So what is happening here is that the treatment is restoring proliferative capacity in cells that have lost that ability because of the signaling from nearby senescent cells.

    The work is not a waste of time however, because it showed that mechanism by which these resveratrol analogues work is by altering splicing factors back to a more youthful pattern of expression, and that this led to telomere lengthening. Also, who knew humble old resveratrol could extend telomeres in near senescent cells. Certainly cool, but it’s not reversing cellular senescence.

    • I was surprised by the telomere lengthening but the bioavailability of resveratrol is not great so we’ll see in vivo.
      Also surprised that the resveralogues 1-4augmented the TOR activity of the cells.

      Your books sound interesting Jeff. I’ll get one from Amazon.

  4. ” In Judeo-Christian tradition, man would have been immortal if only Adam had not tasted the forbidden fruit.”
    If any of your blog readers want to have some fun check out my book titled Creavolution….that examines the book of Genesis as a metaphor for early evolutionary events on the earth. available at Amazon..the correspondence of the bibles metaphors to early evolution can be quite amazing…and fun to ponder..
    If Adam was orignally an immortal photosynthetic plant…then the act of eating an apple is what caused him to become a predatory animal…He ate from the (evolutionary) tree of knowledge of good and evil…and his eyes were opened like Gods…The evolution of animals from plant life eventually leads to the evolution of intelligence as well as the evolution of sex and aging as a defense to predation mainly amongst animals…as explained in my more scientific book,..”What Darwin Couln’t See – The Missing Half of the Theory”

    • Genesis 6:3 Then the Lord said, “My spirit will not contend with humans forever, for they are mortal; their days are numbered a hundred and twenty years.”
      So far we have not proven that prediction wrong.

  5. Nice discussion on immortality etc but I thought the idea was patently ridiculous on its face. First had nothing to do with math just lot of aging nonsense.
    I make following prediction: 1000 years from now biotech company is able to remove all senescent cells and reprogram epigenetics back to age 20.
    How can there be mathematical proof that not possible.
    I don’t think they know what is math and meaning of impossible.
    Seems like anti-aging nonsense is new game

    • I think it is basically true that cells have to have their vitality constrained in multicellular lifeforms. And epigenetics seems to be the mechanism by which this is accomplished (not mutations as they postulate). Hence we do see a trade off between senescence and cancer. However i dont think this paper places any specific constraints on anti aging efforts, because a 500 year lifespan is no different to a 50 year lifespan in this model, but it is very different to us. They also don’t consider how we might re establish equilibrium from outside the organism. For instead inhibiting MTOR is a way of rebaselining metabolism to a younger age. Removing senescent cells is a way of rewinding this even further. Epigenetic reprogramming rewinds it even more. We never stop aging, but we don’t need to so long as future interventions are possible.

  6. I read I read the first article and I saw nothing that in any way persuaded me to believe in their theory. It was so simplistic that it was almost verging on a child’s comic rationale. They excluded everything else that can be developed in the future. I think if our ancestors had thought like that we would have never left the cave or the jungle

  7. I have looked into the recent ‘splicing factor’ study. If you examine the study, you can see that one of the ‘resveralogues’ that they looked at was resveratrol itself. In fact, resveratrol itself led to the greatest increase in telomere length of any of the tested compounds. This was obtained by innoculating the cells in 5 micromolar resveratrol for 24 hours and it resulted in dramatic reversal of cellular senescence and doubling of telomere length. This is a concentration that is easily obtained in human plasma after oral resveratrol. So the big question considering these findings is why does oral resveratrol not have dramatic and immediate effects on humans?

    • Yes I noticed resveratrol was the most effective. But is it possible to maintain those levels? I thought resveratrol was vert rapidly eliminated by the liver?

      • It seems likely that you are right. This study:

        High absorption but very low bioavailability of oral resveratrol in humans
        Drug Metab Dispos. 2004 Dec;32(12):1377-82. Epub 2004 Aug 27

        Found that resveratrol is absorbed very efficiently and rapidly, but is likely converted to modified metabolites (most likely by the liver) equally rapidly, so that only trace amounts of unaltered resveratrol are actually found in the plasma. Although the half-life of labeled carbon compounds in the study I posted was about 7-8 hours, those carbons are probably in less active and less useful forms. So this leaves the possibility that if we could somehow maintain the concentration of resveratrol in the plasma at a high level, we might see some really interesting results. Perhaps skipping first pass metabolism by the liver by some kind of parenteral administration (sublingual, transdermal, etc) would be a good consideration for future study. I am ABSOLUTELY NOT suggesting that anyone try this as there could potentially be serious deleterious effects as well. It does warrant further study though I would think.

        In a nutshell, what we have is this-evidence this week that resveratrol might essentially be able to reverse cellular senescence in actual human cells BUT we don’t know how to maintain it at substantial concentrations in plasma. This warrants further study IMO.

        • Hi John
          I guess we’ve known about the poor BA of resveratrol, which is why all of the interest in pterostilbene, but I suppose tha pterostilbene doesn’t have the exact same effects or we’d know about it by now. I wonder if enough would survive if we took resveratrol in a really high dose.

          • Maybe that could work. My suspicion is that the liver’s capacity to degrade this is higher than we would be able to overcome with any reasonable ‘megadose.’ It seems even when given as an IV (bolus) in humans and mice, it is degraded to metabolites rapidly. I found a mouse study which pointed to a half life of like 0.13 h, which is just a few minutes. So even getting past first pass metabolism doesnt solve the problem. I could imagine someone trying an IV infusion (drip) in a future study. That way you would be repleting it as fast as the liver could clear it (same principle as a propofol drip in sedation/anesthesia). Dangers here would be interference with metabolism of other cyp-metabolized drugs and unknown effects of accumulating the metabolites. It is certainly interesting stuff though!

        • Suppose one were to suppress CYP1A2 for 24 hours while loading up on resveratrol. According to the Wikipedia CYP1A2 entry, Verapamil is a strong CYP1A2 inhibitor, and seems to be available in 24 hr slow release form.

          • Rwhigham, I like how thinking! That’s a clever idea. I would imagine it could potentially work IF verapamil and resveratrol are metabolized by the same CYP (I don’t know this). It is the same principle behind why verapamil causes digoxin toxicity. Again though, this is for further study and not something someone at home should be doing as it could be dangerous. Could be a magic bullet. Who knows!

  8. As far as mitochondrial bioenergentics and biogenesis is concerned Dr. Bruce Ames has long ago demonstrateted that R-lipoc acid in combination with ALCAR works well.

    • James Watson also mentions Aicar as a synthetic exercise mimetic. Bodybuilders stack it with GW for endurance and fat burning.

  9. Aldebaran
    If you’re getting extra D from any source it will drive down K2 levels to a point that it would be almost impossible to get from foods like eggs, cheese. organ meats, butter, etc.

    • Hi Paul,

      I was not aware that vit D supplement would drives down K2 levels. So vit D and k2 should be supplemented together then. Thanks for the info.

  10. So we’re always on the lookout for new, independent avenues by which to extend life and attack aging. This was a new one on me and I’d appreciate the knowledgeable commentators here giving their take on it.

    ‘Yeast longevity promoted by reversing aging-associated decline in heavy isotope content’ (free paper).

    Cheers, Mark

    • Hi Mark
      The article is both unique and complex. They began by defining various known longevity pathways including a decrease in anabolism ( rapamycin), an increase in catabolism ( AMPK), or mitochondrial bioenergetics. They also distinguish between replicative and chronological aging. They then introduce the notion that heavy stable isotopes make up a small portion of common elements in biological systems.
      Yeast cells gradually lose the ability to retain heavy metabolites with aging. Also with aging the more abundant amino acids, such as glutamine, declined in heavy isotope content. They then demonstrated that under mild CR, D2O caused significant lifespan extension which they claimed was independent of TOR.
      The isotopes conserve metabolism by slowing the pace of nutrient consumption and waste disposal, but not growth. They confer resistance to both total 62% and mitochondrial 46% ROS. By suppressing ROS , D2O slows chronological aging.
      If I got any of that right, it would seem that this offers a unique and complementary pathway to the longevity effects of mild CR and rapamycin.

      • It’s crazy isn’t it? I’m still trying to get my head around this to be honest. Addition of D2O instead of H2O seems to be similar to CR in that it slows everything down, but it’s not quite the same, as it didn’t affect growth. It must be to do with the greater weight of the heavy water and the stability of the bonds. Clearly something is going on in with regards to mitochondria as ROS was so suppressed. I think there is a lot more to be understood here. I think experiments with mammals are warranted. From what i’ve read though they definitelt couldn’t tolerate such high concentrations of D2O.

        • Apparently lipids were completely saturated with deuterium rather than hydrogen (mentioned in the discussion section but data not shown). This might mean mitochondria membranes are much more resistant to lipid peroxidation, (total guess work on my part here). Again and again we see how important the mitochondria are in aging. Maybe deuterium is even intentionally used this way by the body in conditions of stress, like CR….

    • Hi Mark,

      Interesting finding.
      It would certainly be worth to try that in mice. The price of heavy water is about 600$ per kg from what I understand so not cheap but affordable for mice.

      Ideally, as you said, you would want to have Deuterium specifically located in mitochondrial membranes but I am not sure if you can do that without having a substantial part of total body water replaced by heavy water.

      From wikipedia:
      “Heavy water is slightly toxic in eukaryotic animals, with 25% substitution of the body water causing cell division problems and sterility, and 50% substitution causing death by cytotoxic syndrome (bone marrow failure and gastrointestinal lining failure). Prokaryotic organisms, however, can survive and grow in pure heavy water, though they develop slowly.[16] Despite this toxicity, consumption of heavy water under normal circumstances does not pose a health threat to humans. It is estimated that a 70 kg (154 lb) person might drink 4.8 liters (1.2 gallons) of heavy water without serious consequences.[17] Small doses of heavy water (a few grams in humans, containing an amount of deuterium comparable to that normally present in the body) are routinely used as harmless metabolic tracers in humans and animals.”

      • Well we might be lucky, as it seems deuterium is preferentially located in lipids. So you wouldn’t necessarily have to load up with say 20% of D to get 20% of your mitochondrial membranes protected. It seems the body can tell the difference and uses it accordingly, but for some reason this ability is lost as we age. Definitely much more work to do in this area, and its also dependent on good enough imaging technology.

  11. Hi Josh:

    Another well written, insightful article. I appreciate very much your insights and efforts to communicate information. You seem like a one person research foundation. Please keep up the good work!

  12. This is an interesting (free) paper that Josh may have something to say about.

    ‘Developmental diet regulates Drosophila lifespan via lipid autotoxins’.

    It unpicks some of the different contributions of early and adult dietary restriction in Drosophila flies, and purports to explain the differences because of the production of lipid toxins by adults that shorten the life of both males and females. I need another cup of coffee to understand this paper properly, but it seems to be saying a greater calorific intake means more sexual reproduction and progeny, but a shortened lifespan – because of these self produced lipid toxins. So they are literally killing themselves! Nothing said yet about applicability to mammals.

  13. Dear Josh, a little off topic but anyway, I ask you here. Have you tested yourself for epigenetic age? In case you have done it, how much did you score? Do you consider it the “better” age marker? I have started my own “antiaging interventions” at 40 and, being now almost 47, I tested 41, which I found quite good in absolute terms (younger than 95% of the rest of tested people of my age) and even awesome if assuming I would have been 40 at 40 (I don´t have a baseline, actually it wasn´t even available 7 years ago!). Anyway, Id like your opinion, if possible, about all this….

  14. I am very impressed that you tested out that young in comparison with your chronological age.

    I have studied Horvath’s work and I would expect very few interventions to have any effect on it. Therefore it is in my opinion the Gold Standard of aging tests. I had it tested last year and came out exactly at my chronological age at that time (38). I would expect most people to have a similar result. So if you don’t mind me asking, what do you attribute your young biological age to, nature or your own interventions? Do you practice calorie restriction?

    For my own part I will have the test repeated in 5 years to find the delta. I think the accuracy is 3-4 years, so not much point doing it sooner.

    • I am on calorie restricted low carb diet since 2011 (BMI 21), I do sporadic metformin and rapamycin since a year ago and went through my own version of senescent cells clearance during 2016 (just two treatments).It doesn’t seem so impressive in the report looking at the entire population as there are tested people with a lot better results as absolute deviation with the 1 slope line, (unfortunately I cannot paste the image here) but the trend assuming 40-40 as zero is really impressive, as implies an aging rate of about 0,15 y/y.

      • Who did you use? I used myDNAage.

        From what i can tell your epigenetic age is just a gradual drift in methylation over time. It’s hard to see any specific examples of it being harmful; it may well just turn out to be nothing to do with the diseases of aging and we may all still be alive and healthy with a epigenetic age of 500! Or Horavth may elucidate it further and demonstrate it is linked to actual deterioration.

        From what i can tell the higher your underlying growth rate (MTOR) the faster your epigenetic age will advance. So calorie restriction and rapamycin should slow it down. I do rapamycin weekly at a low dose and some intermittent fasting, so we’ll see in around 4 years if it has had any effect!

        So what did you do for senolytics?

        • Yes, DNAage, Got my results yesterday. Senolytics were a mix of dasatinib, quercetin, navitoclax and mebendazole as a single dose while fasting and taking itraconazole to inhibit CYP3A4 (plus metformin and rapa the days before). No bad side effects neither any noticeable result (until now?)

          • Pretty impressive and daring mix. The combination of quercetin and dasatinib is a known potent senolytic, I didn’t know about the other 2 drugs, but I’m surprised that you were able to get anyone to prescribe you the chemotherapeutic agents.

          • Hi Paul,

            There is a recent paper from Judith Campisi et al. about navitoclax:

            “Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice”

          • The usage of mebendazole to clear senescent cells seems to be pretty new and original. Maybe you are onto something Guillermo!

          • I wouldn’t expect senescent cell clearance to have a big, immediate effect on epigenetic age – which according to all the literature is independent of cellular senescence. CR almost certainly behind your results.

  15. Inhibition of PAI-1 (Plasminogen activator inhibitor–1) protect against aging-like pathology and prolong life span in humans. In particular, levels of fasting insulin and diabetes in carriers of the null SERPINE1 mutation were significantly lower than in non carriers. This is unusual for a single mutation to be associated with a significant life span increase in humans.

    “A null mutation in SERPINE1 protects against biological aging in humans”

    Science Advances 15 Nov 2017: Vol. 3, no. 11

    http://advances.sciencemag.org/content/3/11/eaao1617.full

    • This is a lucky find – some Amish with a rare mutation!

      Seems PAI-1 is a downstream target of P53, involved in cellular senescence, contributes to the SASP, and it’s reduction results in lower fasting insulin and longer telomeres. Fascinating. There are PAI-1 inhibitors going through trials in Japan, but from a practical point of view I would expect the removal of senescent cells with senolytics to have a larger effect.

      • Also, looking at the lifespan curves, this suggests senescent cell burden has a real and measureable effect on mortality by age 50 and is very significant from ages 60-80. Not much if any extension to Max Life Span though.

      • I am very interested by the insulin reduction (and impact on diabetes), obtained without any weight loss (as opposed to CR mimetics) which seems to indicate that it is orthogonal to CR.

        From a practical point of view, I am not sure when senolytics will be available and PAI-1 inhibitors could be there sooner.

  16. 80-90 years extra sound encouraging, if we can maintain a reasonable quality of life at the same time. But how about the gradual damage to the mitochondrial rich retina of the eye? How about the fact, that we are genetically programmed to lose inner- and outer hair cells of the cochlea as we age? How about the gradual collagen and elastin degradation (the very glue that holds our body together), which is not only due to the lack of new collagen being created, but most importantly due excessive matrix metalloproteinase. There are so many ‘IF’s. We may be biologically alive, but if a can barely see or hear anything at the age of 160, what’s the point?

    • I didn’t say it would give you 80-90 years more, just that mortality at ages 60-90 would be significantly reduced if senolytics do the same as PAI-1 inhibition. Sorry if my last comment was misleading (you need to read them together).

      It’s hard to say at this point what the contribution of various aging effects are on retina and cochlea deterioration. The same goes for collagen and elastin. The solution may be a combination of clearance of misfolded proteins and sugary crosslinks and increased cell turnover driven by senolytics and telomerase or stem cell infusion. In the meantime CR, intermittent fasting and rapamycin are reliable ways to slow down the accumulation of such junk through reduced cell growth and upregulated autophagy and mitophagy.

  17. Thanks for clarification Mark. My point is that there as so many aspects of aging, that it almost seems overwhelming. We will need at least a dozen therapies. The examples I mentioned were just top of mind. How about the loss of gait and balance in elderly persons? Multiple body organs must be functioning properly like muscles, bones, joints, vision, the balance organ in the inner ear, nerves, heart and blood vessels The list goes on and on…

    • I expect that what appears to be a multiplicity of issues is due to much fewer root causes. We don’t necessarily need to address every organ individually, but apply a handful of therapies that each individually produce some benefit across the body, with some being more effective in muscles, some better for the brain, etc., but with the sum of the therapies being highly synergistic against aging. That’s how I see it going, anyway.

    • I don’t think that any significant life span extension (30-40 years) is possible without corresponding health span extension. From the statistical point of view, mortality rate of centenarians is about 30-50 % due to many causes. Even if we could stop them from degrading more, they would not survive more than few years on average. The probability of surviving 10 year with mortality rate of 50% is 1/1000.

      Only possibility to live to 150 is to have a much lower mortality rate once you reach 100 than what it is today. But cannot it be achieve only if we are much more fit and healthy?

      • Yes, centenarians are not healthy, otherwise they would not have a mortality rate of near 50%. They seem to have genetics that allow them to limp along in that state.

        So with the rare exception of single genetic polymorphisms like the above, I’m not sure we can learn that much from them.

        • I agree.
          Well to be clear I have read in multiple papers that centenarians are generally healthy but it is of course relatively to other people of age 80/90. It means they are mentally sharp for their age and generally can live independently (they can walk, read, cook and so on). They are evidently not healthy in comparison to someone in its 40 or 50.

          • Yes, they are healthy compared to their peers, who are normally dead! But they are not healthy any objective metric.

  18. So as we all know metformin and rapamycin have terrible side effects and can’t be used for anti aging purposes LOL 😉, so we need to find natural alternatives.

    ‘Towards natural mimetics of metformin and rapamycin’ in Aging has just done that with machine deep learning.

    Despite my sarcasm above its always good to have alternatives and think about other interventions, and it is interesting what compounds the computer program came up with. So please read if interested!

    • Very interesting paper. I do like their methodology. ML and Neural Networks might be useful to navigate through all the intrications of metabolic pathways. I am curious about their intentions regarding the 4 undisclosed rapamicyn mimetics. Are they going to patent them? Create a startup?

      Interestingly, they have identified alantoin as the compound with highest similarity to metformin according to the metformin classifier. Now, alantoin has recently shown some synergistic effect in combination with rapamycin to increase LS of C elegans.

      • I’m on the fence with this paper. In some ways machine learning is a great way of unlocking cellular pathways that are too complex for humans to visualise unaided. But I think the conditions they were feeding it may have been too simplitistic in this case. For example the whole idea of a rapamycin mimetic without side effects is an oxymoron in my opinion. If a substance effectively inhibits MTOR then this will have side effects if taken for too long or with too high a dose. Obviously inhibiting cell growth and proliferation can be dangerous, which is why an intermittent dose is used. So finding a safe MTOR inhibitor really means finding a less effective version. So an AMPK activator is safe because it only indirectly supresses MTOR, it doesn’t stop it dead. It mainly works through the CatABOLIC functions that oppose MTOR, rather than stopping it directly.

        I would not be surprised to see a new supplement involving the new substances that they just so happened to test, appearing soon. But they won’t be as good as rapamycin.

        • I agree that side effects of efficient mTOR inhibitors are likely unavoidable. Maybe, in this particular case their investigation won’t lead to anything useful. However, I do like the ML / DNN/ CNN approach from the productivity point of view. It is not clear to me as much we can expect from it but it is certainly worth pursuing it.

          The main problem is that we have now many promising compounds to retard aging and only 5 to 10 are tried every year on mice.

  19. Aldebaran
    I agree that of course healthspan is very important, and all kinds of things contribute to that, but the main thing is to avoid all terrible illnesses at all costs. There is a saying that goes ” old people are old because they didn’t get bad shit”.I’ve seen alot of really bad diseases ruin many lives, not to mention radiation, chemotherapy, and constant fear of test results. I’ve also seen the toll that these things take on family members.
    So as usual, when well meaning family and friends ask me this holiday season why I take all of the supplements that I have sitting in virtually every room of my house, I remind myself that even if I took 1000 pills a day it would be far better than those devastating illnesses.

    Ole, you make some valid points, but it would be both daunting and depressing to think that we would have to address each and every organ system one at a time in order to combat aging. Our hope is that by inhibiting senescence with CR and rapamycin via the TOR pathway, and perhaps the future use of senolytics, we will hit all cell lines at once. At least that’s my hope.

    I saw something just today out of the University of Hawaii where they looked at the upregulation of the “longevity gene” as its known,( FOXO 3.). There have been several supplements in the past identified as FOXO 3 activators such as Vitamin D, selenium, butyrate, skullcap, and R-lipoic acid. But it would seem that perhaps the most potent of all is Astaxanthin which was shown in mice to upregulate it by 90%. I’ve been on this one for years and it’s considered very safe, it also upregulates catalase and SOD, suppresses tumorogenesis, promotes DNA repair. We all have the FOXO 3 gene, but only 1/3 have the longevity version.The researchers stated that by activating it via astaxanthin they were able to make it act like the longevity version. Specifically it was the compound CDX-085 that conferred this benefit.

    • Hi Paul,

      I can barely imagine the shock to have someone in my family having one of the terrible devastating diseases of old age. So far I have been lucky but this might not last. Of course, I agree that taking many pills each day is a very minor annoyance in comparison.

      Very interesting what you said about Astaxanthin. Do you remember the title of the paper that show up-regulation of FOXO in mice?

      Thanks

      • Bradley Wilcox out of the University of Hawaii is the lead author and he has published several articles on the longevity benefits of FOXO 3. I don’t seem to be able to find this particular study, so maybe it was presented at a conference, but there are many articles about it online. It could be as Mark states that it’s longevity without great health.

        • Thanks. I will try to find more information. Astaxanthin is also known to be a very potent anti-oxidant but I have mixed feelings about the applicability of anti-oxidants to retard aging (or extend health-span).

          • I have very mixed feelings about all antioxidants as well. I tend to cycle them. What I really can’t tolerate are the AMPK activators. With both rapamycin and CR , Blagosklonny comments that the liver reacts by developing an insulin resistance so that gluconeogenesis can continue without interruption, similar to a starvation state. I then read that the AMPK activators, other than exercise itself, act to inhibit gluconeogenesis which can seriously impede your ability to vigorously exercise ( especially weights and high intensity). That is exactly how I react. I’d rather have modest blood sugar elevations than to feel like that.

          • Gynostemma tea makes me yawn, so I take that as a sign it is a powerful AMPK activator. I was on Berberine for a year and it never made me tired, and I was doing HI IT most nights. But it did help make me lean. But i dont want to get leaner now so im off it. Plus berberine and intermittent rapamycin was just too much. Living a long time is good, but i dont want to spend it all feeling like I’m on a fast. Resveratrol really affected me. It made me more muscular and lean, gave me cognitive benefits and made my endurance amazing. But it also made my joints ache, and after protracted use really hit my testosterone. So a lot going on with that supplement, probably much more than just AMPK. I’d love to try it again in light of the evidence it can extend critically short telomeres, but it would have to be an occasional megadose combined with something that slowed its metabolism. Incidentally I’m a slow caffeine metaboliser, which uses the same enzyme as resveratrol, which probably expalins why resveratrol affected me so much.

            Right now I’m using gynostemma tea (not too strong) and a honokiol and magnolol extract for glucose control, and exercise of course. Nothing else.

            I think the key thing with anti oxidants is, do they down regulate your own endogenous supply, and if so, do they do a good enough job on their own? I’d say the general answer is no, unless it’s something really special like C60. So generally speaking you’re better off taking supplements like broccoli extract, rosemary, ashwaghanda, etc., that upregulate your own endogenous supply via Nrf-5. Just what I think, anyway.

    • Aging certainly takes on a different meaning when it starts taking family members.

      I’m not certain how much we might want to upregulate FOXO3. It basically resists apoptosis so you will be left with lots of old, crappy cells. I fact the most promising senolytic therapy right now involves stopping FOXO associating with p53. So a great gene for surviving to very old ages in a decrepid state, but certainly not what you want to do to stay healthy, and probably not great for cancer prevention either, something else supercentenarians don’t seem to sufffer from. Guess they dont have any stem cells left!

      • Interesting Mark. I was under the impression that lowering inflammation in general was a safe way to keep P53 active. Do you have a reference?

        • Yes that is one way, but even with p53 active it can still get associated to FOXO and this stops apoptosis so increases the number of uncleared senescent cells.

          Josh wrote extensively on the senolytics treatment involving blocking this association.

          ‘Senolytics against Aging: Snapshot of a Fast-Moving Field.’

          • Thanks Mark. However, Josh only mentions FOXO4 and not FOXO3. I’ve not been able to find any studies, which show that FOXO3 activation should bind to P53, thereby blocking cell apoptosis. Until more information becomes available, I might consider cycle or reduce dose.

  20. I’s amazing how different supplements effect people in such different ways . I can handle almost anything on a sedentary day, which is rare, but on most days I exercise, and it’s very limited what I can handle. None of the AMPK’s, and not even ashwaghanda or andrographis, they make me both fatigued and even anxious. Pine bark is always good for me in every way. The antiinflammatories all seem ok.
    But supplements and flavonoids have a very real effect. Yesterday a study was published in The Faseb Journal showing how the flavonoids in nuts cross the blood brain barrier and effect brain waves. Dr. Bert and colleagues demonstrated that peanuts exert a strong delta wave response, which is linked with a healthy immune response and deep sleep. Pistachios gave the strongest gamma waves, associated with perception, REM sleep and cognitive processing. Pecans did both.

      • Yes. Pine bark is my overall favorite because I can actually feel the difference in my stamina levels; mainly if I take it daily. I can also notice melatonin for sleep. Otherwise, the only thing that I could actually feel was rapamycin. I worry about the possibility of antioxidants undoing the benefits of my exercising. I’m also concerned about things like astralagus and ashwaghanda that can chronically lower cortisol levels because the body can compensate for this by raising catecholamines . Everything has an effect on everything else, which makes all of this so challenging doesn’t it?

        • How about willow bark? Wasn’t it the stuff that make yeast live so much longer? There was the question though that, since it is a derivative of aspirin, it might not do much more than aspirin in humans (although perhaps mitigate GI issues).

          • You’re right ! I take it in the AM and only 80mg ASA in the PM, but because of that I stopped ginkgo and feverfew due to possible bleeding concerns.
            I’m watching Wizards basketball because I’m a sports fanatic and it amazes me how incredibly fit and athletic these guys are. But I bet that their TOR levels are really high. Some of these guys are close to 7 feet by high school age

          • I wonder if anyone’s done lifespan studies on athletes and whether it would be possible to un pick the pro age of effects of higher MTOR from the anti aging effects of general health and fitness?

            Another way to do it might be to plot age of onset of puberty with age of death.

        • What i worry about is supplements cancelling each other out.

          There are studies showing strong synergistic effects of some supplements together on telomere lengthening. And I’ve also now found similar studies showing much higher nrf-2 endogenous anti oxidants response with the right combinations of supplements. But get the combination wrong and you might lose most of the effects. We also dont understand what the relative levels of those supplements should be. I suspect you can’t just chuck 500mg of everything in or you might swamp some of the positive effects. I think we need more in vitro studies, possible combined with the in silico machine learning algorithms.

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