Yesterday, the TRIIM study was described in science news headlines around the world, though, through a glitch, the original research paper is not yet on the Aging Cell web site. (You saw it first here.) I refer you to the writeup in Nature’s News section for a full summary of the paper, and in this column I will add my personal framing, and what I know about the study from private connection to its authors and one of the subjects. The big news is setback of the epigenetic clock, by several methylation measures. Instead of getting a year older during the trial, nine subjects got a year younger, on average, based on the version of the Horvath methylation clock that best predicts lifespan. The study had been originally designed to regrow the thymus. (Loss of thymus function has been linked to the collapse of the immune system that occurs typically before age 70.) Imaging showed that the functional part of the thymus expanded over the course of the trial, and blood tests confirmed improved immune function. The treatment included
- human growth hormone (HGH)
- Vitamin D
It is my belief that the age of our bodies is controlled by several biological clocks. (Greg Fahy, who conceived and conducted the TRIIM study, shares this perspective.) Candidates for clocks include
- Thymic involution
- Methylation profile
- Timekeeper in the hypothalamus
- Telomere length
- Perhaps some changing homeostatic state of signal molecules and transcription factors circulating in the blood
This story is about #1 and #2. To be explicit, I’m saying that the body doesn’t wear out with age, but rather aging is a continuation of the timed growth and development program into a phase of late-life self-destruction. Just as growth and development are under epigenetic control.
The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink, simultaneously losing its functional tissue and filling with useless fat. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives. A healthy immune system is important for fighting infection and for eliminating cancer cells before they become tumors. Immune aging may be related to systemic aging in other ways. (Of course, aging affects the immune system, but it also seems that the immune system may be a driving force in other aspects of aging.)
Thus, a rejuvenated thymus might have generalized anti-aging benefits. I first learned this story from Greg Fahy, PhD, chief scientific officer at 21st Century Medicine. and, indeed, he was the first to think of thymic involution as an aging clock, and remains the most enthusiastic and most knowledgable expert on the relationship of the thymus to aging. Twenty years ago, Fahy experimented on himself, and found evidence that he was able to reverse decline of his thymus with HGH=human growth hormone. Ever since, he has wanted to conduct a clinical trial to see if his N=1 result could be replicated.
Already seven years ago, several of us were speculating [Johnson; Mitteldorf; Rando] that aging is controlled by an epigenetic clock. Epigenetics is gene expression, which changes from moment to moment, from tissue to tissue, and also from young age to old. There are many modes of epigentic control, but the one best studied and easiest to measure is methylation of the cytosine C’s that appear in repetitive islands (C-G-C-G-C-G-C) in our DNA. (Cytosine is the C in ATCG, the four nucleic acids that form the DNA backbone.) Also at this time, Steve Horvath published the first paper using methylation to measure age; Horvath has led in this fast-moving field ever since. I’ve written [here, here, here, and here] about aging clocks based on methylation. The most important things to know are
- The methylation state of a person’s DNA is the most accurate known measure of his biological age. The latest methylation clocks can predict morbidity and mortality even better than chronolotical age.
- I am among the biologists (still a minority but growing in acceptance) that believe methylation is a prime driver of aging. In other words, changing the methylation state of the body’s cells to a more youthful profile will actually make the body younger.
The TRIIM Study
In 2015, Fahy finally had funding and regulatory approval to replicate his one-man trial in a still-tiny sample of ten men, aged 51-65. That it took so long is an indictment of everything about the way aging research is funded in this country; and not just aging—all medical research is prioritized according to projected profits rather than projected health benefits. The protocol included frequent and extensive testing of many aspects of age-related health. Treatment consisted of
- Human growth hormone (HGH), 0.015mg/Kg body weight, adjusted individually according to metabolic response. HGH doesn’t survive digestion, so it is self-injected with a tiny needle in the belly
- Metformin, 500mg daily
- Vitamin D, 3000 IU daily (5 times RDA)
- Zinc, 50mg daily (5 times RDA)
- DHEA, 50mg
The hypothesis was that HGH would stimulate regrowth in the thymus. Zinc and vitamin D were added because they are known to enhance immune function. Metformin, a standard diabetes drug, was added because HGH can cause insulin resistance, a pro-diabetic effect. DHEA is a proto-hormone from which all sex hormones and steroid hormones can be made in the body; and blood levels of DHEA decline steadily with age. DHEA is linked to both better immune function and expression of IGF1. The TRIIM paper says that DHEA was added to help counteract any tendency toward insulin resistance, but according to Examine.com, DHEA does not affect the insulin metabolism.
As the study was planned, the primary endpoint was to be thymus size, and so, at considerable expense, MRI images of the thymus were planned up to 5 times during the 12-month study period. Various blood tests were planned to track other metabolic changes, especially to assure that subjects were not being exposed to increased risk of cancer or diabetes. HGH is weakly linked to cancer risk and more strongly to insulin resistance.
Subjects felt a kick from the daily HGH and some reported temporary weight loss and endurance improvement; but the increase in energy was associated with anxiety and insomnia for some. There was no sustained effect on youthful feeling or appearance.
MRI imaging confirmed that, though the thymus wasn’t increasing in size, the functional matrix of the thymus was indeed regrowing at the expense of the fatty, atrophied portion in 8 of the 9 subjects. Several blood tests indicated better immune function.
- C-reactive protein, a marker of inflammation, decreased.
- The ratio of lymphocytes to moncytes is an emerging measure of resistance to cancer, and TRIIM subjects showed a decrease in monocytes.
- Portion of the T cells that wer PD-1 positive went down. PD-1 is a means by which cancer cells shield themselves from the immune system.
This level of success might have led to a modestly encouraging publication, but fortuitously, Fahy made contact with Horvath toward the end of the study, and Horvath volunteered to analyze changes in the subjects’ methylation. (TRIIM had preserved some blood samples from each of the patients at each time point, so this could be done retrospectively.) The result demonstrated a decrease in methylation age, consistent enough to be visible in a sample of only 9 subjects. This was the first time that a treatment in humans led to a setback of the epigenetic clock.
There was no reason a priori to imagine that HGH would affect methylation age, either directly or through its effect on the thymus. If anything, theorists (including Fahy) imagined that the thymus and DNA methylation functioned as indepdent aging clocks.
Fahy reached out to Steve Horvath, who responded with enthusiasm. Horvath did the methylation analysis and the careful statistics that could draw significant conclusions from a marginal effect in a small sample.
Methylation testing procedure: white blood cells are run through a kit that measures methylation at 850,000 sites in the DNA. Then computer programs are used to extract an age from some small subset of a few hundred sites. Once you have done the lab work, the difficult and expensive part is over. Calculating several different methylation ages is as simple as running the appropriate software package.
- At the start of the test, the average epigenetic age of the group was already well below average chronological age. This is presumably because the subjects tended to be highly-motivated anti-aging enthusiasts. Whatever they were doing before the TRIIM study was already working well. By the Levine Clock, they were 17 years (!) younger than their chronological age, and by the GrimAge clock they were 2 years younger.
- A year of extra chronological age would be expected to add one year to the methylation ages, but instead all methylation clocks registered an average decrease in age.
- The so-called Grim Age clock, new this year from the Horvath lab, is the best available measure of life expectancy. By the Grim Age clock, subjects became a year younger while their chronological age was a year older.
- For most of the clocks, the big drop in epigenetic age came during the last three months of the trial (months 9 to 12), raising the possibility that there is a latency period, and a longer trial might produce a bigger drop in epigenetic age.
- After the trial was over, months 12-18, there was a marginal tendency for epigenetic age to “catch up” with chronological age, a loss of the benefit during the test period. The Grim Age clock, arguably the best indicator, did not regress, but held firm at 18 months.
The Bottom Line
There is no known mechanism whereby HGH is expected to affect the methylation profile. This is not to say that it does not do so, but it is just as viable to think that the combination of vitamin D and Zn is affecting methylation age.
High blood levels of vitamin D and zinc are known to be correlated with lower all-cause mortality and longer life expectancy. Metformin is being investigated in its own right as an anti-aging drug. DHEA has been promoted as an anti-aging supplement for decades, though existing studies indicate DHEA does not increase lifespan in mice. The principal effect of HGH is to increase the hormone IGF1, and DHEA also does this, far more cheaply and over-the-counter, but to a much smaller extent.
HGH is both expensive and theoretically suspect for long-term use. Elevated levels of IGF1 are known to decrease lifespan in rodents; dwarf mice and dwarf humans without IGF1 receptors live longer, healthier lives [ref]. Readers looking to make immediate changes to their personal stack based on the results of this experiment might try the four cheap and proven ingredients, leaving out the HGH for now.
The results are tantalizing, and will certainly motivate follow-up studies, despite the fact that there is no patentable element to the TRIIM protocol. There are five ingredients in the cocktail, all credible, and the interactions among the five are completely unstudied. This first TRIIM study presents good reason to believe that there are anti-aging synergies among some of these ingredients, and it should be an immediate priority to study which among the five are synergizing.
Important, though unrelated news:
Cell phone carriers the world over have plans to roll out 5G technology in the next few years. There is growing evidence that existing 4G technology increases cancer risk, and can cause acute symptoms in sensitive individuals. Lab tests indicate that higher frequency radio waves are a more serious threat. 5G operates in a frequency range ~10 times higher than 4G, and because of absorption in the environment, signals have to be stronger.
(This is not ionizing radiation that can directly break chemical bonds. The biological activity of radio waves is not well understood, but there is a theory that it acts by opening calcium gates in cell membranes, which are a primary mechanism of nerve firing, among other ubiquitous metabolic functions.)
There has been no health testing of 5G frequencies, or if the telecomm companies have performed tests, they haven’t published results. We should be demanding extensive animal and human tests before the technology goes into service.
This weekend, a series of videos about health effects of 5G has been opened at The 5G Summit.
This statistical strength here is very encouraging to me. With the DataBETA project, I hope to use the same kind of methylation re-testing to screen thousands of supplement and drug interactions. The fact that just 10 individuals can produce such strong statiscal significance bodes well for this venture.
You may be correct Josh that methylation patterns drive aging, but what drives methylation patterns? Is it genetic? Environmental? Perhaps intrinsic like say hypothalamic? Some combination?
What’s your thoughts on that?
I have assumed that epigenetic change over time is coded into us. There is either (a) a central clock, perhaps in the hypothalamus, or (b) an attractor in the space of signal molecules that moves in time. (b) is more abstract and harder to explain but worth exploring as a mathematical possibility if there are math geeks out there who would like to work with me.
In either case, my assumption is that development and aging are part of the same continuum, subject to the same time-keeping mechanism, and driven either at source or at least far upstream by epigenetic state.
I earlier found is evidence for antioxidants catalyzing the methylation of cytosaine and free radicals catalyzing the demethylation of 5mC (cytosine). . Given that a number of hormones are antioxidants like melatonin and dhea which decline dramatically with age..estrogen and testosterone also are strong boosters of total antioxidant capacity. I expect the hormones that increase dramatically with age also in some way increase the free radical level in various tissues. So ultimately what controls the aging profile of DNa methylation? At the top of the food chain I would suggest hormone changes
It’s interesting how stress can have profound and genome wide epigenetic effects even leading to lasting psychological disorders https://www.whatisepigenetics.com/excess-stress-changes-marks-dna-epigenetically-harm-mental-health/
Yet, male concentration camp survivors, under extreme stress , and one would think marked changes in methylation patterns, live to a very old age.
I’ve also seen stress lead to very rapid weight gains, and losses, without much alteration in diet or exercise. Altered gene expression may very well account for both of the extreme outcomes.
There you go! Hormones (including stroid hormones like cortisol) affect methylation patterns.
So it sweems pretty reasonable to expect that the changing hormonal milieu surrounding the DNA (which changes with age) can drive the DNA methylation program/clock.
As regards concentration camp survivors ( assuming don’t get murdered, I would expect survivors to have low TOR due to starvation and hard labor and non-survivors to have high Cortisol due to stress reaction.
Interestingly when people are starving their cortisol levels go up as well I think by about 67% if I remember correctly..While other hormones change like melatonin levels double testosterone drops in 1/2 dhea goes up 100% GH goes up LH and FSH drop by 33% or more…..this was mostly form a study of them starving some saiolrs for 5 days to see what happened…SO I am guessing high cortisol does not affect your health negatively if you are starving
Here are excerpts from my interview with David Sinclair in July concerning his theory of aging, which he covers in his book,
Lifespan due out tomorrow
Robert Kane Pappas
how do senolytics impact the methylation clocks? Did they measure it during senolytics tests or they do not measure any epigenetic clock at all?
Instead of injecting HGH I would propose MK-677 as a much cheaper and possibly safer replacement. It’s an HGH secretagogue that has been widely used in the fitness and body building community.
HGH is for people who want to be the best looking corpse in the grave yard.
That is why called this a very mischievous study. It will encourage the clueless to kill themselves with HCG and testosterone.
That is a vast generalization. As I mentioned below, the methylation markers clearly showed a year of rejuvenation. Although there are concerns about HGH, reactivation of the thymus is a big deal and thus may represent a net benefit.
Calling it mischievous is absurd and is obviously intended to discredit both its goals and the authors of the study and furthermore, cut down the tallest blade and quiet attempts by more risk taking individuals to actually move things forward in this arena. Nobody but potential Darwin award winners would manage to kill themselves with HGH.
Response to Nathan
Mischievous because people will not understand that Metformin caused positive result and will poison themselves with HCG.
Yes, we too are working with Steve Horvath and hope to have similar results though I’m not yet admitting that DNA methylation is the determinant of cellular age phenotype. It would seem from present results (we’re expecting more), that we are able to reset the age-phenotype of our rats from middle-old age to beginning adulthood. After a time, aging again commences, but not at abnormally steep rates (so far as I can tell), re-treatment is the obvious answer once aging become apparent (or just before that – on a regular schedule). We still don’t have many answers, but the original contention in my 2013 paper in Biochem(Moscow) was that there are substances in the blood that control the age-phenotype of cells, and hence of the body, and we have purified just such a ‘substance’, (elixir), shown by experiment to reset the body’s ‘age clock’ (a metaphor) to a young age-phenotype. That seems to confirm my hypotheses. A series of injections given to an old rat within a week starts to lower the time in which mazes are solved and lowers the concentrations of blood inflammatory markers (IL-6, TNF) to juvenile levels and this has been repeated three times with a total of 22 rats. The youthful characteristics increase following the end treatment with some rejuvenation taking place a month after treatment ended.So far, 75 days after treatment, the treated rats are still much younger than when they began and much, much younger than age-matched controls. 75 days in rat-time, wherein two weeks of rat-time equals one year of human time, the treatment is still effective more than five rat-years later, though the treated rats are ‘older’ (by our criteria), then their peak ‘youthfulness’. Next, we will work with Greg Fahy on testing the elixir on dogs. We are very certain it will work on dogs, but the dose is yet uncertain – and then, though several people have asked us to stop with dogs, onto people. Finally, a real medicine one without negative effects and the beginning of the end of aging. Of course elixir will first have to be applied to the diseases of aging as aging is not regarded as a disease. But because it should help with all aging conditions perhaps special efforts will be made to accelerate it’s use, it would save the government a bundle of money, (or people will try to bury it (and us)). So I’m very hopeful about this – and working with Greg should be a real experience as Greg gets things done. We have been working with Horvath for a time now, and we hope to get some good results soon. The meaning of those results is still contentious but we’d like them to show rejuvenation – though there are many other characteristics by with rejuvenation can be shown (telomere length, mitochondrial effeciency, lack of senescent cells etc.) What I find most interesting though is that there may be several routes to rejuvenation, of which, we believe elixir to be the best , but we’d like to add some others in the meanwhile.
So Greg Fahy has demonstrated what I have been shouting for years, that aging is a reversible process that doesn’t depend on the tissues involved so much as their environment. The age-phenotype of a cell depend more on its environment than its history. Aging may be completely reversible.
Hello All- regarding Harold’s elixir …(this seems related)
Many years a go a guy named max odens published a paper where he claimed he was able to acheive dramtic lifespan extension in elderly rats with weekly DNA / RNA injections. The study was very obtuse and did nto give a lot of detials.like what kind of dna/rna….here is the abstract>>
Prolongation of the Life Span in Rats
MAX ODENS MD, DTM
First published: October 1973 https://doi.org/10.1111/j.1532-5415.1973.tb01207.x Cited by: 2
Read the full text
To test the effect of RNA‐DNA in preventing the deleterious effects of old age, an experiment was conducted that involved 10 rats with a normal life span of 800–900 days. All were fed the same diet; 5 rats were not treated, and 5 were given weekly injections of DNA + RNA. After twelve weeks the difference in appearance, weight and alertness was remarkable. The 5 untreated rats died before 900 days. Of the treated rats, 4 died at ages of 1600–1900 days, and 1 at 2250 days. A parallel cannot be drawn with aging in human beings fed RNA‐DNA, but the findings on rats may have some application to cellular studies on cancer.
I tried injecting 8 rats with various types of DNA or RNA but gave up on the experiment because he injections seemed ot be too cruel to the rats. There were 2 rats per each of the 4 groups. Each group got a differnt kind of dna one was salmon sperm I think then there were two that got RNA adn two got calf thymus dna…I forgot the other one . Anyway I carefully weighed the rats every day and charted their increase in weight, I was using growth retardation as a marker for aging suppression. Three of the DNA or RNA injections had no effect as compared to the 2 conrols,(maybe an 8% growth retardation) however the two rats injected with calf thymus DNA had a 25% reductioon in growth!! So if there are any experimenters out there this would be a good experiment to look into!! Let me know if you want my original write up I think I can find it somewhere…I never published it.
I’m not yet admitting that DNA methylation is the determinant of cellular age phenotype. It would seem from present results (we’re expecting more), that we are able to reset the age-phenotype of our rats from middle-old age to beginning adulthood.
In this context, an experiment proposed by J. Mitteldorf seems to be relevant:
If it turned out that whatever the young brain was contributing to blood plasma was similar to the biochemical treatment that you have developed, would that not be a highly significant result?
We still don’t have many answers, but the original contention in my 2013 paper in Biochem (Moscow) was that there are substances in the blood that control the age-phenotype of cells, and hence of the body, and we have purified just such a ‘substance’, (elixir), shown by experiment to reset the body’s ‘age clock’ (a metaphor) to a young age-phenotype. That seems to confirm my hypotheses.
I hope it’s OK to provide this link, to that paper:
Amazing that the Horvath clock measurement was not part of the original study design and came about via a “fortuitous” meeting! Josh, perhaps you are in a position to suggest that such measurements are added to other ongoing studies, especially with this result being in the news right now?
There are, for example, a number of metformin studies going on right now. Tacking on Horvath measurements to those studies could start to disentangle the effects of the 5 factors applied here.
This is so important that I’m wondering if there is some crowdsourced way we could help researchers cover the additional expense.
The study was completed in 2016. That was before many of Horvath’s tests.
Of course, I agree completely. I’ve written to Barzilai and tried to buttonhole him at a conference, but he’s a busy man.
But thymus has a marked effect on the hematopoietic compartment so no wonder peripheral blood cells were somewhat stimulated to be produced with better quality. But how about tissue that was not connected thymus at all.
Happy to hear about the success of a pharmacological approach anyways.
Thank you Josh for a great summary and the pointer to the paper (could not find it in the DOI link https://doi.org/10.1111/acel.13028).
Do you have a reference for the DHEA curve? Strange the variations around 55 and 65 (men)…
I pulled the graph off a site that didn’t reference a source. I used it knowing that it is generally right, even though I can’t vouch for the research that went into it.
Here’s another study that produces a comparable curve.
The DOI link works now.
This is very mischievous study.
Metformin excellent drug decreases TOR expected to slow aging.
HGH expected to accelerate aging and very bad drug
So very ambiguous result.
My guess is metformin and H2O .abetter than metformin and HGH
I don’t think this is such a big mystery. I’ve been saying for quite a while that what Horvath is actually measuring is how often cells are replaced by the stem cell compartment.
It’s well known there are very small embryonic like stem cells held in reserve around the body (quick summary here: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.314287) . Although nicely sheltered from insulin signalling to keep them quiescent, these cells can be stimulated into action by sex hormones. So likely the thymus growth and epigenetic regression is being achieved by HGH (and DHEA maybe). But this may not necessary extend life. It might even shorten it because of the using up of valuable stem cell reserves.
I agree that the perturbation of the hematopietic compartment can bring along unexpected changes in PBMCs methylation state.
However as far as I read VSELs are not mainstrain science yet there are groups who dispute their pluripotency. I am sitting at the fence.
I think there’s been enough replication of VSELs to put their existence beyond doubt. But regardless, any quiescent stem cell niche will do to explain the observed rejuvenation. But VSELs are most interesting because of their pluripotency and ability to self renew. It sounds too good to be true that we’d have such cells still within the body, but there you go.
This is interesting. So we would have the epigenetic appearance of a more youthful state, but all we’re ultimately doing is unnecessarily exhausting a very valuable stem cell source .
Welcome back Alan. Rapamycin does retard epigenetic aging :
I have never seen any evidence for metformin doing the same and we know that it impairs endurance.
Agree with you on HGH.
Yes, rapamycin has exactly the opposite effect to HGH (albeit in vitro), preserving cells by making them more quiescent and less metabolically active (you’d expect in Vivo for it to reduce use of stem cell niches). But don’t expect it to make you young.
I really have my doubts about HGH.
From my own observational perspective, people who take HGH injections, in surpa-physiological dosages are constantly saying that they look great, but I do not agree.
To me, it appears that their skin is aging more rapidly.
In addition, if they are taking an unusually high dosage, their facial features often begin to skew toward the neanderthal..I.e. the forehead, jaw an nose appear to enlarge.
It also causes raised liver enzymes.
Also, their muscles may enlarge, but apparently, studies show that they are not stronger, their muscles are just larger and more defined.
Also, their muscles may enlarge, but apparently, studies show that they are not stronger, their muscles are just larger and more defined.
Yes Heather, this is what I know about taking GH from many years ago. Told me a good sk. muscle researcher long time (years) from Autonoma University, Severo Ochoa Center of Molecular Biology (CBM)
As regards HGH you did perfect description of acromegaly secondary to pituitary tumor making growth hormone.
The side data would be more interesting to Harold: The epigenetic age regression accelerated after 9 months of treatment. Secondly post treatment after dosing stopped the epigenetic age again began to catch up with levels pretreatment. From my understanding at 6 months there was 50% benefit still left so probably it will take a year to lose the epigenetic age benefit completely. This shows that any treatment for reversal of aging may require continuous dosing to maintain reversal. We have seen similar pattern emerging in our rat trials. What is also interesting is that length of dosing is also a factor. In our natural extract trial the first month of daily dosing did not show significant results but at the end of 60 days the reversal was incredible. For Elixir we are finding out those parameters.
The most evident sign of aging is the skin. If there was a mechanism of rejuvenation then it will also works on skin and the result will be evident,
The cosmetic industry is multi-billion industry and if such mechanism would exist then it will bring a fortune to the firm it would have discovered.
The most simple way to see if a rejuvenation treatment works is to look at the skin. The skin never lies.
In that case you must definitely see photos of Harold’s skin especially his forearms looks like a 35 year old’s.
Very nice comment about skin.
Best anti-aging skin cream Rapamycin powder in petrolatum.
Need to roll your own.
On a long term basis, yes, perhaps. But you can’t measure genetic aging by looking at someone’s skin. Even if there is improvement in terms of collagen and elasticity a year of rejuvenation would be difficult to measure.
I’m not a scientist – but I’m an engineer. And to that extent I must tell you that if we cannot even agree on a unit of measurement then we’ll end up running in circles.
Huge amount aging is harmful action seneccent cells. Rapamycin reduces senescent cell burden. Absence wrinkles on back hands is real thing can see.
I noticed many of you focus on skin aging…I have a little discovery to share with you-. the hyaluronic acid content of the skin decreases little by little each year after about age 40 so that by age 75 you only have about 25% of the hyaluronic acid in your skin that you did at age 40. This is what plumps out your skin and prevents wrinkles. HA is also the clear goo in your eye and in the cartilage of your joints. If you take oral HA for a period of time ( 1 to2 grams a day) it is like a face lift in a pill. Bill Sardi has a good book on it. And Connie Chung did a report on a Japanese Village where all the people eat root vegetables hjigh in HA instead of rice and none of them endure much in the way of visible skin aging even whiloe working on teh sun nansd smoking into their 90’s You can find that on youtube
So you are proposing a method of measuring aging that offers a precision of maximum 5 year intervals? As posters above have already mentioned – this is highly individual and racial plus it is subject to lifestyle changes. If do intermittent fasting, take NAD+, exercise, healthy diet, etc. but spend all my time sizzling at the beach (especially with my white skin) I’m still going to look like a dried up raisin.
Alan. Ok The skin “ages” a lot, I agree. But most of skin damage is not truly aging (endogenous), which is the subject of interest in this blog. Most sking damage comes from sun radiation (see face compared to ass, or face of peasants agricultors on underdeveloped countries (12-16 hours living outdoors) compared to e.g. white collar executives (most time spent outdoors) working on multinational companies established on tge same poor country.
In addition, tissues suffering MOST from aging are those with non-replicative postmitotic cells, like cardiomyocites, sk.musle and almost all neurons at the CNS (brain and medulla).
That’s a most important OLD truth, nowadays too frequently forgot, surely in part because stem cells (important, no doubt, but not so much for NATURAL aging) are in fashion. But true science is not a question of fashion.
Maybe should check out Horvath paper, just posted by Paul which showed Rapamycin slowed epigenetic aging in skin.
The skin was first organ Judith Canpesi showed senescent cells.
This is true. I’m a dermatologist and geneticist. By far most skin aging is “exogenous” (sun, pollution, nutrition, gravity, etc.). In the cosmetic industry, there is a movement to “heal your skin from within” via nutritional elements, etc.; rather than topicals.
I agree, Florentin.
Even though poor skin quality can be associated with photo-aging from too much exposure to UVA and UVB rays, a true rejuvenation drug should be able to regenerate skin cells in a way that would cause the damaged cells to be eliminated and replaced by newborn skin cells.
Retin-A can reverse photo damage only to a certain degree. The skin may look clarified and more rosy, but deep winkles are not eliminated.
Sun protection starting early will keep skin looking youthful longer.
There are studies that suggest that Monks and nuns often look more youthful than other people their age because they stay cloistered and do not regularly engage in outdoor activities.
Also, you can often know that a person has liver damage by the condition of their skin.
You recommend leaving out HGH if one wants to try it now, but the Mayo Clinic warns against DHEA, because of serious side effects. https://www.mayoclinic.org/drugs-supplements-dhea/art-20364199
By the time this thread concludes we are probably only left with zinc and that with reservations. Look guys, the methylation markers clearly showed a year of rejuvenation. Although there are concerns about HGH reactivation of the thymus is a big deal and thus may represent a net benefit.
19 instances of the word “might” doesn’t lend itself to credibility.
Rejuvenation of degenerative thymus by oral MLT administration and the antagonistic action of melatonin against hydroxyl radical-induced apoptosis of cultured thymocytes in mice
1) Fahy et al Aging Cell 2019 is, potentially, a most POTENTIALLY important and interesting PILOT study (SO, IT DOES NOT “DEMONSTRATE” ANYTHING, NEITHER AGING REVERSAL NOR ANYTHING ELSE) for gerontology and perhaps the human future.
Although today it is Sunday, and have just arrived from long trip, I am now trying hard to wake up important researchers and Professors here in Madrid, who are good colleagues of mine, to help me to better evaluate this pilot study paper. I am especially looking for the opinion of specialists on both immunology and epigenetics, as well as gerontologists here specialized in both these critical areas (in strong relation to this paper). As soon as I have their opinions I will come back here to tell you that plus mine own better based opinion. I will also suggest them to send their opinions on Fahy et al 2019 directly –without only any “filtering” through me- to Josh blog.
2) Concerning the initial question of Paul Rivas (“Josh, i it genetic, epigenetic, environmental?), Paul, “Environmental” is simply impossible if it has to do really with aging, because aging is ENDOGENOUS, and GENETIC, yes, ABSOLUTELY FOR sure, NO REASONABLE DOUBT ABOUT THAT. Epigenetic? i THINK PERHAPS yes too, most likely, these are my “global answers to your question to Josh”.
But, please see also my more detailed “Pre-answer” to you (it was published last July!). It is summarized on Fig. 2 and accompanying text of my last o”Oinion Review paper”:
“Barja G. Towards a unified mechanistic theory of aging. Experimental Gerontology. Exp Gerontol. 124, 110627, 2019 Jun 5;124:110627. [Epub ahead of print]
The main intention of that paper from myself is to propose that ALL the until now called (mechanistic) “Theories of Aging” can ONLY be unified into a single theory, IF that single theory is a PROGRAMMED THEORY. I suggest there that all those “theories” or “hallmarks” (Cell, Lopez-Otin-Blasco etc), or whatever you want to call all those (100 theories? UF!), INCLUDING OF COURSE the MOST IMPORTANT ONES LIKE:
the UPDATED MFRTA-Mitochondrial Free Radical Theory of Aging- (not the old antioxidant based one of course), TELOMER SHORTENING, AUTOPHAGY, PROTEOSTASIS, APOPTOSIS, INFLAMMAGING, EPIGENETICS (sorry, the true full list is surely longer and still for unveil…) ETC ETC ..
all these ARE NOT “THEORIES” AT ALL (that´s main poin on the 2019 paper).
What are they then?
According to FIG. 2 of my paper, they are AGING EFFECTORS (EXECUTORS) OF THE AGING PROGRAM.
Please read my paper if you like to. I consider it the best AMONG the 180 papers that I have published on my whole career. If some of you does not have access to Exper Gerontol, please tell me (firstname.lastname@example.org)
Most importantly, my 2019 paper is dedicated only to the INTRACELLULAR arms of the aging program (what I call “THE CARS” = “The Cellular Aging Regulation System”). The original ms. of this paper, ORIGINALLY, WAS DOUBLE or even more IN SIZE. I had to cut last year in full the second part, among other important reasons, because it was too long to get published at Exper Gerontol (I also had to cut the word “programmed” -now unfortunately missing in the final published form- in the title of the paper). That second part of the original ms. is the one that contains the EXTRACELLULAR PART of the aging program (I call that the “EARS” = Extracellular Aging Regulation System), plus the EPIGENETICS, INFLAMMAGING and AGING CLOCK/S clock/s parts of my ms. (these are all also extracellular, of course).
That´s written. I am working now to re-adapt that second EARS part as a 2nd Hypothesis Article, and see if some good enough sci. journal would agree to publish that….. If not possible in the west, on a nice IF journal, I will go to publish on another continent (not America)…
It is a shame that I still could not publish part 2 (EARS), because it is the main one concerning Fahy et al 2019 paper. But it will be too log to put the whole paper into this Josh´s blog, so I do not do it.
ERAS conception came to me years after my developing the CARS model finally “suddenly”, as a final shot after many accumulating decades, on a hot and strongly stressed day of 2015.
My ms. CARS (now published at Exper Gerontol 2019) passed through 4 journals and 4 years waiting (strong patience on my part…..) before being finally accepted. I am greatly “indebted” to the Editors of Exper. Gerontol. for having published me that.
I also think, as some of you said here, that the aging program controls aging, continuing development, of course.
I can not understand how can any SERIOUS biologist support a non-PA (non programmed aging) evolutionary “theory”? of aging….
The reason is simple: Each animal SPECIES has a DIFFERENT species-specific life span, and that fixed number (e.g., 4 years in rats, 115? years in humans) can vary up to 1 million fold! -or even more?- among animals!. If that value is species-specific, it means that IT IS , NECESSARILY, GENETICALLY (and, most likely, also epigenetically) DETERMINED (genetics and epigenetics “collaborate”, they work together like “good friends”, or, LIKE Archea and alpha-proteobacteria, or hybridizing species, or foreign DNA entering our liver by HGT etc (during evolution, I mean).
Longevity (species longevity, or maximum longevity, the name you prefer to give to it) is then jus another one trait of the species, like body size or body shape, or , or, OR….ETC
Please read my paper if you like to. I consider it the best AMONG the 180 papers that I have published on my whole career. If some of you does not have access to Exper Gerontol, please tell me
I hope you don’t mind if I provide this URL; your paper deserves to be widely read:
I am working now to re-adapt that second EARS part as a 2nd Hypothesis Article, and see if some good enough sci. journal would agree to publish that….. If not possible in the west, on a nice IF journal, I will go to publish on another continent (not America)…
It is a shame that I still could not publish part 2 (EARS), because it is the main one concerning Fahy et al 2019 paper. But it will be too log to put the whole paper into this Josh´s blog, so I do not do it.
It seems like that paper deserves to be widely read, also. Would you consider hosting it somewhere like Google Drive, and posting the link here, so that other Programmed Aging researchers could benefit from your work?
HAH Gustavo’s paper looks a little like a theory I was toying with back in 1998 here is the abstract…while I had a few glaring errors in it most of it was correct
maybe 90%…note hthe prediction that “antioxidant” hormones would remethylate the genome while “free radical” or reproduction related hormones would de methylate the genome……….
Med Hypotheses. 1998 Sep;51(3):179-221.
The evolution of aging: a new approach to an old problem of biology.
Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems.
The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome.
Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation.
Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases.
Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation.
Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner’s syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner’s DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6. The Hayflick limit is reached primarily through loss of cytosine methylation of genes that inhibit replication. Men suffer the diseases of AS#4 at a higher rate than women who suffer from AS#5 more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging, is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer’s disease is caused through LH suppression.
Jeff, yes I remember reading your paper when it was published. Reading again its very dense abstract too many questions came to me to be posed here. I ask you then only a few among them.
1) What -if any- among the many conclusions of your abstract do you think should be adjusted/modulated to the around 20 years of time elapswd and science produced?
2) The abstract states that, “without predation, aging gives no advantage”. But why so? And, could you perhapa eelate this to Jos’s Demographic theory of aging (including predator-prey relationship gazelle-lion “tale” for instance.
3) I see again that you are an expert on hormones and aging. What do you think ofthe choice of selected hormones given to participants on the last Saturday Fahy et al. study: GH, IGF-1 and DHEA.
Also a) GH reversing aging but Ames an Snell dwarf mice etc. have LESS (GH)-insulin-IGF-1-like signaling! b) DHEA was strongly studied on the last XXth century of research but now one rarely sees it on aging papers. It surprised me somewhat to see DHEA selected among a maximum possible use of 5 substances.
Thanks for the questions…When I first wrote that paper in 1998 I made 2 major mistakes basically due to my over reaching and trying to solve the Rubik’s cube of aging while missing some facts. The cause of childhood progeria had not yet been discovered, but I had seen a paper describing progeria as beng caused by a defective DNA helicase..I later learned that the paper was referring to Werner’s syndrome but calling it progeria (adult progeria) . I mistakenly assumed that childhood progeria was being caused by a defective helicase as well. It turns out it was being caused by a defective lamin A protein. Only Werner’s syndrome (adult progeria) was being caused by a defective helicase. My second big mistake was I assumed the defective helicases had gained a function rather than lost a function. I assumed that their purpose was to remove DNA methylation to control/drive the aging program and they were just doing it at a faster rate than normal. It turns out that the lamin A proteins in progeria were truncated incrroectly so tht they lost their function somewhat of binding to DNA and suppressing genes and mainting cellular differentiation. Likewise it tuirns out the DNA helicase protein defective in Werner’s Syndrome actually had 2 functions, 1. was to come together with 5 other Wrn helicase proteins to make the helicase protein, and the single WRN helicase proteins were , like lamin A proteins, functioning as proteins that bind to DNA to suppress genes and maintain differntiation in stem cells. Like the lamin A protein the WRN helciase proteins was improperly truncated which prevented proper binding to DNA. Turns out these two proteins displayed the general theme of anti aging proteins-things that bind to or cover up the DNA to prevent transcription.(like DNA mehtylation and chromatin condensation)
As far as the hormones go i would not have used HGH -like many say Hgh might just give you a good looking corpse-it probabyl does not slow aging , just makes you look more youthful and kills you quicker. I think Fahy must have thought “we want to grow the thymus so let’s use growth hormone”. I know of an unpublished study by Donner Denckla and Jim Morley where they cut out the hypothalmus (or maybe pituitary) of rats and then replaced all the hormones it produced except for Growth hormone-the rats went on to live ridculously long lives. Actually the first cases of thymus regrowth were caused by using melatonin and zinc. Melatonin is the ultimate anti aging hromone and has been used to reverse menopauise in women who had recently entered menopause. the hormones I would have used to remethyulate the genome are simply the hormones that decline dramatically with age like melatonin, pregnenolone, progeserone, esrogen, testosterone, dhea. I had deemed these antioxidant hormones in my paper and they all seem to be associated with cGMP stimulation ( 2nd messenger hormone signal), as opposed to any hormones that increase with age and cause aging (like LH and FSH) ..which all seem to stimlate the cAMP pathway as their 2nd messenger effect.
As far as agng and predation goes… aging is only useful as an evolved defense to evolving predation ( evloved throguh species selection which is one order higher than group selection). It helps maintain diversity of the gene pool by preventing any one individual from contributing too much to the gene pool which would reduce diversity. Diversity is only important when a species needs to quickly mount *(evolve) a defense to a new form of predation.-not enough diversity t? then the species goes extinct at the local level.(If they are all identical clones-if you kill one you can kill them all). If a species no longer encounters predation ( a constantly changing force of mortality) the diversity is actually harmful to the species survival and will be lost over time as it perfects defenses to NON-evolving forces of mortality like starvation, drought, fires, etc…..whicb are alwesy the same. In the absence of predation evoluton will select thsoe individuals who move closer and closer to having perefct famine and drought defenese…and then here we will find reproduction increasing with age like in some tortoises.
Thank you Ian. I thaught that the 30 days open that Exp. Gerontol. gave to my article was finished at least one month ago…
But, it seems to work. I do not have any problem with you posting it and eould be happy with it. What I do not know is if it is legal or not since Elsevier helds the Copyright and I do not had grant money to pay thousands of US$ to make it open. I can not pay from my own pocket every paper that I publish to make it open.
Concerning EARS it is written, but I must enter some new important findings like Fagy et al .I will not delay much I hope. I hope to find a fast and nice publisher for that.
I continue previous comment here (it was too long to be posted in full according to the machine):
So, it is IMPOSSIBLE Mr Medawar, Mr Williams, and Mr. Kirkwood, absolutely impossible that longevity be non-genetically determined as you pretend.
I do not need to do any experiment or scientific observation, in the wild or, in the lab., to KNOW THAT self-evident thing. I knew that, already, when I started to study aging and ROS (then I studied only antioxidants, not still mitochondrial ros) back on 1988.
Another question you could pose to me would be: -after ACCEPTING the evident fact that aging is programmed (because those not accepting what is evident are not scientists…; and my Fig. 2 is correct for sure, although of course NOT in the details)-
OK Gustavo, but, please tell us: WHAT IS/are the aging effector/s PROGRAMMED?
There, a non-PA would always answer: MAINTENANCE! (MORE DEFENCE plus REPAIR IN LONG-LIVED SPECIES).
But I know this is false!. Because both Antioxidant enzymes and GSH either do not correlate or correlate NEGATIVELY with longevity across species (various species from mice to men). They DO NOT APPROPRIATELY correlate with longevity. See not only our review Pérez-Campo et al…., Barja-G J. Comp. Physiol. B. 168:149-158, 1998. That was a review including all the THEN available data from ours as well as from any other lab. around the world known published data to us). By the way, THAT paper is the ONLY other paper in my life that also had to pass through a calvary of 4 sci. journals and 4 years before being published in a non-American country (Germany, JCP was then the BEST journal of Comparative Animal Physiology). Still, they (JCP) needed 2 whole years! to decide if they will publish my paper or not. Thanks god, they finally did it. I am also most grateful to them for finally doing it.
And, MOST IMPORTANTLY, both the REPAIR OF NUCLEAR DNA DAMAGE AND the REPAIR OF PROTEIN -cellular- DAMAGE…from ENDOGENOUS ORIGIN does not appropriately correlate with longevity either, because they do not correlate or long-lived animals have LESS (instead of more) repair than short-lived ones, like for antioxidants. It is logic. Long-lived animals generate less endogenous damage “on purpose”, so that they do not need to maintain high expensive levels of antioxidants and repair. That is why humans have less repair and antioxidants than rats, at least in ALL cell regions OUT of the mitochondria…(INSIDE MITOCHONDRIA, IT IS STILL NOT RESOLVED TODAY…Remember Nature paper in mice by Schriner et al: overexpressing MITOCHONDRIAL, but not peroxisomal or “” CATALASE, INCREASED MOUSE LONGEVITY, THE ONLY ANTIOXIDANT OVEREXPRESSOR SUCCESFULLY INCREASING MOUSE LONGEVITY WAS THAT INCREASED INSIDE THE MITOCHONDRIA….)
(please note that for repair of DNA damage from EXOGENOUS ORIGIN -the one NOT relevant for longevity-, there is, IN THAT CASE, of course!, POSITIVE correlation with longevity, see the first Hart and Setlow 1970´s seminal paper on “unscheduled DNA synthesis on dermal fibroblasts, followed by many others agreeing which were put together in a review by Cortopassi and Wang?). PLEASE LOOK, MOTHER NATURE HAS ALREADY CREATED a species aging slowly, like a cow. But then, mother Nature forgot to add extra protection from sun rays radiation including UV radiation. The result is that that animal would soon die, e.g., due to cancer-induced skin cancer (exogenous source of mortality), in spite of its slow-endogenous- aging in all the rest of the endogenous organs. It could live 2 years, like a mouse instead of 30 like a cow. Fortunately, mother Nature is not so stupid, and added (to cows) extra DNA repair protection in the cow skin, to ensure that the slow aging inside cow organs could BE PHENOTYPICALLY EXPRESSED instead of being nullified by the sun rays.
That endogenous repair of, LOOK OUT- NUCLEAR- DNA and protein, SIMILARLY TO the case of the endogenously synthesized TOTAL CELLULAR antioxidants, AGAIN either are not correlated or are INVERSELY correlated with longevity (see many papers on this from Stuart, Page, and others, from the well known and prestigious Vilhelm Bohr´s DNA repair group at NIA/NIH (so, it must be well done work, I am pretty sure of it).
Then, if neither total cellular defence nor repair can be the explanation, what is left TO CAUSE AGING?:
The answer is on the long list above: mitROS production, DBI, autophagy, apoptosis, telomere shortening, inflammaging (that is EARS-related), epigenetics in concert with aging genes (please see also my Biogerontology 2008 “Gene Cluster Hypothesis of Aging” paper PROPOSING the AP could perhaps be HIERARCHICALLY organized).
Please note that all these better known aging mechanisms, with the only exception of autophagy, are PRO-AGING effectors, NOT ANTI-AGING ones. My proposal in the 2019 paper is that all these are controlled by the Aging Program lying mainly in the nucleus of each of our cells. It was inherited during millions of years of biological evolution from early eukaryotic cells (after the first symbiogenesis event creating the first eukaryotic cell by fusing an archaea? and an proto-mitochondria (alpha-proteobacteria?). That is why “Aging IS VERY OLD” (Clark, 2004, LA, CA). That is why yeast (unicellular) has the same insulin like-signaling of aging than mice….(highgly conserved aging genes)
And then Josh does not agreed with me on this because, he said, (CARS) is “cellular”, not systemic. OK Josh, but please wait to read my second paper (the EARS one) still unfortunately unpublished, only because they rejected it, the 4 journals (to be more precise, 3 journals and one USA book…..since 2015).
On my 2nd paper I will try to explain how all the millions of CARS of our body (there is 1 CARS per cell) are coordinated with each other SYSTEMICALLY. This could explaining the amazing? results from heterochronic parabiosis experiments, as well as inflammaging, and, perhaps epigenetics and aging study results, and , PERHAPS, even, as Josh himself and some others have published how a central clock/s could coordinate all those cellular clocks.
I can advance to you that my idea is very analogous to what we already know about coordination of free running circadian clocks: you put a single cell into a Petri dish, and many approximately 24 hours free running circadian ryhtms continue to be expressed! at single cell level. Only one cell is necessary to show the circadian rythm. What the hypothalamus (SNC nuclei) does, we know it rather well in physiology, is, in essence, to coordinate all those millions of single cell clocks. If it were not like that, the different cells and tissues in your body would have very different rythms, which would be of course disastrous for your health and whole body homeostasis. Perhaps something similar occurs for CARS coordination between cels as well superior control by putative brain? central clocks.
3) Mark, I also think most contradictory with long-lived Ames and Snell dwarf mice and (GH)-IGF-1-like signaling clearly being PRO-AGING, what now Steve Horvath Fahy et al. paper suggests. They resurrect the old proposal of GH as antiaging. It is contradictory with the long-lived mouse mutants. So, again ¿? In addition, we all know about the high RISK OF CANCER of taking GH supplements (Steve says no problem, but 1,5 years is nothing about cancer risk…). GH is good to strengthen somewhat my old wasted muscles (I am 64), but I would never take it because I do not want to increase my cancer risk. It is already high enough, 1st due to aging, 2nd due to heavy industry related pollution etc, I do not want to add MORE! No thanks) .
Concerning the antidiabetic metformin, do you know that it inhibits mitochondrial complex I, precisely the ETC complex on which the longevity-related mitROS are produced (not the complex III ROS) (see many many papers on this from my lab on 1997-2002 approx.
4) Have you noticed the most important Maria Blasco paper on PNAS around July? 2019. They demonstrate, for the first time, that the RATE of telomere shortening DOES APPROPIATELY correlate longevity in around 10 species of mammals and birds (like mitROS production, and mtDNA oxidative damage, and fatty acid double bond index….ALL ros-RELATED, AND NO OTHER PARAMETER DEMONSTRATED UP TO NOW). She chosed a mix of around 10 species (I do not remember exactly at this moment), Of which, around half of them are mammals and around half are birds. Previous studies by many labs. had previously shown that, contrarily, telomere LENGTH, correlated with longevity on the WRONG way (NEGATIVELY), or did not correlate at all (mouse telomeres are much longer than human ones, which was “opposite” to the telomere hypothesis of aging). But now she shows that the parameter important CAN be the RATE of teleomere SHORTENING, not the length. So that rate (like mitROSp rate) is much slower in humans than in mice, and that could perhaps CONTRIBUTE TO explain why HUMANS live longer than mice.
However, please remind that correlation DOES NOT DEMONSTRATE CAUSATION, at all.
But, MOST IMPORTANTLY, ANY “theory” of aging, to be accepted, it must BE ABLE TO explain WHY DIFFERENT ANIMAL SPECIES CAN HAVE DIFFERENT LONGEVITIES. So, these new data are a new important addition to the telomere hypothesis of aging, and TO CARS.
I will come back here if I obtain more specialized immuno or epigentic criticisms/support about Fahy et al.
Good to see you comment here again Gustavo. I read your CARS paper when you sent it to me a while back. Very interesting and I agree most interventions that extent lifespan WITHIN a species are not really touching the real aging program.
Ok but as you wiil see on my CARS scheme of the AP at list CR impacts the program (part A, afferent signaling from insulin to the nuclear AP; CR shares in part same signaliing as the Ames Snell and many other dowstream mutants in ECF, nembrane receptors or cytisol to finally modify AP gene expression through TFs like FOXO and others. Same as C.elegans and even yeast.
I expect the species AP (the “big effect”) to have more target genes and aging effectors (part C in Fig. 2 of Exp. Geronto. 2019) and/or higher effector intensity of them, compared to the inteaspecies increase in longevity to CR, MetR or Rapamycin (small effect). But part of the interspecies AP would be used, to “economize genes”, for the intraspecies longevity response. Non sense to have 2 separated APs specially since in CR we know already (microarray studies) that the number of target genes involved is in the order of hundreds. Another question, fortunately for us is that hierarchical organization of genes and their dialectical relatoonships within the nuclear AP reduces strongly the number of MASTER GENES (equivalent to tge Hox genes controlling development) . See my hypothesis paper Barja Biogerontology 2008 on the AP gene cluster of aging
Genes don’t seem to be very different between species Gustavo, so we are left with their position on the genome and hence epigenetic control of their expression.
For example, mouse telomerase gene is in a different chromosome from humans and is far from the telomere in mice but not humans. End result = much greater expression in mice. Nevertheless their rate of telomere shortening is far greater than humans, due to effects of other genes.
All genes seem to effect all other genes. Total confusing spagetti of influences. If we want to live long enough to figure all this out, we better come up with a better way to delay or reverse aging.
Mark I agree. There are data both between species and within them (e.g.CR) pointing to regulation of gene expression as most important fot longevity. If you look at both Fig.2 on may 2019 review and to the gene cluster hypothesis figure (Barja-G, Biogerontology, 2008) what I suggest is that either different sets of target genes and or different degrees of expression of these genes could explain 30 fold diff. In longevity and aging rate between mice and men (big effect!, and also 1,4 fold difference in them between CR and AL (or Dwarf mice and wild tipe (“small effect”).
Concerning interactions this is exactly what I tried to schematize in highly simplified form on the gene clúster of aging Figure (target and master genes, intermediate ones, their regulatory proteins, etc).
Do not dispair . A human is a network of 100.000 mllion cells (surely much more complex than rge AO, and still we manage to teach Physiology and Neurophysiology (Brain) to our students…without confusing them. I hope!
It has hit the web.
Aging is a very long term process. Any treatment that slowed aging for a year doesn’t prove nothing
Likewise in the majority of cancer cases the cytostatic drugs are effective in the short time but in the long time only few proved effective and only combined with other factors.
At best a successfully anti-aging treatment will slow aging for a sufficient time that other factors will cause the death. A permanent rejuvenation of one person is impossible. The “immortality” could be achieved only by reproduction as the evolution have already proved.
as the evolution have already proved
If you would read through the archives of this blog, you would find that this sort of argument has been fairly effectively refuted.
Is there any organism on this planet that is “immortal” as entity. ?
you probably would want to look in the plant kingdom for immortals…there is a creosote bush in the mojave desert that is 11,000+ years old. A 13,000 year old eucalyptus tree in Australia, Thre are also Junipers, yews, Giant Seqouias,cypress and cedars that live many 1,000’s of years old.How? Defense to predators/insects. So you find they make mulch for your garden from the oldest living trees to repel insects.They also say the amoeba is immortal>>>>>
Amoeba is divided by binary fission in which a parent cell produces two equally half daughter cells and each daughter cell grows into an adult. There is no natural death in these organisms. There is no remains of parent body cell and parent cannot be said to have died. … That is why, Amoeba is considered as immortal.Jan 18, 2018
Amoeba is considered an Immortal comment – Brainly.in
https://brainly.in › question There are soem really long living animals like the artic clam…500 years+ maybe immortal? Sea Cucumbers down at thermal vents 800 years+ maybe immortal…??
If by “immortal” you mean “lives forever”, then there is no such thing. We have not experienced forever yet.
If by “immortal” you mean “does not age”, then there are many, many plants and a handful of animals in that category. Some are in my book. Google “oldest living things” and you’ll find many lists.
HAHA right josh we don’t even know if God is immortal if there is one.
.I think he meant immortal as ..if not killed by outside forces….would the organsim just keep on living on and on and not destroy ittself from within someday
in that case it would be impossible for us to know for sure…but there are quite a few candidates that seem likely to be immortal in the plant world.
You are a physicist. You know that aging in general is according to the second law. If an organism age slowly compared with the human life doesn’t mean that it doesn’t age. Everything ages not only organisms, even stars. Each at their own pace.
Aging is a biological, not a physical process. Stars age for a different reason than biological systems age. Curiously, most plants and animals and even protozoa age for closely-related reasons. The genes that regulate aging are related in mammals, worms, and yeast cells.
As Ian B reminds us below, living things maintain their low-entropy state by turning sunlight or chemical energy into waste heat. There is no physical reason they cannot do that forever, but biologically most are programmed to do it for a finite time, then give up the ghost.
Many trees get larger and their probability of dying gets lower, year after year after year. This is “negative senescence”. Clams and lobsters and (maybe) sharks do the same.
The “second law” of thermodynamics applies to closed systems, which living organisms are plainly not. If you wish to see what would happen if they were, try not eating for a month, and see how that works out for you.
After that educational experience, perhaps you could explain what relevance the same “second law” has to the process whereby an adult human develops from a single cell, over the course of about twenty years. A naive observer might conclude that the entropy of the organism decreases considerably in that process, at the cost of increasing the entropy of the surrounding environment, not least the municipal sewage treatment system.
Now, can we be done with these silly, pseudo-scientific objections?
I agree Ian. We’ve known for about a century that every animal is itself a cell line, the result of 2 to the power of 40 or 50 cell divisions from a single original cell. We also know the germ cell line has been alive, as a cell line, for hundreds of millions of years, otherwise we would not be here.
So there’s at least 2 types of aging. That of the individual cell, which could be inconsequential to a multi-cellular organism. And that of the somatic cell *lines*, which, since the germ line is immortal, should not happen.
Despite this, the conventional perception of aging in humans constantly mixes up the two, and entropy is the first cause people think of. No wonder the free radical theory of aging is so popular with the public.
This reminds me of Steve Horvath’s comment that the only treatment he knew of that could reduce the eAge of a tissue was hormone replacement therapy in women.
Not sure if I can paste links here, the study can be found searching for “Menopause accelerates biological aging” from a couple years ago. They report that “a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078)”.
Also linked to the fact that menopause in women seems to accelerate eAge, so it would stand to reason that a restoration of a younger hormonal balance would affect it. But somewhat contradicting the earlier finding that female breast tissue shows higher eAge than other organs, presumably because it is exposed to more, is more sensitive to, sex hormones.
I’m wondering whether I could see age-reversal effects if I had access to Horvath methylation clock? Beside other interventions and supplements, I take
– high dose Vitamin D3
– Vitamin K2, to counterbalance D3
– Glucosamine, instead of Metformin
This is a fascinating article discussing epigenetic drift and life span across species. It’s particularly interesting to us because it discusses the impact of calorie restriction on methylation patterns. CR rather clearly lessens methylation and this may well account, at least on part, to its longevity effect.
Since rapamycin is a CR mimetic, it’s fair to ask if its universal lifespan extending properties may be secondary to its epigenetic influence. This may or may not be in addition to its inhibition of mTOR, or it may be a very separate longevity pathway not related to mTOR at all like we’ve seen with rapamycin and autophagy.
Epigenetic changes with age go in both directions, with some genes turned on and others turned off. If I remember right, demethylation with age (turning on genes) is more common than the opposite. So your observation that CR is linked to demethylation isn’t obviously an explantion for the anti-aging effects.
I believe that it is the epigenetic drift that is crucial here. Much more drift in short lived species like mice, much less drift in those following CR. This doesn’t appear to be mTOR related.
Yes but what are we talking about here? Are all cells having this drift? Or is it just that cells are having to extend their working life because they are not being replaced by stem cells with correct, young methylation patterns?
It is the analogy of old people living in a block of flats moving out and being replaced by younger people. The people did not get younger, old people were just replaced by younger people.
Until we answer this question it is useless to speculate about epigenetic aging.
If we look at epigenetic drift we have :
We also have less drift in those following calorie restriction and they too live longer and have methylation patterns similar to young people on certain areas of their genome.
None of this proves cause and effect, and it may be a stem cell phenomenon as Mark suggests, but it’s getting more interesting.
“It is the analogy of old people living in a block of flats moving out and being replaced by younger people.”
Well, from the perspective of the building the people did get younger. If the building was made out of people it would have gotten younger by this measure. Of course the process that has led to the “getting younger” is different than each tenant rejuvenating. But the measurement (of eAGE) might be equally meaningful.
I think you are pointing out to stem cells being epigenetically younger than older ones. They could also have longer telomeres and so be capable of spawning a longer lived cell line. I haven’t found much definitive information on this (need to research it more though).
It is interesting to speculate as to why the body keeps a reserve of stem cells. Plants seem to have independently evolved this as well.
It could be that the body finds it advantageous to have a reserve of less differentiated cells, so that replenishing tissues is more efficient and less epigenetically error-prone. There was also a theory of the ‘master strand’ of DNA which would be kept as a stem cell each time the progenitor divided, but I believe this theory has been discredited as no association was found between the master and the copy and which ‘fate’ each cell endured. Stem cells also tend to be smaller, could they be ‘protected’ by having a less active metabolism? And what is being protected here, the genome or the epi-genome?.
I have only seen a couple of papers on this question. “What’s the evolutionary advantage of stem cells?”. I think this may point to problems evolution has encountered with replenishing tissues out of ‘terminally’ differentiated somatic cells. Then again, I believe recent findings point to some somatic cells acquiring stem-cellness so things may be a more bi-directional than originally thought.
Another thuoght for Gustavo- Hi I know your focus has a strong mitochondrial aging component, and if you look at the table in my 1998 paper which assigns which aging symptoms belong to which aging system, there was a set of aging symptoms illuminated by the lamin A defect seen in progeria. This erroneous truncation of the lamin A protein has been seen in older normal healthy adults so it likely does reflect an acceleration of one segment of normal aging. However there are a whole host of accelerated unique aging symptoms caused by various defects in mitochondria. as well as another group of aging symptoms that overlap mitochondrial aging symptoms which are caused by a defect in a DNA tyopisomerase in ataxia telngiectasia, defective XPA protein (dna repair) in xeroderma pigmentosum, and defective CSB protein (for DNA repair) seen in Cockayne syndrome. So my thought without researching this further is that if all aging is controlled epigentically, the same theme over and over, then when it comes to mitochondrial contol of aging we mnight weant to look for some sort of proteins made by the mitochondroal DNA that bind to nuclear DNA to prevent aging. . We also should look for proteins in the 3 segmental progeroid diseases of AT, XP, and CS that has a double duty to bind to DNA in stem cells.
I agree Adrian, there is no difference to the body (the building) by which mechanism (rejuvenation or replacement) cells got younger.
That is why I’ve been at pains to point out that cell replacement is a viable rejuvenation strategy, and that Horvath might (in vivo) actually be measuring cell replacement. Of course it is more complicated than that – but that brings me to you next point.
Stem cells are required because metabolism damages cells. I believe this ‘damage’ is mainly epi genetic. So the body has somatic cells that have a certain attrition rate, depending on the tissue, they have progenitor cells that stand ready to replace them, and a deeper reserve of quiescent stem cells that are protected from epigenetic changes by the fact of their metabolic inactivity. This can be seen by the fact the more primitive the stem cell, the less mitochondria it has; and they are always round, fused mitochondria. To all intents a purposes they are asleep.
So maybe aging is what we see in the soma, but deep down there might be young, sleeping cells available to rejuvenate tissues. This is what we might be seeing in this study – rather than a cell intrinsic rejuvenation effect.
Hi Mark. I agree that stem cells may be a reservoir of epigenetically protected cells. Evolution may have found that proliferating only terminally differentiated cells is not efficient or may result in less controlable tissues. At least if we discard the ‘immortal DNA strand’ hypothesis, I’d say this is the most likely one now.
But regarding your idea that aAge reflects the time a cell line has differentiated from its stem cell progenitor. There’s one result contradicting it.
The Horvath clock, at least for the 353 sites it tracks, yields the same age in peripheral blood than slowly proliferating tissue like neurons or muscle cells. So it seems that stem cells also ‘age’ by their DNAm measure. And as we have discussed here a few times, in bone marrow transplants it is the age of the donor which is maintained, further proving that this is the case.
So, I wouldn’t discard the idea that an increase in proliferation is the cause of health and life-span increases in these studies, but DNAm itself appears to be an independent measure.
This works for all rates of proliferation Adrian.
If a cell is permanently in place to do a job, i.e. a neuron, it will obviously age epigenetically, but will try and minimise this – as neurons are known to do by only burning sugars or ketones, never fat.
If a cell turns over rapidly, its own epigenetic aging is irrelevant, i.e. a leukocyte, which lives for 6 days tops – but in order to service this rapidly turned over tissue a large pool of progenitors has to exist, and this will age epigenetically.
An intermediate cell, like a muscle cell, which is turned over but only slowly, will be a mixture between the two – itself will age epigenetically, as will its smaller progenitor pool.
My statement ‘time since a cell differentiated’ is correct, but some more elaboration was required to explain the concept fully. A video would communicate this a million times better. Imagine cells in a tissue falling away like water from a pool, only to be replaced from a higher pool of progenitors, in turn supplied by a higher reserve of less committed stem cells. A faster flow of water (cells) means the water cannot grow stagnant (epigenetically old), but also erodes telomeres faster. That’s the gist.
Yeah the first studies about DNA methylatyion and aging were done by Al mazin and I think he was correct when he said he had found that dna methylation decreases globally with age…and the methylation content of the cell was as accurate a maker of the age of the cell as the telomere length//
But then as usual things are not that simple and that durign aging there is demthylation of various sites and methylation of others…but ioverall it is supposed to be a net decrease with age.
Mark – The methylation clocks based on white blood cells work because the epigenetic age of these cells reflects the epigenetic age of the progenitor cells in the bone marrow from which they were derived.
I believe there is a lot of emphasis now on cellular aging. However I suspect that cellular aging itself might not be that fatal. I keep finding articles like this where for example muscle and liver cells preserve their proliferative capacity in aging.
Aging Does Not Reduce the Hepatocyte Proliferative Response of Mice to the Primary Mitogen TCPOBOP
Primary human muscle precursor cells obtained from young and old donors produce similar proliferative, differentiation and senescent profiles in culture
It is the autocrine and paracrine extracellular signalling that makes muscle and liver waste away. If we look at the physiology of aging it is mostly the tissue composition, extracellular matrix composition or waste deposition that causes the frailty of old age.
So my idea that there is cellular aging, because of epigenetics, organelle damage, DNA damage, telomere shortening, you name your favorite. But the function of the cell does not decline that much as seen from the aging organism phenotype. The aging cells keep up their function but feel the stress of internal damage. So they signal this stress and the resulting changes in the tissue and cell behaviour causes the aging phenotype. For example wnt signalling.
I wonder if there is any intervention that is aimed at the extracellular signalling level. So not nucleus level, like OSKM reprogramming, not metabolism like rapamycin, CR, metformin, etc and not endocrine, like growth hormons, but tissue local intervention.
GaborB best deduction so far on this post. What you have shared is the reason why cells rejuvenate so fast in some of the successful anti aging trials. We do have an intervention that works via extracellular signalling.
Hi Gabor, I’d say causality is the other way around. Cellular ageing causes organism phenotypic ageing. Decline in immune system function, bone or cartilage maintenance are good examples. The root cause can be traced back to a change in cellular behaviour, and for that happen there must have been a change in gene expression.
If eAge is either a positive adaptation to the medium, or unimportant for cellular function, why do interventions that specifically target it seem to improve life and health-span?
Old cells may be quite capable of proliferation and appear functionally similar to young ones, particularly if immortalised with telomerase. But the gene expression profile of those cells, and as a result their behaviour and signalling in vivo, could be quite damaging to living tissue.
You’ve homed in on an essential split in the anti-aging community. There are two positions, and they imply very different approaches to anti-aging research.
1) Aging is caused by accumulated damage that the body is unable to fix. Epigentic change with age reflects the body’s response to this damage, trying harder to fix it. Our job is to repair damage, in all its forms.
2) Aging is an epigenetic program akin to growth/development, but with an explictly destructive purpose. Damage is secondary. It is both self-inflicted (e.g., inflammation) and a result of repair mechanisms that have been dialed down. If we can restore the body’s youthful epigenetic state, the body will take care of the damage itself.
These two ideas about what aging is lead to very different strategies. For one thing, if we believe (1) then restoring a youthful methylation profile would be expected to slightly shorten life expectancy, while if we believe (2) then a youthful methylation profile might be the Philosopher’s Stone.
I think most people reading this know where I stand. I’ve been a proponent of position (2) for 22 years. My book Cracking the Aging Code summarizes the evidence for this position, and then goes on to describe the implications.
Josh all processes in nature are irreversible You cannot restore a previous state of a process whatever that process would be.
1 – a tree absorbs carbon dioxide from the atmosphere, and using electromagnetic energy for photosynthesis, transforms the carbon into cellulose, and releases the oxygen back into the atmosphere.
2 – somebody cuts down the tree and burns it as firewood. The cellulose of which the wood is composed combines with atmospheric oxygen, releasing carbon dioxide back into the atmosphere, along with heat energy.
This process has been running for several billion years already (with bacterial decomposition instead of fire), and will remain fully reversible as long as the sun keeps shining and biological life exists on earth.
You don’t know what you’re talking about.
I think what Florentin means is that we still can not unboil an egg.
Hi Adrian, Josh, I think my opinion is quite close to yours. Maybe its just a revelation to me – I have always thought about aging as 50% decline in cellular function causes 50% decline in tissue function causes 50% decline in organism function.
Now my opinion is something like: 1% deviation in nucleus causes 10% decline in cellular function causes 30% decline in EM and tissue function causes 50% decline in organism function.
I think its not really important if it is damage or program, we must somehow fix as much as we can, but maybe the easiest target to fix is the extracellular signalling component. And I havent really seen interventions targeting for example Wnt signalling, it doesnt mean such interventions are non existent of course.
It is totally plausible to me that ECM changes can rejuvenate cells. After all we know the ECM mechanically interacts with the cytoskeleton inside cells, which influences cell size and shape. And we know cell size and shape can influence the characteristics of a cell type, from somatic to stem cell.
Unfortunately we know so little about these processes.
I digged a little bit into Wnt signalling.
I have found some recent papers on poricoic acid. Anyone heard about it before?
This is a fungal toxin from traditional chinese medicine. Seems to inhibit Wnt signalling.
Together with melatonin there are some early results in preventing kidney scar formation.
Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum
Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a
Wnt/beta-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling
The degree of damage that you are suggesting may be true but it’s not evident using any clinical measurements. For instance, my renal and hepatic function, as well as my cardiac ejection fraction and CRP are the same at 64 as they were at 24. I’m also skeptical that on biopsy my tissues would be riddled with any significant degree of fibrosis.
you are doing really well. hats off.
how about defining the organism fitness as chances for 1 year disease free survival.
What organ tissues fail the most obviously with aging?
Probably the arterial wall. Maybe also the skin. Anything else?
We should look for clinical measurements there.
….which brings us back to the topic of this post, ‘declining immune function’.
You can have the cleanest arteries, lowest CRP, best cardiac function ever, but once your immune system mistakenly attacks your own tissue, it’s usually a one way street.
Strong immune suppressants and/or chemo drugs will accelerate aging dramatically.
The immune system wears out long before your heart and arteries do.
IMHO we need much more focus on strong immune system. We know how to eat well and exercise, but immunosenescence will eventually catch us.
Yes, it’s easy to forget we are under constant outside attack – and the immune system has to deal with this AND clearance of senescent cells produced by our own body.
Our systems are incredibly robust and as one can see with very very small error rates over millions of years. Even small degree change in the error rates could have wiped out all biological life forms. Age related changes are deliberate and that’s why so successful ensuring 100% death rate within a given lifespan. Giuliano and Paul are exceptions who through research have Incorporated regimes both in interventions and lifestyle to show such great results. Their core secret could be conquering chronic inflammation. That alone can be sufficient for bulk of their favourable results. In fact Vince monitors it very regularly and maintains it consistently at youthful/normal levels.
Increasing numbers of cells become senescent, what has to deal with it? Immune system.
Intestine starts getting more permeable, who clears it up? Immune system.
Skin barrier function weakens, who holds the line? Immune system.
So absolutely Greg Fahy is right to be targeting it as possibly the most important system in the defence against aging.
Sclerosis, fibrosis, inflammation. These are the hallmarks of aging tissues. Most probably these are brought about by extracellular signalling. If we could target those extracellular signals we could extend healthspan decades out.
As many mentioned here, most likely this result comes from the combination of opposing factors (met, znc, on the – side, hgh on the + side, for a net -). I have posted previously I have been tested twice by DNAge with -5.6 y at 46 and – 8 at 48 on May 2019 a definite epi-age reversal. DNAge database includes people with up to -16 years and they have commented they do see reversals of about 2,5 years on metformin users (from my own private communication with them).
I think, as previously stated, youthfull phenotypes are tightly linked to stem cell niches depletion/higher telomere erosion and ultimately to earlier death so when it comes to my own interventions I keep betting to minimizing cell renewal at the cost of less repair. Getting a lower epiage is kind of a signature I am in the track I chosen and getting effects from my interventions BUT concluding this is a real antiaging in the sense of REVERSING age is, to myself, going way waay too far.
I do think it is worth doing Josh trial on many drugs versus epiage, surely we will find the usual suspects (met, rapa, CR, etc.) and luckily many more but my own view is this will only help us minimize the aging rate more effectively but not much else. I doubt epiage can be regarded in the end as the CAUSE of aging.
Josh, if you are interested on the math side of methylation, i have been working on my free time myself on simulating methylation patterns following Zagkos approach in “Mathematical Models of DNA Methylation Dynamics:
Implications for Health and Ageing” and exploring some modifications into it. Didn’t go to far on it anyway although I have the simulation set up and running and have done some sensitivities. I was interested in extending the model to incorporate cyrcadian rythms on DNMTs to get an epidrift as result (as the methylation sites showing cyrcadian oscillations happen to match quite well the ones from Hovarth’s clock) but I left it aside a couple of months ago (moving from spain to asia got me busy on my real work 😉 ) Let me know if interested or who else could…..
“careful statistics that could draw significant conclusions from a marginal effect in a small sample.”
How likely is it that this cannot be replicated?
I would say highly likely.
Mark and Gabor
Even the arterial endothelium can remain in a very youthful state and maintain its elasticity with low inflammation and in the presence of adequate nitric oxide.
Skin aging is dependent on skin color and sun exposure to a very large degree. Genetics also plays a significant role.
I like the definition of aging as increasing probability of death over time. I’m not sure that organism fitness is related to being disease free.
I think the key lesson to take from people like you, Paul and even more so the likes of Vince Guiliano, who is almost 90 (!), is that being highly proactive can stop the runaway deterioration that leads to death. One can get by with minor physical complaints, and many do for much of their life, but when older people have some sort of problem, a downward spiral often starts. Whereas if one attacks each new problem as it occurs, it seems to be possible to remain extremely healthy. I expect there is a limit to this, but it is not clear to me exactly what this is.
Also the broader point is that even in the 60’s and 70’s ,
“ damage” isn’t all that apparent from either clinical testing like renal and hepatic blood work, or even tissue biopsies. There is no loss of cardiac function or fibrosis on biopsy, unless in the presence of some disease state. If cellular damage results from aging, it doesn’t seem to present itself.
You may argue that this is due to constant repair mechanisms, and that may be true, but it’s still difficult to link the functional declines of aging, which can be rather minimal actually, with some sort of massive tissue damage.
Paul, isn!t sarcopenia universal as we age?
Changes in the extracellular matrix are underinvestigated IMHO.
This is a good and thorough study, I hope we will see more of its kind:
An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics
The authors study ECM, expression profile, protein profile in the lungs of aging vs young mice.
In my reading they dont find that many differences in expression profile. Maybe it is the reaction to stress that is altered.
That’s true. There is a steady degree of muscle loss starting at age 50 in most people, but this may largely be a reflection of lifestyle more than an inevitable consequence of the aging process. It can be prevented , and even reversed, with resistance exercise, adequate protein intake and anti-inflammatories. Most elderly people become sedentary, eat a poor diet and have a fair degree of chronic inflammation.
Perhaps it is the biomarkers that are lacking. Or our interpretation of them.
I remember watching a documentary about elite cyclists in their 70s. Apparently their mitochondria were ‘indistinguishable from young peoples’.
They looked indistinguishable from old people to me.
I’ll share with you an analogy with obesity. For many years the calorie in / calorie out model has been accepted as causative of obesity. This model is so problematic that it’s generally rejected at this point. What I’ve observed is more like this:
Someone has one or more relatives who are obese but they themselves are at a relatively normal, or even thin weight, for much of their life. Then something occurs which triggers these genes to express themselves. This may be a stress event, pregnancy, surgery, or most commonly some medication.
I believe at this point the hypothalamus is triggered to significantly upregulate its set point. When this happens weight gain can be drastic and relentless regardless of behavior changes ( for the most part). It’s also mostly irreversible.
Of great interest, certain medications can dramatically downshift this set point resulting in very significant and almost effortless weight loss, but there is always a limit. It’s as if there is a new set point established which can’t be affected.
Aging may be similar. I’ve seen many highly functional and illness -free patients in their 80’s and 90’s until something happens. It’s often not clear what that something is, but at that point aging seems rapid and relentless. It’s quite sudden and it’s as if a switch has been hit and is irreversible at that stage.
We need something that can greatly delay or even reverse that process. It doesn’t appear like a gradual deterioration to me , but more like a sudden doomsday trigger.
I was 175+ pounds for 50 years. Took rapamycin and 3 months down to 155 pounds.
Stayed that weight for 2 years. Then increased dose rapamycin, 2 months later 140 pounds.
Not a big mystery.
It check out Koschei paper, 5 different ways lowering TOR causes weight loss.
I think it is because in aging, at variance with cancer (they on the contrary, proliferate!), the worse cells (those with most heavily damaged mitochondria) went away long ago (they died), so you cannot see them. That happens durin aging sarcopenia
Hi Alan, what mechanism would you attribute the weight loss to, thanks to rapamacyn? Would it be an inability of adipocytes to grow and accumulate fat? Or a reduction of proliferation of the same?
I wonder because if one ingests an excess of calories and they get absorbed into the bloodstream, those sugars should go somewhere. That reminds of the starvation-like diabetes that Blaglosklonny has talked about in some of his papers. Would that excess of calories just be filtered by the kidneys and discarded?
I say this because although the calories-in calories-out model is a simplification, in my observation it holds largely true, when it comes to weight gain and loss.
In general, young men are thin and lean and many old men are fat with big bellies. That is mTOR at work. Turn down mTOR and very easy for old men to be 13% body fat instead of 50%. Does not make old men athletes; but can have the athlete percent body fat. For a discussion of why see the Blagosklonny paper, Koschei the Immortal and anti-aging formula, 2015.
The medical component of this is insulin resistance, high blood insulin levels, high mTOR, metabolic syndrome and accelerated aging and age-related disease. Nobody should have a waist/height ratio over 0.5
Yes, I’ve read that paper and what you describe is a perfect example of a re-set of the hypothalamus to a new set point by a drug and then it sits there as long as you remain on the drug. Of course, when you raised the dose of the drug, the set point moved again before once again leveling off.
This may be from mTOR inhibition or perhaps via some yet unknown rapamycin mechanism apart from TOR,.
I think that rapamycin delays age related diseases via mTOR as Blagosklonny brilliantly suggests, and this in and of itself gives a certain degree of longevity, but it may well have an epigenetic impact that , if dosed properly, can have a very substantial effect on lifespan . I think that we’re just at the tip of the iceberg with this drug.
It might be a microbiome effect. If I change my eating habits (such as intentionally trying to either gain or lose weight), there is always a long delay and then suddenly the change happens. It definitely isn’t just a calories in/out,more like a downstream sequence of consequence bases on the type of food you eat. I can certainly see how medication could cause it. Rapamycin is a sort of antibiotic, after all.
You are correct about epigenetic effect.
Horvath study which you cited shows epigenetic effect
Matt Kaeberlein short term mouse study in which one mouse lives to equivalent 150 years.
Concentration camp victim, 5 months, then lives to 113 years all suggest epigenetic effect.
However, I think biggest effect Rapamycin is reducing burden of senescent cells.
Yes, I think that’s true. As others have stated, senescent immune cells are the biggest problem. Rapamycin helps with that and is still the most proven thing that we’ve got.
Regarding cells senescence and inflammation.
US Hispanics generally live longer than Caucasians, on average they also have younger eAge according to the pan-tissue Horvath clock. But they show an ‘extrinsic epigenetic age acceleration’, which is a variation of the Hannum clock adjusted to account for changes in blood composition.
I heard Horvath commenting this relates to higher levels of inflammation. However, Hispanics still live longer. This finding is replicated in a Bolivian native American tribe still living as hunter-gatherers. Only their eAge is even lower. Pointing to this ‘deceleration’ to be partly genetic.
Rapamacyn decreases the metabolic rate of cells and also inhibits proliferation. These are the 2 processes most strongly associated with the advance of DNAm age. We see this in a faster rate of eAge speed in cultured cells. Also in a host of ‘insults’ that supposedly result in cell damage and increased proliferation to make up for the loss: UV radiation, smoking, alcohol consumption, etc.
What I’m getting at is, what if the biggest benefit of rapamacyn is a deceleration of DNAm age? But maybe not so much by inhibiting cell senescence and inflammation.
Of course, on the face of it, “inflammaging” seems a very harmful process, but perhaps, we’ve exaggerated its impact on the aging phenotype.
Horvath claims that senescence and eAge are independent but really they’re not. They’re both driven by metabolism, as you’d expect. So rapamycin doesn’t have two independent effects, just one.
Take care reaching any conclusions from human global population data. We in Spain are at the top of world longevity together with French and Italians (the 3 of us Old-Mediterranean diet consumers; by the way, not existing any more) just after tge first ones, Japanese.
But other factors intervene. Inside Spain there are very large differences im total calories or fat consumption from north to south provinces, but very small differences in mean lifespan. And tge the new “Theory”up at USA that all carbs are bad without distinguishingbetween simple sugae and more complex carbs (potatoes, french bread and rice) contradicted by longevity and eating habits in France (saturated fats), Spain (bread potatoes, rice), Italy (high pasta), and rice (Japan).
I also suspect that our very nice Public State Social Security Health System (100% coverage to everyone here, including those who never contributed a single Euro to the System because they never worked), explains part of the phenomenon. Not just ethnic intrinsic biological differences
In regard to carbs, your point about good vs bad carbs is of extreme importance. However, I think all but the most ignorant recognize the extreme importance of glycemic index.
Also just about everybody in USA understands that the Okinawans when they followed the diet that had extreme longevity which consisted of 85% carbs, those carbs were not white rice; but mostly Japanese sweet potato. Everybody in USA also know that Japanese sweet potato has glycemic index of 44 compared to glycemic index of 80s of white potato and white rice etc.
Most people in USA never eat a carb without knowing the glycemic index, glycemic load and almost never eat carbs with glycemic index over 50. [Just Kidding]
Ah! I undertood you point (kidding!. It wasmy wife Ana who got it first!
Hi Mark, The very title of paper is “Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation”.
The last line is:
“These observations also suggest that the life-extending property of rapamycin may be a resultant of its MULTIPLE actions which include, but not necessarily limited to suppression of cellular senescence and epigenetic aging, with the possibility of augmentation of cellular proliferative potential.”
Paper showed the epigenetic aging effect was not the senescence effect. The paper showed number of actions that could increase life span; but did not know what caused epigenetic aging; just showed what did not cause epigenetic aging.
It is nice that you know what causes epigenetic aging; but Steve Horvath certainly doesn’t know. Furthermore, Horvath also does not appear to know if epigenetic changes are leading or following aging or both.
I’m really starting to suspect that myself with rapamycin. A youthful person has certain ares of the genome that are demethylated and those same ares are methylated in old age. Since CR prevents that transition, it’s fair to assume that rapamycin as a CR mimetic does the same thing.
Rapamycin has so many effects on inflammation, autophagy, TOR, stem cells, lipolysis, insulin, etc. , that it’s almost impossible to weed it all out , but deceleration of mDNA may be a major player .
Yes. And we showed in Martinez-Cisuelo et al. Exp. Gerontol. 2016 that rapamycin also lowers (100% decrease back to young levels) both and by similar amounts mtROS production and mtDNA fragments inserted at nuclear DNA, nmostly at pericentromeres.
Several months ago I posted that my max heart rate increased after taking Rapamycin for 1.5 years. After many tests, I’m sure that those results were due to a faulty HR meter. So my max HR is 177 instead of low 190’s. Still not bad for someone close to 59 but not an increase over my pre rapa numbers. I have closely monitored my power output on a road bike and my power numbers are the best I’ve had since I kept records starting in 2013. I’m sure the power meter is accurate because it matches my stationary bike power meter and I keep breaking records on various climbs. I did take D&Q in April and that is what really made a difference in my power numbers and recovery time. I believe senolytics and rapamycin work well together.
What exact dose Dasatinib
Any side effects.
Rapamycin reduces senescent cells 3 fold; but still have senescent cells.
I use Fisetin 1200 mg X 5 days once a month.
Would like another useful senolytic
I’ve not seen any evidence that rapamycin actually removes senescent cells or reverses senescence. We know it upregulates autophagy very significantly and that would have the effect of keeping cells healthy longer. But once a cell is senescent upregulating autophagy does not help to reverse senescence.
The only good thing can do with senescent cell is kill them.
Keeping senescent cell alive by any means would accelerate aging.
200 mg Dasatinib, 2000 mg Thorne Research Quercitin, (used in Mayo study) 175 pounds.
About 3 years worth of Dasatinib $207. I took one dose April 28 and felt a mild headache the next day. Felt nothing else. Went for a hard ride two days later and felt a dramatically reduced post-ride fatigue. It was very noticeable and continued for months. So I call it better recovery both during the ride (after all-out efforts) and post-ride. Took another dose 3 months later to see if I could get another boost but besides another post-dosing headache, I did not notice anything notable. N=1 but for me maybe once a year is all you need. The source was India. I tried high dose fisetin a few months before my first D&Q dose but noticed nothing.
Your personal experience with Dasatinib of great interest.
“Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A”.
Rapamycin is not a senolytic but helps in supressing the SASP phenotype.
Would someone in his mid 60ties who is still doing rigorous resistance exercise five times a week and practices time restricted feeding, intermittent fasting and fasting, benefit from taking Rapamycin?
Dr Peter Attia thinks so. He takes Rapamycin, he does IF, once a quarter seven day water-only fast and intense workouts but is only 46.
My Comment concerning :
“Important, though unrelated news: Cell phone carriers the world over have plans to roll out 5G technology in the next few years….”
And here in Spain, they started already to sell them!, without studing/clarifying before anything at all…
We are in a much worse position that you are
It is always like this. Whenever there is something NEW, here it is adopted no question studying before whether it is good or bad.
So much antiaging effort…..neutralizaed with so much dirty things (antibiotics, pollution etc
Professor of Physiologu
UCM University, Madrid, Spain
Let’s suppose that there will be discovered a treatment which stops aging.
That treatment will be used after a time by rich people to exploit and control the others
When someone thinks of living forever, thinks in living forever in the garden of eden, but most likely he/she will end living forever in the hell.
I agree with you in that no one in this universe can escape the 2nd law of thermodynamics. Nevertheless you are wrong. Here is the answer although I am not physicists but physiologist:
The second law applies to CLOSED systems, like e.g. the whole universe itself, or most inanimate matter
But animals are OPEN systems! that take in energy (food) from the environment and use it to perform physiological work and maintain homeostasis, which, o n physics language means to decrease their own entropy. Then they release HEAT (high entropy).
Therefore animals can self-organize (they decrease their entropy when developing from egg to adult, and avoid increasing internal disorder-entropy- only because they increase entropy in the energy and materials they excrete to the outside environment. It is crucial to understand that if you consider the following:
“ANIMAL+ ITS ENVIRONMENT”, then the TOTAL entropy of these two taken together does increase as the 2nd law states.
This is possible simply because the increase in environmental entropy due to the animal activity is MORE than the decrease in internal entropy when the animal grows from egg to adult.
In aging there is a slow increase in internal animal entropy from 20 to 90 years of age of course. But this increase is NOT due to any necessity imposed by the second law. The old individual still eats, then ingesting chemical energy from its environment, similarly to what a 20 year old young person does. Therefore, there is no reason why the old could not continue to use this energy (take advantage of its OPEN system nature, “same” in old and young) to autoorganize itself, to continue avoiding loosing its internal order. It does looses it, nevertheless because IT DOES IT ON PURPOSE.
I have explained that in the Introduction to my “Longevity and Evolution” Nova NY, 2010 book, with the metaphore of the builders/destroyers of houses (anabolism/catabolism). If that is so (a mouse is all “new” within a few weeks aproximately) thanks to that high “turnover rate” we say in physiol/biochemistry), therefore, why the mouse is not immortal?. If we renew ourselves constantly… Without waiting even for a single amino-acid in a protein to be damaged, the protein is broken down to its constituent amino-acids and then synthesized up back a again to full protein. Then, if this is so, the strange thing is not immortality. The “strange” thing should be AGING!. But this is exactly THE REVERSE of what we see everyday on the natural world. Why? Not because of thermodynamics Florentin. It is so, we the pro-PAs believe, because we Endogenously Produce/Generate aging ourselves (mitROS, Lipoxidation-FAs-DBI, telomere shortening, apoptosis, inflammaging etc etc) ON PURPOSE (LIKELY FOR THE GOOD OF THE GROUP.
If you want I can send you that Introduction to my book (much better long and better written explanation of what I said above). Anyone interested just send me an email (email@example.com) and I resend to you the introduction, or any chapter pdf of my book (these guys of Nova behaved very “dirty” with “me”. Mainly (and not only!), because they they established the price of the book at 180 US$!!! -¿? Crazy prize! Disgusting malpractice of NOVA Sci Publishers- without telling to me about this at all! (when I knew, the irreversible “damage” was already done…). Even though I had asked previously to them to put the price at around 20 US$ to be read by as many as they wanted without economic barrier (and they did not say no). So,they did not have scruples with me, not me with them then…
I include the Contents list of the 7 chapters of my book for you to see what is inside in them:
-Title Longevity and Evolution Nova Science Publishers. NY USA 2010
-Introduction (this is the Turnover/Immortality metaphor that I mentioned above)
-Chapter 1 Aging, longevity and disease : from ephemeral life to eternal youth
(about main traits of aging, survival curves, loss of functions etc)
-Chapter 2 What causes aging ?: theories of biological aging
(mechanistic theories, on HOW do we age now; called now “aging effectors” on Barja 2019 paper)
-Chapter 3 The double edge sword : oxygen as needed for life and as a main cause of aging (ROS and aging, and focus on mitochondrially-derived ROS)
-Chapter 4 Eating less prolongs life (about caloric and protein and methionine restriction)
-Chapter 5 Only change is eternal : mechanisms of biological evolution
(about how present “Modern Synthesis” from the 1930s-40´s -usually called Neo-Darwinism, not to confuse please with Darwinism- Evolutionary Theory in general is wrong, outdated, and needs mayor revision, update. It is not “Modern”!, it is, I call it the “Old Lady” since it is 80-90 years old now (so soon must die perhaps?..). I suggest on this Chapt. around 10 mechanisms of evolution IN ADDITION to natural selection. Most (although not all of course; e.g. Epigenetics is environmentally related, see e.g. Eva Jablonka huge work, Tel Aviv Phylosophy Department, Israel) are related to ENDOGENOUS mechanisms of generation of variation (EVOLUTION SOURCE IS MAINLY FROM INSIDE, curiously like aging as we the pro-Programmed Aging propose!)
-Chapter 6 Why aging ?: evolutionary explanations of longevity
(About how the 3 mainstream wear and tear non-programmed EVOLUTIONARY theories of AGING are flawed. About the WHY do we age, how aging appeared in old evolutionary times and was selected for, -by group selection?)
-Chapter 7 The States of the Evolution of Complexity
(on my own theory on how at least some -not all of course- phylogenetic evolutionary lines show increasing complexity from dust…. and bacteria to man in four big evolutionary sudden jumps: STATES (1, 2 , 3 , and 4). State 4 is social humanity (or the ant nest, or a group of gazellas at Serengueti, etc, the social animals, so many animals); STATE 3 is the multicellular animal -you, or I, the “individuals”, if such a thing really “exists”, please forgive me Plato and Aristoteles for saying so…., you… supporters of City-State = ancient greek state 4, as more important than the “individual”); STATE 2 is the “modern” Eukaryotic cell obtained by symbiogenesis of alpha-proteobacteria (proto-mitochondria) that entered and fused with an old cell (archea?); STATE 1 IS THE BACTERIAL CELL.
States 3s are, in a sense, different disguises of STATE 1 (so, in a sense, only bacteria really live on earth, you are just another form that bacteria take…like ants, jellyfish,protists, etc). So my position on that has nothing to do with the old LADDER to higher COMPLEXITY, “higher superior human step”, the “top best of creation” of old XIX century biologists including Jean Baptiste de Lamarck –although he seems to have guessed well, however, on epigenetics-transmission of acquired traits, and on ENDOGENOUS source of evolutionary drive now confirmed by modern genomic studies- . So I do not adhere that old LADDER prejudice. Perhaps even the reverse. Or both, the opposites. STATE 1 (low complexity) and STATE 4 (high complexity) in a sense, are “the same” as Heraclitus from Ephesus would say, and Nitezsche would say the eternal return. because……
STATE 1 is now leaving the solar system on the USA Voyager spacecraft, launched by NASA on 1977, leaving us in direction to outer space…perhaps, very small likelihood, to fall in a planet on which an analogous whole story to the one that happened on Earth during the last 3,500 million years of biological evolution could start and develop again on another planet…. (different trajectory but at the same time similar of course: Heraclitus again!…). Perhaps when at that far away planet STATE 1 manages to successfully evolve into an extraterrestrial STATE 4 that “thinks” and is conscious of itself and of its Mother Nature around him, and can develop modern technologies like us, perhaps those new STATEs 4 could, hopefully, get to be STATE 4s that do all those marvelous things, BUT also takes into account that LOVE is more important than HATE……. That emphasize LOVE as much as we, although supposedly followers of Jesus Christ, we paradoxically insist in continuing to emphasize HATE. If that different solar system, or other galaxy newly evolved “STATE-4ers” choose LOVE instead of HATE, then, there is no problem (globally at Universe scale) even if we here now continue to insist on choosing ONLY competitiveness-HATE (present global problem) and finally destroy ourselves, the humankind, using as “dying effectors” the Climate Change, or the Global Nuclear War on this small planet. If really “THEY” choose HATE (please see above who I call “they”). I do not have preferences which way to hell “they” choose for us all, the people, the ones without any real power…Almost every power appertains to “THEM”, a global dictatorship of huge monopolistic transnational companies; each time less and less people have more and more….Remember for instance Josif Stalin the leader of CCCP for decades until he died in bed, just like Franco here, impossible for the people to get rid of them…….. Please remember, when a single individual has ALL the POWER, there is no true democracy any more, there is TYRANNY, and the disaster for the people is served…We in Spain have 40 years of experience with such tyranny, so we are strongly conscious of it …)
You got some interesting and significant results. Rapamycin prevents senescence by inhibiting the geroconversion of arrested cells into senescent ones. This inhibition is incomplete and still allows for senescent cells to some degree. I’ve always felt that this is safer than senolytics since senescent cells have evolved for a purpose, that being cancer prevention, and I’m hesitant to wipe them out.
Maybe once a year is a good compromise. There’s still much left to be learned about all of this but your results on the combination are impressive.
Some other things I noted that can be tested is a significant increase in my balance after D&Q. I bought a Yes4all balance board trainer about a year ago to improve my balance but found it frustrating and difficult. I could stay on the board maybe 30 seconds with difficulty. I put it away and stopped using it. After one dose of D&Q I can stay on for minutes and that effect has persisted.
That got me interested to try out a hulu hoop I had in the garage. That was even more dramatic in that before I had difficulty hooping for even 30-60 seconds but after I could go until I was just worn out (> 5 minutes). It suddenly became easy.
I can’t say for sure they are real effects (N=1) but if anyone else wants to try D&Q I would at least do some extensive balance tests before dosing.
I also “felt” more clear-headed. Maybe like less mental fog and a better ability to focus and multitask? This effect is slowly fading. Is it habituation or an actual reduction? Very subjective but maybe someone can test themselves before dosing and get better data than feelings.
I’m looking forward to the results of human D&Q testing that are ongoing in various studies.
Where do you get your D&Q? Of course dasatinib is prescription only but do you have a particular pharmacy? Also, how are you dosing rapamycin?
The balance thing is fascinating and is very linked to aging. I like real life experience biomarkers like that and I now dose rapamycin based on my weight. I go up on the dose when my weight starts to climb.
I don’t have a prescription so I get it through India. Same source as my rapamycin prior to getting a prescription for that.
I take 4 mg of Rapamycin every 10 days and 1000 mg of Metformin a day. Age Reversal Network has a forum with lots of info on sources, dosing and results.
The senescence response means cycle arrest and marking the cell for disposal which the immune system does. Yet some cells survive this cleaning phase and turn into “lingering senescent cells”. “Anti cancer senescence response” cannot be extended nor equated as “anti cancer” to lingering senescent cells which are a failure of this anti-cancer mechanism. And these lingering senescent cells have all the mechanism that support cancer survival already in place, so they are only one single DNA damage away form cancer. And due to SASP they will acquire one anyway.
That may well be true, but there are both acute and chronic senescent cells and they play a role not only in cancer prevention but also in tissue repair and regeneration. You’re right of course in stating that the SASP gives rise to a proinflammatory microenvironment that allows for cancer growth and metastasis. What isn’t known is what the outcome would be in eliminating a very high percentage of senescent cells. Would this lead to tissue dysfunction and even atrophy?
In my view , at the state of our present knowledge, it’s safer to use rapamycin and various supplements to optimize immune function which should eliminate/prevent some percentage of senescent cells.
Perhaps senescent cells aren’t doing anything wrong. They’ve reached the Hayflick limit (or been damaged earlier), and are signalling growth factors to trigger their removal and replacement. It could be the fault is either with removal and/or replacement. Which brings us back to the immune system. If it becomes exhausted senescent signalling continues, eventually triggering a corrupted form of regeneration – cancer.
What do you think starts inflammaging?
I mean, the earliest effector coming out of the aging program (e.g. on part C right of Fig. 2 on Barja, Exp Gerontol. 2019).
Same question posed otherwise:
HOW do you think the aging program (AP), after reaching the peak mature adult young age (20-25 years) STARTS inflammaging on the first place. (A person without any pathology).
I have my suspictions but I would like to hear yours first.
My personal hunch is that most cancers originate in local stem cells ‘gone rogue’. This is why they express telomerase to begin with. This would be the source of ‘cancer stem cells’ that keep the illness going. I think the failure is mostly at the immune system, progressively getting worse at clearing them.
It is possible that the SASP further depresses the ability of the I.S. to clear potential cancer cells. Perhaps by overwhelming it with SC’s clearance. It may also help disrupt normal stem cells gene expression making it more likely they would become cancerous. But I think it is mostly a correlation. I do think cell senescence is a normal process, and precisely because they remain arrested I’d say it is unlikely they would spawn a cancerous cell line.
Again, the failure is at the I.S. for not clearing SC’s as we get older. And what has changed? At least 2 things we know of: thymic involution and gene expression.
That’s why I harp so much about gene expression. Cell lines all throughout the body change the way they behave as we age. It appears to be an **intrinsic** cellular process.
I believe its too simplistic to blame cancer on senscent cells and immune system only.
I think besides immunoaging, the quality of chromatin degrades with age, so each and every cell has a progressively higher chance of going rogue.
And I think senescent cells have more function than just signal their removal. They have a role in tissue remodeling during wound healing too.
Actually the way I look at aging is that aging cells all feel the stress much sooner than they become senescent. p16ink4a, p53 levels increase in presenescence cells. Then they signal that stress via increased paracrine signaling like wnt. The ECM is remodelled as the neighbouring cells take this as wound signalling. Remodelled ECM limits cellular and tissue function.
Eventually some cells became senescent and do SASP signalling but its only the tip of the iceberg and the bulk of tissue damage is done much earlier.
The main cause of age-related cancer is when cells continue to divide past their hayflick limit. This causes chromosomal fusions and rearrangements, i.e. cancer. Why some cells keep dividing past their limit is not entirely clear. I’ve posited that it is because of inflammatory signalling from other senescent cells that have accumulated. I also have my suspicions about viruses being behind many cancers because of their ability to drive uncontrolled growth. So the immune system is clearly involved.
But Gabor is right that senescence is gradual, an analogue not a digital phenomena if you like. Far before complete arrest cells are changing their behaviour for the worse. I’ve always believed this is primarily down to telomere shortening. It is more complex than this, because many cells are supposed to die via telomere shortening and be replaced from the stem cell pool. But overall in each important tissue we look at telomeres are getting shorter, so there is a failure of tissue maintenance. No one can deny this.
Dr Peter Attia’s take on the study, part I. He is in contact with the author and has some new insights:
“First hint that body’s ‘biological age’ can be reversed.”
In a world where the population aged 60 or over doubled in the last 30 years, and is expected to double again by 2050, how’s that for a sensational headline? The story, written in the journal Nature, is referring to a study published by Aging Cell. Amazingly, only 137 of you sent it to me within the first 24 hours of its release.
Nine healthy men, given a cocktail of human growth hormone (hGH), metformin, DHEA, vitamin D3, and zinc for 1-year, shed about 2.5 years off their biological ages, according to an analysis of their epigenome.
As a result of this study, I’ve had more people than usual ask the following questions:
Should I be taking hGH? Should I be taking metformin? Should I be taking DHEA?
To address these questions (and others) will be a bit of an undertaking, so I’m breaking this topic up into at least two emails. In today’s email, I want to explain the study’s purpose, how it was done, what it found, as well as some of the nuts and bolts behind it, and—most importantly—propose a framework for evaluating studies in general. I’ve covered a lot of the groundwork in the Studying Studies series so I may sound a little like a broken record in places. That said, if you are tired of being held hostage by the media’s interpretation of science, you will need to buck up and learn this stuff. The Studying Studies series is the starting point. I realize it may seem like Groundhog Day for you to see more prose from me about how to think about studies rather than the tactical bits we think we can immediately extract and employ from them. Just remember, it’s better to learn how to fish than to be given … you get it.
On to the study.
The stated purpose was to investigate the possibility that using hGH in a population of men in their 50s and early 60s can prevent or reverse signs of the gradual deterioration of the immune system that has been attributed to natural age development (i.e., immunosenescence). The trial, dubbed Thymus Regeneration, Immunorestoration, and Insulin Mitigation, or TRIIM, reveals its aims. (Note that nothing in the initial aim of the study dealt with assessing the impact of the hormone/drug cocktail on the epigenome, for which all the attention has been generated.)
The thymus, a gland located in the middle of the upper chest, converts white blood cells from bone marrow into T-cells, which play a central role in the immune response. The “T” in T-cells is named after the thymus. As it turns out, the thymus reaches its maximum size by the end of the first year of life. After that, the thymus decreases in size and activity, particularly after puberty, in a process referred to as thymic involution. Along with the decrease in size and activity of the immune system with age comes an associated functional decline. The lead investigator of the study, Greg Fahy, wanted to see if he could regenerate the thymus and restore immune system function using hGH.
All things equal, a more youthful immune system would suggest greater longevity. But there was a catch with using hGH. The investigators worried that using hGH to regenerate the thymus might induce hyperinsulinemia (high insulin) and noted a “diabetogenic” effect of growth hormone. Hyperinsulinemia and diabetes are obviously not desired side effects, regardless of how much thymic regeneration takes place. So Fahy and his colleagues added metformin and DHEA to try and counter these potential effects. Vitamin D3 and zinc were also added as a hedge against cancer and inactive thymulin, according to Fahy (personal communication, email).
It’s not a surprise that the investigators chose metformin as a drug that can aid in “Insulin Mitigation” (the “IM” in TRIIM; for a nice overview of why, revisit the interview with Nir Barzilai), but DHEA? This was news to me. After doing a little, I mean a lot of digging, I would say there is not much in the way of evidence supporting the use of DHEA as an insulin lowering agent. According to a related article, it appears Fahy was working off his own hypothesis. Young people have higher growth hormone without an increase in insulin, and Fahy believed this to be due to them having higher levels of DHEA. Fahy tested this on himself by taking hGH alone for a week and found his insulin levels elevated by 50%. He then added DHEA and the increase was apparently reversed.
In the TRIIM study 9 men, ages 51-65, first took hGH alone (0.015 mg/kg, or ~3 IU for a person weighing 70 kg) 3-4 times per week for one week and then added DHEA (50 mg) the next week, similar to Fahy’s n=1. The week after that, the same doses of hGH and DHEA were combined with metformin (500 mg). At the start of the fourth week, the doses were individualized based on each participant’s particular responses. (To put the hGH dosing into context, while it’s individualized, athletes using it for performance enhancement may take 10-25 IU 3-4 times a week and “longevity” clinics may prescribe somewhere in the ballpark of 1-2 IU/day.) The goal of this titration approach was to maximize IGF-1 and minimize insulin by varying each of the hormones and drugs. The study didn’t reveal what the effect DHEA hay have had after week 2, so we contacted Fahy to check. He wrote that the results with DHEA were qualitatively the same but quantitatively different, with each person having their own specific response (personal communication, email).
It’s important to highlight that not only was this study multifaceted in the number of independent variables introduced (i.e., hGH, metformin, DHEA, vitamin D3, zinc), it was also personalized, since the subjects did not all receive the same dose of each agent. It’s possible (actually, likely) that all nine subjects were consuming a different cocktail in terms of the dosing of hGH, DHEA, and metformin. Also, it was a very small sample size and lacked a control group, consisting entirely of 9 healthy (see Supplement 2 for exclusion criteria) 51-65-year-old men.
So why, you might (rightly) ask, all the media hype for a very small, not especially well-controlled preliminary/exploratory study?
The investigators reported a mean “epigenetic age” approximately 1.5 years less than baseline after the 1-year intervention. In other words, their epigenetic age got 1.5 years younger while their chronological age obviously went up another year. For example, let’s say “John” entered the trial with a chronological and epigenetic age of 60. After the trial his chronological age is 61 and his epigenetic age is 58.5. Presumably, he increased his life expectancy (LE) by ~2.5 years, or got ~2.5 years younger biologically, depending on how you look at it. And it’s exactly for this reason that this study is being talked about at all.
Which brings us to the framework I would suggest you apply to every study you read or attempt to evaluate. In a study like this, lacking a control group and utilizing a surrogate outcome (i.e., something other than actual morbidity or mortality), such an analysis is essential. Let’s walk through the possible outcomes with respect to the intervention (the independent variables) and biological aging using the epigenetic clocks (the dependent variable). So now consider a 2×2 matrix of the following scenarios:
(i) the dependent variable (the clock) is a correct (i.e., representative) output measurement versus it is not.
(ii) the independent variables (the cocktail of inputs) did versus did not lead to the outcome we saw.
Again, the former question is necessary whenever evaluating a study with surrogate (i.e., not “hard”) outcomes and the latter question is essential in the absence of a control group.
The exercise, then, is to evaluate each of the 4 quadrants in this matrix and ultimately decide, for yourself, which one has the highest probability of being correct. This is the scientific method. It is not absolute. There are no “proofs.” It’s all about probabilities. Let’s start with the assumption that there was no foul play by anyone involved in the study. In this case, either:
1. The intervention accounted for the improvement, or
2. Something other than the intervention accounted for the improvement.
In the first case, there are also many scenarios, and in the latter, there are also many scenarios. In the first case, it may be that the metformin alone accounted for the improvement, or the hGH alone, or there was a synergistic effect between the hGH, DHEA, and metformin, or perhaps one compound in the cocktail was detrimental, but the other compounds more than made up for it. And, remember, not only was there no control group, there was no consistency in the intervention. Everyone got their own signature cocktail. In the second case, it could be the Hawthorne effect at play. This is a type of bias where individuals change aspects of their behavior in response to knowing that they’re being observed. Maybe the participants changed their eating, sleeping, or exercising, for example, which confounded the experiment.
So this tells us how to consider the inputs to the study, but what about the output? Next, we consider if there was some sort of epigenetic clock malfunction? Here, we’ll consider the next two scenarios:
3. The clock estimate accurately represents biological age, or
4. The clock estimate is inaccurate.
Either we’re not being fooled and the clock is accurately picking up a change in mortality risk in this study or we’re being fooled and the clock is malfunctioning for some reason. We’ll pick this up next week (or the week after) to assess the likelihood of each matrix quadrant.
Oh, and I almost forgot, what may have gotten lost in the shuffle is whether the treatment showed promise for TRIIM, the intended aim of the study. After 1-year of treatment, there was “highly significant” evidence of a restoration of thymic functional mass along with improvements in age-related immunological parameters, based on MRI imaging and favorable changes in monocytes and T-cell changes. Insulin levels were reportedly controlled, so as far as preliminary studies go, it’s an intriguing finding, with certainly a lot more to learn.
Now I have already recieved comments from immunologists and epigenetics-related experts concerning aging here at Madrid University (UCM), which I would add to my preliminary opinion already entered into this blog last week.
-My immuno-aging scientist friend main criticisms on Fahy et al., Nature 2019 were that:
a) The number of various immune cells were measured, but not their functional activity, which could have been easily measured too, and is most important. The problem is, according to this expert opinion that it is frequent to observe, e.g., increases in immune cell numbers in old mammals which however can be accompanied by a decreased functionality of these cells. These changes are usually interpreted as failed compensation declines in immune activity in the old..; and
b) The increase in lymphocyte/monocyte ratio is expected since the main change observed was a decrease in monocyte number.
c) Many other more informative parameters, in addition to, or instead of, some measured parameters could have been assayed.
-The epigenetics expert said that the number of participants (N= 9) and the too short time period studied prevent reaching statistically sound conclusions. Although the “pilot study” character of TRIIM is recognized by the authors, the preliminary character of the results prevents reaching the strong conclusion that human aging has been reversed for the first time. Instead, the methylation age seems to have improved as well as some parameters of the immune system .
Finally, although epigenetic age was measured using four different epigenetic clocks, some of which “can predict diseases better than chronological age”, it is not yet clear if what those clocks measure is functionally related to the aging rate and the biological age, as opposed to chronological age. Aging corresponds to root processes proximal to the appearance of degenerative diseases but it is not equal to them. I also notice that most authors on the most interesting epigenetics and aging area seem to try hard to avoid stating whether the methylation clocks represent (partial) evidence that aging is programmed as a continuation of development. Continuation of traditionally attributing DNA methylation changes with age to random processes, drift or noise, seems fully contradictory with strongly stating that these methylation clocks predict human mortality and aging better than chronological age. It is unclear to me how such excellent correlations (e.g. ) could have been obtained if epigenetic changes were not part of an aging program, or if most of them would only represent random noise. It seems that the present state of the field is ripe enough for scientists in the epigenetics area to decide if their observations correspond or not to important regulated phenomena linked to aging.
I would like to add that in the Discussion (3rd before last paragraph) the authors favor the use of GH/IGF-1 therapy in the old in spite of large and strong data on mutant long-lived mice (and DR experiments) indicating the implication of GH/Insulin-IGF-1-like axis in pro-aging signaling to target tissue cells. The authors argue against the long-lived mutant mice being meaningful for normal aging in healthy individuals, but do not discuss the contradiction of the results obtained also with very abundant data on many pro-longevity DR effects being mediated in part by decreased insulin/IGF-1-like signaling. In addition, they tend to relate low insulin resistance to human aging causally. But fail to explain how GH and IGF-1 can be pro-longevity hormones while they work in the same endocrine axis and sense than insulin.
What assays would you say would be the best for measuring the functional activity of the immune system? I may soon be doing a little self-experimenting with senolytics. Before and after assays for immune activity would be very interesting.
I think many people here are cautious to call DNAm age a program because we have been let down by telomeres failing to prove they drove such a program. I would say though, that it was pretty close: Telomere attrition -> change in gene expression -> cellular dysfunction -> tissue dysfunction.
Replace telomere attrition with a yet unknown process (metabolism?, circadian rhythms?, cellular proliferation?) and I still believe it gene expression the upstream cause.
Inside Ake Lu’s paper last year on the role of the hTERT gene and epigenetic age acceleration there was a very interesting finding. That fibroblasts immortalized by telomerase continued to age and divide, BUT regular fibroblasts reach their replication limit and STOPPED their DNAm age progression. Moreover, quiescent immortalized fibroblasts also never ‘aged’, they stayed at a near zero DNAm age (nice summary on fig. 3 on the nature version of the paper, “GWAS of epigenetic aging rates in blood reveals a critical role for TERT”).
This could mean it is stem cells, which in most tissues show *some* telomerase activity, together with reduced metabolic rates, the ones that register the aging methylation state, and pass it on to their progeny. So it would be proliferation of stem cells, and not somatic cells, that drive the aging program in humans.
This could explain why processes that arguably result in higher rates of cell damage or stimulate cellular turn-over are also associated with accelerated epigenetic age: smoking, alcohol abuse, HIV infection, UV radiation… I would also include HGH on this list, as it should drive growth and cell proliferation, but I will keep an open mind. If it I had to bet, I would attribute the DNAm age decrease on this study to DHEA, as hormone replacement therapy has already shown to decrease eAge in certain tissues in women.
In short, I believe it is cell proliferation (with stem cells as time keepers) that drives the DNAm program. This could also explain why men show a higher DNAm age than women: men are on average bigger and need more cell divisions. Despite perhaps ‘appearing’ healthier than women in advance ages, as men have higher bone and muscle mass to begin with, but as DNAm would predict it, men tend to die a few years earlier.
However, it would not explain why brain or muscle samples show comparable eAge to other tissues. Unless we have underestimated the role of stem cells in those adult tissues, or proliferating cells have found their way into those samples (glial cells in the case of brain tissue for example).
Good morning everyone, I regularly read about the importance of Melatonin but I am surprised by a post today at https://microwavenews.com/news-center/ntp-turns-search-mechanisms, about the implications it may have on Effects of oxidative and DNA damage.
There is a lot of emphasis on damage from the inside but there is not so much diffusion about causes outside the human being of extreme danger, such as radiofrequency electromagnetic radiation what induced DNA strand breaks https://onlinelibrary.wiley.com/doi/abs/10.1002 /bem. 2250160309
As I read today, the NTP plans to investigate on gene expression, oxidative stress and DNA damage and repair, as well as on the possible role played by heat.
The NTP has already reported finding more DNA breaks —as detected with the comet assay— among the RF – exposed animals, including in the brain where rats later developed tumors
Those results, presented at a conference two years ago, have been submitted for publication. The paper is currently under peer review, according to Sheena Scruggs in NIEHS ’Office of Communications and Public Information.
A recent review of some 100 journal articles found that more than 90 percent “confirmed that [low-level] RF radiation induces oxidative effects in biological systems.” It was published in Electromagnetic Biology and Medicine in 2016 https: //www.tandfonline. com / doi / abs / 10.3109 / 15368378.2015.1043557.
In your Microwave News Louis Slesin posting: When they (Lay H. and Shingh N.) treated the rats with melatonin – a natural hormone that neutralizes free radicals – before RF exposure there were no more DNA breaks.
If the radiation could indeed generate free radicals, they pointed out, the risks would go beyond cancer to include premature aging as well as Alzheimer’s, ALS and other neurological diseases, https://microwavenews.com/news-center/ntp-turns- search-mechanisms
I don’t think it’s that complex. Let me explain DNAm age again.
Neurons have to last a lifetime, but they are metabolically very active. So DNA breaks will be happening all the time. Therefore there is plenty of opportunity for errors in methylation during this repair process.
Fast dividing cells will also accumulate such methylation errors through cell division, when methylation has to be removed and then re-added, but so long as they are replaced by more quiescent stem cells (which have less such errors) DNAm age is kept under control and advances only as quickly as it does in the stem cell compartment.
So there are two things going on regarding methylation ‘aging’, 1) aging of somatic tissues that are not replaced, and 2) aging of the stem cell compartment that is replacing proliferating tissues.
A consequence of this is that extending telomeres in proliferating tissues will obviously increase DNAm age because these cells then require replacement by (less metabolically active) stem cells less often. This is why people with longer telomeres have an older DNAm age. But this is a different situation to old people who have a high DNAm age because of the aging of their stem cell compartment, which slows the rate of replacement of somatic cells and therefore leads to the advance of DNAm age in somatic cells as well.
Almost no one, including Horvath, seems to grasp this. But the data is all there in pubmed, for anyone to discover.
But if we could maintain stem cells indefinitely, we would solve both the telomere ‘aging program’ and the methylation error ‘aging program’. This is why I am so interested in ex vivo pluripotent stem cells infusions and also very small embryonic like stem cells (VSELs) that still exist in even old tissues.
That makes perfect sense. Speaking of pluripotent stem cells, it’s amazing to me how a well differentiated cell , like a fibroblast, can dedifferentiate back to a pp stem cell. There’s also the debate about the origin of the immortal and very difficult to eradicate, cancer stem cell. Is it coming from a differentiated somatic cell , or from a normal stem cell.
If from a normal somatic cell, it must have a p53 mutation ( in p53) , so that when telomeres hit a certain level of loss, the cell bypasses replicative senescence and continues to divide until we reach that very critical telomere shortening phase and then end to end fusion. Maybe one in a million of these cells escape death and upregulate telomerase leading to a CSC.
These CSC’s are both immortal and capable of fooling the immune system into not recognizing them as invaders. They even survive chemo and radiation.
I’m not sure that this represents a failure of the immune system, but it certainly is more common in the elderly. Very complicated
Re: de-differentiation to pluripotency, I know the early studies had appalling efficiency, like 0.1%. I believe this has been hugely improved on, but I’m not sure you can yet say that the process is simple or easy, many cells die from the process or become senescent.
I believe that cancer happens the other way around from what you describe Paul – short telomeres precede the mutations. Loss of telomeres allows end to end fusions and genomic rearrangements via transposable elements and this is how CSCs arise. In rare cases you can get mutations even in cells with long telomeres, and this is probably what drives those rare but deadly cancers in non-proliferating tissues like the brain. In this case long telomeres allow the (pre)cancer to grow bigger (eroding telomeres), which then leads to the process I describe above.
The key to beating CSCs is almost certainly not immunotherapy, which relies on a specific karyotype, but probably something much more simple, such as described here: https://www.ncbi.nlm.nih.gov/pubmed/31002656
In order to bypass senescence and eventual cell death, it seems to me that a tumor initiative mutation, like a p53 loss, would be a necessary prerequisite.
Of course, somatic NSC’s May be the source of CSC’s since telomerase expression is already present. Or the ALT pathway and no telomerase necessary.
All of this makes it even more remarkable that IP6 can cause a dedifferentiation from poorly differentiated cancer cells to well differentiated ones which aren’t likely to metastasize. Mayo Clinic is using this with success in advanced melanomas.
What strikes me Paul, is that it’s very hard to categorise cancer cells by their karyotype. Some have a completely alien chromosome structure (I suspect CSCs must be like this) but bizarrely from their phenotype you can still tell they came from a lung cell (say). Some ‘cancer’ cells have NO mutations (just epigenetic disregulation, I would guess).
Maybe IP6 is a strong epigenetic modifier and it can tell cancer cells to behave themselves, even in the presence of mutations.
Most of the mutations that you are ever going to get you already have and you got them in the womb! So systemic signalling and epigenetic control must be keeping the whole show on the road.
Looking at the hTERT study it is possible that stem cells are the time keepers of the Horvath clock. At least after puberty. Interestingly the arrested somatic cells stopped at age 13, after which there is not much more growth in humans (at least not in height, which I think is highly indicative).
So indirectly, you can say the clock is tracking the state of the stem cells niches. But it is an open question how much the change in gene expression is an upstream cause of the ageing phenotype.
I think you point to stem cell depletion and decrease in regeneration as the primary cause of ageing. And that may well be the case, or at least be one of the several processes/programs.
But I don’t think we can put DNAm age down to errors or ‘drift’. It would not proceed in such a predictable fashion. To say it is a highly predictable random process is a bit of a contradiction. Studies such as the one the Sinclair lab published recently, or the original re-programming one by Izpusua, also indicate that methylation changes that show a decrease in eAge also improve health. These were treatments directly aimed at epigenetic reprogramming that resulted in improved function.
You could say those improvements were brought about by increased regeneration by more active stem cells. But even so, then we have found an effective way to do just that.
You’re right – it’s not JUST drift, it’s also ADAPTATION (for example, to accumulated metabolic damage and no ready cell replacements). But at the moment the epigenetic clocks cannot seem to distinguish the two.
“Neurons have to last a lifetime, but they are metabolically very active. So DNA breaks will be happening all the time. Therefore there is plenty of opportunity for errors in methylation during this repair process….
So there are two things going on regarding methylation ‘aging’, 1) aging of somatic tissues that are not replaced, and 2) aging of the stem cell compartment that is replacing proliferating tissues. ”
Neurons have been transplanted to longer lived animals and lasted as long as the longer lived animals(twice as long). The researchers commented that they may last even longer in even longer lived animals, potentially indefinitely, if I’m not mistaken.
Dr. Michael Fossel, has commented that nondividing cells that last a lifetime potentially do not actually age, if I’m not mistaken.
So I think at least for some tissues that have cells that are not replaced, it is the aging of the dividing supporting cells that jeopardizes such tissue’s function.
you point out an interesting question. how much nondividing cells age by default. I somehow always thought that cells cannot perfectly fix themselves but cell division can make them younger as they have to reconstruct much of their organalles so the structures get built of scratch thus they become young again.
I wonder what the turnover of different organelles is.
One has to admire cancers engineering for building immortal cells
There’s a few studies that point towards asymmetric cell division in yeast. The mother cell retains most of the molecular waste. I think the assumption that a similar process occurs in humans is at the basis of the dominant view on aging and the SENS project.
Looking at yeast, this may still be true. But I’d be surprised if evolution has managed to keep cell lineages alive for billions of years, but it has not figured out how to effectively clean up molecular waste.
The fact that neurons can live on for decades, perhaps centuries, makes me think the asymmetrical division of some cell lines after just a few days or weeks is a bit arbitrary. Sure, it may confer an advantage to those cell lineages, but the mother cells can still go on for quite a while, it may just be less fit.
This discussion is slightly tangential to my explanation for why methylation clocks work in both dividing and non-dividing cells, but it is interesting, so I’ll chip in.
If you look at bacterial ‘aging’ it is basically a matter of accumulation of metabolic waste – so long as the cell keep dividing they can keep ahead of this problem. And in very stressful environments where accumulation accelerates, they can do asymmetric division and leave one cell line as the ‘bad bank’, which will probably die off unless circumstances improve, but the other cell line will be fine.
Long lived cells like neurons produce metabolic waste, but they have dividing glial cells to remove it for them. So in that sense the aging is starting in glial cells not the neurons (presumably relating to telomere loss as Fossel advocates). Hence why transportation of neurons to a younger host enables them to live longer.
I beeleive Sinclair defense circuit has no relationship at all with the aging program lying on the cell nucleus. Too many, and different, reasons indicate the AP necessarilly exists.
Most important, the species-specific longevity, varying up to 1 million fold betweeen species.
What is known is that, except for autophagy, all the other best known aging mechanisms, which I think are aging effectors (executors) of this program, are Pro-aging (analogously to most single gene Pro-aging mutants in mice) instead of Anti-aging.
Please note that UNIFICATION OF ALL PREVIOUSLY CALLED”THEORIES OF AGING” (Barja, Exper. Gerontol. 2019) is possible only if we accept the existence of such program.
In theory you might be able to genetically engineer a mouse to age as slowly as a squirrel; a factor of 10, say. But in its natural environment that extra life would be irrelevant, as no mouse would survive anywhere near that long. So why would we expect evolution to do it?
Put another way, would an immortal Adam, put upon the earth, continue to sire immortal progeny? Or would the harshness of conditions put a limit on the advantage of a well-maintained soma? I suspect his grandchildren would be mortal.
I don’t know if that’s an argument for programmed aging or not!
Mark – What you say is an intuitive and compelling statement of the Medawar theory of aging, from his 1952 book. Certainly it is sensible, astute and reflects a broad knowledge of how evolution works.
But it’s also dead wrong. The theory was tested first by Promislow around 1990, with follow-up by Ricklefs and a heroic field study by Bonduriansky for his dissertation on antler flies. Everyone who has looked at this question of aging in the wild has concluded that aging does indeed take a big bite out of fitness. Chapter 4 of my book summarizes this argument in detail.
The idea that aging is invisible to natural selection in the wild has been thoroughly discredited for at least the last 15 years. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246505/
I think the idea that organisms age as fast as it is beneficial in evolutionary terms is not wrong. I see both your and Medawars hypothesis align in this sense. Its only that Medawar did not consider group survival as an evolutionary force.
However I think the consequences can be the same. The aging program is a program of calculated neglect. The body could fix the aging soma if it was evolutionary beneficial, but it isnt, so it just controls how fast enthropy is allowed destoy the organism. Just my two cents.
I agree that aging affects fitness in the wild – I don’t think aging is invisible to evolution. But I think that extending a mouse’s life by x10 (for example), would not stop it from dying from cold or starvation or being eaten by a predator or dying from infection, so the advantage slow aging would give a mouse would be irrelevant.
And that is why I agree with Gabor that any aging program is probably neglect rather than self-destruction, or rather starting from the mortal and not bothering to evolve immortality, rather than starting from immortality and evolving mortality.
Of course, I’m happy to be proven wrong, and I do think there is a great deal of randomness to species creation – lifespans could be largely arbitrary, with some fine tuning due to conditions.
Mark the program is self destruction: deliberate changes in predetermined timelines. That’s why all of us age similarly – a 70 year olds look more or less in similar decline. The cheat codes of hormesis allow only gives a little wriggle room to slow down some of the destruction. This study by Morrimoto gives evidence of programmed self destruction:
This repressive epigenetic marks just after puberty interferes with enzymes starting a cascade which deflates efficiency of heat shock response by 70% during the most important phase of protein formation. Starts a journey of degradation we call aging.
Just because turning certain genes up or down extends life isn’t proof of programmed aging. You’d have to prove such gene adjustments poised no disadvantage to the propagation of the germline over evolutionary time scales. It might be impossible to prove programmed aging.
I am afraid that I am like the doubting St Thomas Akshay, I just can’t believe until I see the wounds on Jesus’s hands with my own eyes (however much I might want to).
Mark I don’t know if you read that paper from Morrimoto. Just after puberty on cue Nature is creating deliberate repressive marks that leads to downregulation of Ubiquitin Proteasome system significantly for everyone. This is a highly conserved action across species. There can not be any doubt about how this move at our prime will lead to higher rate of misfolded proteins which would build up as aggregates, etc. From its timing, from its conservation and from its results this can not be anything but part of program that primes us to reproduce and then makes us slowly fade into death. This is just one of multiple deliberate changes that Nature makes amongst all living to ensure death within a narrow range of a lifespan irrespective of predation, accidental or infection related death.
Some further information on HSPs. This study looked at the correlation between HSP70 and male infertility and found a link (https://www.fertstert.org/article/S0015-0282(07)01364-7/fulltext). They speculated that the HSP was activated as a defensive mechanism to preserve fertility, but I find the more likely conclusion that HSP actually contributes to infertility. This is supported by small studies that show sauna usage (which lowers all cause mortality in humans) lowers sperm count and motility (https://www.nhs.uk/news/lifestyle-and-exercise/can-regular-saunas-harm-sperm-quality/), albeit temporarily – it was restored on cessation of sauna usage.
Long and short of it is that it looks likely getting your germline cells hot (or activating HSP by other means, I would speculate) is bad for them, so HSP being turned down at the onset of sexual maturity looks like a sensible move for the germline.
That being said, Saunas are likely to extend your life, so this is still a viable longevity strategy, but not proof of programmed aging.
It’s been known for a long time that heat in the testicles lowers male fertility. It is widely assumed that the reason that the testicles are in such a vulnerable position, hanging out exposed, is to keep the temperature a few degrees lower. So it is no surprise that saunas should lower male fertility. How much damage is done in a few minutes at a very high temperature? Here’s a 2013 study:
“Our data demonstrated for the first time that in normozoospermic subjects, sauna exposure induces a significant but reversible impairment of spermatogenesis, including alteration of sperm parameters, mitochondrial function and sperm DNA packaging. The large use of Finnish sauna in Nordic countries and its growing use in other parts of the world make it important to consider the impact of this lifestyle choice on men’s fertility.”
Thanks Akshay. I did read the paper. I replied but I think the references stopped the post being approved.
HSP70 is implicated in infertility. Sperm motility and count are also decreased by regular saunas. So maybe turning down HSP is a good idea for germline cells.
Hi Mark it is critical for stress response and correct folding during protein formation. And our bodies are run by proteins. There is systemic collapse of this critical support system of a very important process in the body just after puberty. If you look at it in reverse since it is so conserved one can predict puberty from the levels of the efficiency of ubiquitin proteasome system. Probably how Horvaths and other clocks work. If these detrimental changes can predict age they can only be part of a program that recycles all living. I am currently researching on where does this program lie – the origin of all the sequential highly conserved changes that happen to us over our life cycle: one of biggest biological mysteries – as then in future one could probably manipulate it. I will soon publish this essay on my blog.
“But I think that extending a mouse’s life by x10 (for example), would not stop it from dying from cold or starvation or being eaten by a predator or dying from infection, so the advantage slow aging would give a mouse would be irrelevant.”
It is not advantage that should worry but disadvantage. As there are likely a small peak group of mice that are better able to avoid predation and better able survive infection due to getting the best combination of genes making them the fittest in the population, they benefit disproportionately from antiaging vs the less fit mice in the population.
There are several problems that could happen if a mouse lived significantly longer.
One, as said, given that evolution works by differentially propagating the offspring of the fitter organisms at the expense of the reproductive potential of the less fit organisms, this could lead to an inbreeding positive feedback loop(as the members of the fittest families wipe genetic diversity out before the effects of inbreeding become detrimental enough).
Also the mature organisms could outcompete most younger organisms for resources, leading to stagnation.
The loss of genetic diversity would result in greater vulnerability to disease, and later on prolonged inbreeding would lead to species extinction.
Also sperm are fast dividing, and it is said that mutations accumulate in the germline stem cells of an organism the older it gets. Unless a solution was found simultaneously with increased lifespan, a vastly longer lived male could be extremely fit yet introduce vast genetic damage to the population, leading to error accumulation and species extinction.
To avoid loss of genetic diversity(which can be detrimental, even just taking into account disease vulnerability), and error accumulation, an aging program could protect similar to the protections that exist towards incest.
Akshay I look forward to reading your blog.
Darian, I like the idea of inbreeding, such things probably do happen before a change in environment causes die off. Such things show why an aging program would be an advantage. And likely the male germline is ‘an experiment’ allowing for faster mutation. Having said that aneuploidy comes from the old eggs of the female germline.
So here’s the report of a study showing that women who look much younger actually do have gene expression patterns of much younger women. https://www.sciencedaily.com/releases/2017/11/171128102918.htm
So do you think that if we could maintain these youthful gene expressions that we could appear young even at a very old age?
Interesting paper. ” These women had increased activity in genes associated with basic biologic processes, including DNA repair, cell replication, response to oxidative stress, and protein metabolism.”
This would surely grant a advantage over avg humans not only for skin but even overall mortality. In the end the onslaught of other age related degradation would eventually win. They should better chances for longer healthspan and maybe lifespan.
So this recipe lowers biological age by 18 months while whatever the test subjects were doing before – which is unlikely to be anything more cutting edge than eating well and exercising – lowers biological age by 24. I don’t understand the excitement.
First this reversed the epigenetic patterns, what they were normally doing could have slowed the rate of epigenetic change, but it is unknown if it also reversed the patterns.
Second this reversed 18 months in a relatively short period, longer treatment could potentially reverse even more.
Third it opens the door to other interventions that may be stronger, by showing the viability of reversal.
This is an interesting article on triple drugs and very significant life extension https://www.pnas.org/content/early/2019/09/26/1913212116
I have used lithium drops daily for a couple of years now without any issues. I’m wary of dasatinib but I like intermittent theaflavin with quercetin. I really like rapamycin synergies.
Thanks for sharing Paul. Interestingly the Mayo Clinic has just come out with a D+Q study where they showed an improvement of many SASP markers after just a few weeks of treatment. I think this will be a major boost of the combination of these 2 drugs for senolytic treatment.
What the study you just cited, and many others before it make me think about, is the contradiction between aging being the result of a decrease in re-generation, and the fact that dialing down cell proliferation is strongly associated with life extension.
Of course I don’t think it is that simple, and the trade-offs between the two may be complex. But it seems as if reducing senescent cell burden and/or slowing the pace of epigenetic change, results in a bigger life extension than any increase in cell turn-over and regeneration would. It would be useful someone looks into gene expression changes and aging in non-vertebrates so that we gain a better perspective on these studies. I believe they don’t use methylation to regulate gene expression.
Perhaps these mutants would have a much reduced fitness in the wild, and that’s why the balance between the two is what it is. But something to think about.
On D&Q, I’m concerned about the fairly serious potential side effects of dasatinib, including pulmonary hypertension, pleural effusions, and GI bleeding. If I’m going for a senolytic I’d probably choose fisetin or quercetin+theaflavin. Dosing intervals are always an issue and a vast unknown.
I very much agree that reducing senescent cell load and slowing epigenetic changes are within our capabilities even now. I think that GSK3 inhibition has been largely ignored by most people , so I was pleased to see the synergy with rapamycin. A little lithium may go a long way.
Vince G’s latest blog talks about the genome being for the species and the epigenome, being subject to the chaos of entropy, being for the individual and is the cause of aging. So information related to the individual is passed along in the epigenome, is subject to the second law of thermo, and causes us to age. As always he’s an interesting read.
Well it stands to reason that making better use of a limited proliferative capability will make you live longer. I don’t think there’s a contradiction there. Of course turning up proliferation is not always a good thing. It is clear that most animals grow to a fixed size, after which they have a very limited regenerative capacity. This seems to the way evolution works – it doesn’t want or need an individual to be more long lasting. But to beat aging I don’t think we can put up with this. Keeping old cells going will probably not be sufficient. We need them young again, and proliferative competent (in the right circumstances). There is every chance this so doable. Until then though, we’ll have to keep our old cells going a little longer.
Per the point “Readers looking to make immediate changes to their personal stack based on the results of this experiment might try the four cheap and proven ingredients, leaving out the HGH for now.”
Sulforaphane research findings have commonalities with the clinical trial. The four treatments are especially interesting at https://surfaceyourrealself.com/2020/05/27/reversal-of-aging-and-immunosenescent-trends-with-sulforaphane/
The second half of Dr Fahy’s presentation topics’ commonalities with sulforaphane research at https://surfaceyourrealself.com/2020/05/29/part-2-of-reversal-of-aging-and-immunosenescent-trends-with-sulforaphane/
I was surprised that no one suggested some ipamorelin (or related combinations) as alternatives to HGH.
I did a short self experiment for a few months using 5 grams of GABA powder before bedtime in place of HGH. This resulted in an increase in blood glucose and a prescription for Metformin. Soon after I started skipping the GABA on days when I do strenuous exercise on MWF, as the exercise would yield a natural boost of HGH/IGF-1 on those days, and this also seemed to help get the BG back under control. I obviously can’t afford thymus MRIs, and have no degree or reputation to pursue a grant (in anything other than computer science), but perhaps before and after epigenetic clock tests would have yielded something useful. I also wonder if daily exercise with GABA would be better for HGH and/or controlling BG? Too many questions, and no real conclusions.
Roger, I practice strenuous exercise in the fasted state, combined with sauna use, as a cheap and safe way to raise HGH. No pills.