Weight and Aging: a Paradox, Part 2

The paradox: In animal models there is a consistent relationship between eating less and living longer. But studies in humans find that people who are a little overweight live longest.

Last week, I introduced this paradox and offered evidence, both that lab animals live longer when they are underfed, and that humans live longer when they are overfed. In the article below, I introduce nuances and confounding factors, but in my opinion, the paradox remains unresolved.

BMI

BMI is an imperfect measure of how fat or thin someone is for his height. That’s because it is calculated with the square of height, but body volume (for a given shape) is proportional to the cube of height. The result is that tall people will have a higher BMI than shorter people with equivalent proportions of body fat. For example, BMI=20 for a person 5 feet tall means a weight of 102 pounds, an average weight for that height; whereas BMI=20 for a person 6 feet tall means a weight of 147, which is borderline emaciated.

Short people tend to live significantly longer than tall people, and the effect is substantial.  Males under 5’7” live 7½  years longer than males over 6’ [ref]. This fits with the fact that short people tend to have less growth hormone in their youth. There is a genetic variant in parts of Ecuador that prevents growth hormone from transforming to IGF1 (Laron dwarfism); these people are generally about 4 feet tall and tend to live longer. From domesticated animals, we also know that small dogs live longer than large dogs, small horses longer than large horses. Between species, larger animals live longer, but within a single species, smaller animals live longer.

The height association deepens the weight paradox, because short people will tend to have a lower BMI, which we would expect to skew the association of BMI with longevity downward.

Growth Hormone and IGF1

Growth hormone (which is translated into IGF1 in the body) is genetically associated with shorter lifespan, but we have more of it when we’re young and it promotes a body type with more muscle, less fat. According to this Japanese study, IGF1 increases with weight for people who are thin, but decreases with weight for people who are fat. So maximum longevity is close to maximum IGF1.

Here are some partial explanations for the paradox.

Most variation in weight is explained by genetics, not food intake. The explanation I have proposed in the past is that the CR effect is about food intake, not genetics. And people who are congenitally stout are more likely to be restricting their calories. CR humans are not necessarily especially thin.

The CR effect is proportionately smaller in long-lived humans than in short-lived rodents or shorter-lived worms and flies. [ref] If life extension via CR evolved to help an animal survive a famine, then it seems reasonable that the benefit should be limited to a few years, because that is as long as most famines in nature are likely to last.

The CR effect may be due to intermittent fasting rather than total calorie intake. Traditional CR experiments conflate intermittent fasting with overall calorie reduction, because food is provided in a single daily feeding, and hungry rodents gobble it up, then go hungry for almost 24 hours. More recent experiments attempt to separate the effect of limited-time eating from the effect of calorie reduction, and the general conclusion is that both benefit longevity. It may be that humans who are skinny tend to graze all day, while people with a comfortable amount of fat more easily go for hours at a time without eating. 

Mice carry less fat, have less food craving, and have better gut microbiota if they are fed at night rather than during the day [ref]. Mice are active nocturnally; so translating to humans, it probably means that we should eat in the morning. Conventional wisdom is that eating earlier in the day is better for weight loss and health [ref], but I know of no human data on mortality or life span. This classic study in mice [1986] found caloric restriction itself was the only thing affecting lifespan, and there was no difference whether the mice were fed night or day, in three feedings or one.

Smokers tend to be thinner than non-smokers, but they don’t live longer for reasons that have to do with smoking, not weightSo this is a partial explanation why heavier BMI might be associated with longer lifespan. But note that the recent Zheng’s Ohio State study claimed there was no change in the best weight for longevity when correction was introduced for smoking.

Cachexia is a “wasting” disorder that causes extreme weight loss and muscle atrophy, and can include loss of body fat. This syndrome affects people who are in the late stages of serious diseases like cancer, HIV or AIDS, COPD, kidney disease, and congestive heart failure (CHF). [healthline.com] If cachexia subjects are not removed from a sample, it can strongly bias against weight loss, because once cachexia sets in, life expectancy is very short. But the Zheng study was based on Framingham data, collected annually over the latter half of a lifetime; Cachexia is not expected to be a significant factor.

Timing artifact – The Framingham study covers a 74-year period in which BMI is increasing and also lifespan is increasing, probably for different reasons. The younger Framingham cohort is living ~4 years longer than the older cohort and is ½ BMI point heavier. This could create an illusion that higher BMI is causing greater longevity. However, the Ohio State study made some effort to pull this factor out. Greater lifespan is associated with gradually increasing BMI, and this is true separately in both cohorts.

Differential effects on CVD and Cancer This chart (from Zheng) shows how the mortality burden of cardiovascular disease has decreased over the last century, but not so cancer.

But CV disease risk increases consistently with BMI, while cancer risk, not so much (also from Zheng):

These numbers in parentheses are odds ratios from a Cox proportional hazard model. What they means is that a person in the Lower-Normal weight group had 20% less chance of getting heart disease compared to someone of the same age in the Normal-Upward group, but a 60% increased chance of getting cancer. These appear to be large, concerning numbers. But remember that the underlying probabilities are all increasing exponentially with age. Translated into years of lost life, 60% greater probability of cancer is only 1 year of life expectancy at age 50. (60% greater overall mortality would subtract 4½ years from life expectancy.) In my experience, hazard ratios in the range 0.7 to 1.5 don’t necessarily mean anything, because of the difficulties in interpreting data. The numbers in parenthesis after 1.60 in the above table (1.12 2.30) mean that statistical uncertainty alone is a range from 1.12 to 2.30.There are plenty of large effects with hazard ratios of 3 or more. For comparison, the hazard ratio for pack-a-day smokers getting lung cancer is 27.

Zheng’s study found a longevity disadvantage to being underweight, and it was exclusively due to a higher cancer risk. In fact, incidence of cardiovascular disease among the lowest BMI class was lowest (0.8); but their cancer risk more than made up for it (1.6). 

This means that as time goes on and most Americans are getting heavier, their risk of dying from CVD is blunted by improved technology. The mortality risk from CVD is down by 40% in this century [NEJM], while the cancer risk is unchanged [CDC]. So people are dying of cancer who would have died of CVD in previous generations. 

This means that low BMI has less benefit for longevity than it used to have, and the trend over time tends to exaggerate the appearance that higher weight is protective against all-cause mortality.

Is it true that cancer risk does not go up with BMI?

The Framingham result is puzzling and difficult to reconcile with a well-established relationship between higher BMI and higher cancer risk. This review by Wolin [2010] finds a modest increase in risks of all common types of cancer associated with each 5-point gain in BMI. (The RR numbers are comparable to hazard ratios above.)

Lung cancer is the big exception, and Wolin explains the inverse relationship with BMI by the fact that people smoke to avoid gaining weight. This would suggest a resolution to the conflict with Zheng’s study, but for the fact that Zheng explicitly corrects for smoking status and finds it makes no difference at all — a result which is puzzling in itself.

Alzheimer’s Disease is the third leading cause of death, and the corresponding story is more complicated. Lower weight in middle age seems to be mildly protective, while it is certainly not protective in the older years when AD is most prevalent.

“Hazard ratios per 5-kg/m2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66–0.77), 0.94 (0.89–0.99), and 1.16 (1.05–1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis.”  [ref]

This, too, is unexpected in light of previous consensus. Alzheimer’s Dementia has been recast as Type 3 Diabetes, because of its strong association with insulin metabolism. Overweight is supposed to be the greatest life-style risk factor for diabetes. When this study [2009] out of U of Washington found that high BMI is protective against dementia, the authors were unwilling to draw the standard causal inference, so they conjectured instead  that weight loss is a consequence of AD’s early stage. 

There may be a better explanation hidden in their data. AD is the most common cause of dementia, but vascular dementia, a separate etiology, accounts for roughly ⅓ of cases in the Kame data set:

There is a suggestion here that higher BMI protects against vascular dementia, but not against AD.

From you, my readers

Here are some of the suggestions offered in the comment section of last week’s blog:

  • Fat people are happier.  I don’t doubt that happiness has a lot to do with longevity but a lot of overweight is due to compulsive eating by people who are not happy with their lives. Obesity is associated with lower socio-economic status, and lower SES is independently associated with shorter lifespan and lower life satisfaction.
  • Higher BMI can mean more muscle mass, not necessarily more fat mass. Good point. I don’t know how big a factor this is.
  • This study [BMJ 2016] found greatest longevity for BMI in the range 20-22.  I take your point that the larger studies with longer follow-up tend to report lower optimal BMI. The BMJ study is a meta-analysis of a huge database covering 9 million subjects.
  • Dean Pomerleau writes at the CR Society web page about brown fat, cold resistance, and greater longevity.
  • Thin people have greater insulin sensitivity, which can lead to glucose going into cells instead of being stored as fat. This is interesting, and deserves more follow-up. But good insulin sensitivity also means lower blood sugar, so its not obvious to me which direction the effect ought to go.
  • I was grateful for a pointer to Valter Longos recent work, recommending that time-restricted eating becomes counterproductive after about 13 hours a day of fasting. Longer fasts several times a year are still highly recommended.
  • Paul Rivas is my go-to authority on weight, and he recommended this 2015 study, which emphasizes the paradox as I describe it.
  • This study out of Emory U [2019] recommends different diets for different BMI groups for minimizing inflammation.

What story does methylation tell?

Aside from mortality statistics, I regard methylation age as the most reliable leading indicator we have. I’ll end by reviewing data on BMI and methylation age.

The Regicor Study [2017] looked for methylation sites associated with obesity. They reported 97 associated with high BMI and an additional 49 associated with large waistline. I compared their lists with my list of methylation sites that change most consistently with age. There was no overlap. What I learn from this is that there is no association with genetically-determined weight and longevity. If you were born with genes that make you gain weight, there is a social cost to be paid in our culture, but there is no longevity penalty.

Horvath [2014] did not discern a signal for obesity with the original 2013 DNAmAge clock, except in the liver where the signal was weak, amounting to just 3 years for the difference between morbidly obese and normal weight. But a few years later with 3 different test groups [2017], a moderate signal was found, as expected, linking higher BMI to greater DNAmAge acceleration. (Age acceleration is just the difference between biological age as measured by the methylation clock and chronological age by the calendar.) 

This study [2019] from the European Lifespan Consortium found a modest increased mortality from obesity, corresponding to less than a year of lost life by most measures, based on two Horvath clocks and the Hannum clock. This Finnish study [2017] found a small association between higher BMI and faster aging in middle-aged adults, but not in old or young adults.

This study from Linda Partridge’s group [2017] found a strong benefit of caloric restriction on epigenetic aging—in mice, not in humans. 

The bottom line

I’ve had a good time with this project, seeking explanations for the paradox, and I’ve passed along some interesting associations, but in the end, the essential paradox remains. I don’t know why the robust association of caloric restriction with longevity doesn’t lead to a clear longevity advantage in humans for a lower BMI. My strongest insight is that the largest determinants of BMI are genetic, not behavioral, and the genetic contribution to weight has no effect on longevity. But what do I make of the fact that life expectancy in the US has risen by a decade over my lifetime [ref] even as BMI has increased 5 points.

160 thoughts on “Weight and Aging: a Paradox, Part 2

  1. Despite the increased risk of gallstone formation with a time restricted feeding protocol of greater than 13 hours duration, several studies have shown significant biomarker improvements in subjects fasting 14 to 18 hours.

  2. Generally, a search for a trend in the empirical data is unsuccessful. More successful is a search for patterns. Most successful because it provides the maximum possible information gain to a user of the model is pattern discovery under information theoretical optimization. The late theoretical physicist Ronald Christensen discloses how to pull this off in the book “Multivariate Statistical Modeling.”

  3. David Sinclair claims that cell repair only takes place during hunger. Perhaps the percentage of time hungry (during IF/CR) is what affects lifespan.

  4. Josh, you finish the blog saying:
    “But what do I make of the fact that life expectancy in the US has risen by a decade over my lifetime [ref] even as BMI has increased 5 points”

    I think the reason for that is that too many factors affect life expectancy. For instance, comparing now with 70 years back in time I am sure health care and family economic income increased much in the USA (apart from american deaths in WWII).
    My first wife was a maximum authority in Spanish Sociology which made me familiar with the too many problems and huge complexity and confounding factors impossible to eliminate with computers no matter what the corporative interests claim.

    In other words, studies in humans including epidemiology etc are not Hard Science. They can be seriously performed but they will never have the clarifying strength that Science has.
    Medical doctors are the most powerfull corporation among biological system related specialists. But Power is a very different thing to TRUTH.
    If you want to better approach truth (impossible to achieve 100% as Blaise Pascal explained ys so brilliantly many centuries ago) use Science instead of studies in humans. They can sometimes be interesting but they ARE NOT SCIENCE

  5. Oh and the other thing…..as people get older (elderly) their skin wil make less than 50% less D3 from sun exposure than younger skin…thus leading to increased bodyweight in some of the elderly

    • Hi all:

      Maybe the issue is associated with the type of fat a person carries.

      For example, white adipose tissue, brown adipose tissue or beige adipose tissue.

      There are foods that stimulate the thermogenic type of brown and beige adipose tissues.
      Some are: apples & pears with their skins, hot peppers, turkey breast. Fatty fish

      Still a person can gain weight if they eat a lot of apples or pears or fatty fish.

      Perhaps however, if it is brown fat, it results in fewer health issues.

      Visceral abdominal fat is typically the dangerous white adipose tissue.

      IMO, the waist measurement is likely more important than BMI.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336830/

  6. On the other hand , this very recent study out of UCLA shows a cardiac protective effect of excess body fat in females with higher muscle mass in females. In males, the greatest benefit was in those with high muscle and low fat.

    https://www.sciencedaily.com/releases/2021/03/210316183651.htm

    So it’s all confusing and contradictory. So women who are obese should lift weights, and those who lift weights should get fat to protect their hearts? Wow, I really don’t know anything.

    • Hi Paul:

      Regarding fat in women and the paradox you mention:

      https://pubmed.ncbi.nlm.nih.gov/28923177/

      From the link: “Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age.”
      —————
      Paul:

      Perhaps then, in muscular women, the added fat has a protective effect for heart disease because a muscular women who may be too thin may have high testosterone levels and not enough of fatty tissue to offset it with tissue estrogen production,

      Women need small amounts of testosterone but too high is claimed to lead to heart disease.

      Conversely for men who also need some estrogen, a too high level of estrogen and too low testosterone may contribute to cardiovascular disease.

      Because peripheral tissues can create estrogen, fatter middle-aged, or older, men create more estrogen, and if they are not muscular they produce less testosterone, possibly leading to cardiovascular disease.

      Paul you wrote: “So it’s all confusing and contradictory. So women who are obese should lift weights, and those who lift weights should get fat to protect their hearts? Wow, I really don’t know anything.”

      Paul:

      I think that observation may be accurate. A layer of fat on a muscular middle aged, or older, woman would likely help offset the testosterone increased by working out or lifting weights. Not too fat, just some fat.

      And, some muscle on an fat woman may modulate too high estrogen levels.

      • I remember reading somewhere that women with abdominal fat are much more likely to suffer heart disease and that this fat generates cortiosol more than other fat.. While women that carry fat around their hips tend to suffer from breast cancer more often as this type of fat generates estrogen/estradiol better. Don’t quote me on this but you might want to look into it..

      • Heather
        Those are interesting thoughts. Here’s a few more to chew on:

        The overall incidence of CVD has gone down over the past 50 years, but more so in men.

        The incidence in women 35-55 has actually gone Up over that time. Women also have a higher mortality rate after cardiovascular events.

        Even though excess body fat is a risk for hypertension and diabetes, fat around the hips and buttocks, usually more common in women, and this has a protective metabolic effect.

        Women accumulate fat by increasing the number of fat cells, whereas men grow fatter by hypertrophy.

        So I think that ,in general , premenopausal women are more protected than post menopausal women due to a more favorable fat distribution. After menopause, women start storing most of their fat above the waist, similar to men who store 98% of fat abdominally.

        No one knows why the incidence of CAD is increasing in younger women. Stress? Diet? Birth control pills?

        • Hi Paul

          Thank you for the interesting tidbits.

          Endocrinology is complex, no doubt about it.

          Out of whack hormones definitely contribute to weight gain or loss. It’s a complicated balancing act. There are so many factors that effect various hormones.

          • Apparently the post menopausal rise in FSH causes weight gain..and suppressing FSh can block weight gain…You can suppress FSh by taking high dose mealtonin at night

            Now results published in The New England Journal of Medicine and Cell Metabolism have revealed the rise in FSH at the time of the menopause may be responsible for the waist-thickening weight gain. In studies of mice, it was found that blocking FSH increased the calories burned.Jan 19, 2021

            Blocking FSH ‘may help menopausal women fight weight gain …

        • Yes Paul,

          Women working, drinking, eating worse, more stress, not having families … basically feminism in a nutshell. But forget longevity, at least most north american women are on SSRIs or other meds, it’s quite the physical and spiritual disease that the powers that be are high fiving on.

  7. Josh you finish by saying ‘My strongest insight is that the largest determinants of BMI are genetic, not behavioral, and the genetic contribution to weight has no effect on longevity.’

    How about taking this a step further and admitting that the largest determinants of longevity are genetic, not behavioural?

    As life extension enthusiasts, we are all desperate to do something to increase life and health span, especially if it makes us suffer a little so we feel we deserve it. But solving aging will probably not involve being puritanical!

    • Mark. Look at our paper in Redox Biology 2020. After 41 years of searching I found the genes responsible for the lower rate of mitROS generation in longlived animal species. Its name is ndufv2 (harboring inside itself the FeS cluster N1a). Sazaniv and Walker solving the sturucture of complex I at 3 amstrings resolution helped me to find ndufv2. Now we are measuring ndufv1. I am almost sure it is also inviolved. The 3rd actor we found is VDAC (a component of the mPTP permeability transition pore. When it opens this huge pore allows even large molecules like NADH to leave the matrix to the cytosol to klll the cell. Now we know it is ivolved BOTH! in the degerative diseases but also in basic aging. Look at my hypothesis on the triangle and 22,3 amstrongs wide (largest than the Colorado Great Canyon in molecular terms) space impossible for the electron to jump by that abyss to FeS N3 (part of ndufv1-also containing the possible ROS generator flavin on the upper part of Fig. 4 and accompsnying text. See also the review Pamplona R. and Barja G. that FESB J quickly asked us to write after publishing the original Mota- Martorell et al. Redox Biol paper

    • Mark:

      I am not so sure that genetics always overrides lifestyle when it comes to living a long life.

      My grandfather lived to be a healthy 98 years old. He had all his teeth and was still relatively strong and walking upright before his relatively peaceful and sudden death.

      He exercised daily, and always took a short walk after eating dinner. He ate very little meat. His protein sources were mainly cheese, eggs and fish. He also ate a lot of vegetables most of which he grew himself as well as some pasta and bread.

      He had four children, three of whom flouted that lifestyle. Those three ate a high meat diet, very little fish and some pushed the vegetables to the side of their plate.

      Only one of them lived past to 80. The other two died in their 70s.

      If genetics was the sole determinant, it seems reasonable that at least one of the three, in spite of failing to share my grandfather’s “behaviorally healthy” lifestyle, would still be alive.

      Of course, my grandfather did not feel as if he was depriving himself. He actually enjoyed eating the way he ate, and he enjoyed working out, and taking his evening walks. ….So there is that happiness factor.

      • I wasn’t suggesting that lifestyle has ZERO effect on life and health-span, merely that plenty of people survive a long time with supposedly unhealthy lifestyles – enough even to make me doubt the common strategies you espouse.

        • To your point Mark. My mother in law is 86. Diet? Tasty cakes and processed meats. Exercise? Never. Weight? Not good. Longevity genes? Superb.
          Health? Rheumatoid arthritis and stroke.

          I think that lifestyle plays a significant role in health. Modest on lifespan.

          • I agree.

            Studies on people taking nutrients for most of their life show an increase in life span of only about two years. However, their healthspan was far superior.

            Given the choice of a long life or a shorter but healthy life with a quick death…. I would choose the latter.

            My grandfather likely had a combination of genetics coupled with a healthy lifestyle that allowed him to stay relatively strong and healthy until he experienced what his doctor called a “good death” at the end. He had no long period of suffering before he died.

            Whereas his children, with the terrible diets and lifestyle, all suffered with various ailments and debilitations a long time prior to dying.

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Heather, I agree with most what you say…..but….just remember a big truth:
            AGING IS THE BASIC CAUSE OF ALL THE TERRIBLE DEGENERATIVE DISEASES. SO, WE WILL NEVER GET RID OF THEM IF WE DO NOT ERASE AGING ON THE FIRST PLACE.

            IF YOU GO TO SAVANNAH (GEORGIA) ON NOVEMBER 17TH-20TH (USA NATIONAL SfRBM MEETING, I HOPE TO BE THERE, WITH THE PERMISSION OF COVID..AND I SWARE THAT I WILL TELL THERE AT MY LARGE TALK ALL I LEARNED DURING THE LAST 41 YEARS OF CONTINUOUS AND EFFORT ALL MY STRENGTH ON WHAT MUST YOU DO THE USA SCIENTISTS, THE NUMBER 1 WORLDWIDE? TO ERASE AGING FOREVER FROM THE FACE OF HUMANKIND…
            WHAT I KNOW? I PROMISE, IS NEW TO MANY BUT TO GET THE END OF THE WAY WE MUST GO ON DOING RESEARCH ON THE RIGHT DIRECTION. YOU MUST OPEN AND LOOK AT THE CELL NUCLEUS AND CLARIFY, ROUGHLY, HOW THE NUCLEAR AGING IS ORGANIZED. I BELIEVE IT IS THE SUCCESSIVE COOPERATION OF NUCLEAR EPIGENETIC PROTEINS AND DNA WHAT BRINGS YOU FROM 5 TO 25 THEN TO 45, 75 etcetera…
            Whstson and Crick WERE WRONG. BOTH NUCLEAR PROTEINS AND DNA ARE RESPONSIBLE FOR INHRRITANCE, EVOLUTION, AND…OF COURSE…AGING!

            WE MUST DISENTANGLE THE COOPERATION NETWORK OF THOSE NUCLEAR PROTEINS AND DNA IN 4 DIMENSSIONS (THE 3 SPACE ONES PLUS TIME) BEFORE WE CAN SOLVE THE AGING PROBLEM
            GUSTAVO BARJA
            PROFESSOR OF PHYSIOLOGY
            LRMG SPAIN UE

          • Quite possibly a healthy lifestyle has a greater effect on healthspan than lifespan – this would make sense when you consider the difference between median and max lifespan, with the first being much more malleable than the latter.

            But I can also think of counterexamples. My mother in law was super active, plenty of exercise, no red flags in the diet – had a stroke last year and now spends most of her time in a wheel chair. It is tempting for me to say it was a result of her temperament. But it could equally just be a genetic weakness.

          • 80% of us are magnesium deficinet due to centureis long depletion of our soils and foods . Docotrs tes tthe blood which contains only 1% of our magnesium and is tightly controlled and tell us your magnesium is normal..The only real test that will tel youabout youtr magnesium is a muscle biopsy…OR just look a the magnesium deficiency symptoms list and see if you have a few of them…While the deficeincy exists in the tissues! Magnesium protects protects people form stroke and many other things like mitral valvc prolapse…Magensium deficiency leads to weakened tissues all around….Here is a link to a blog post on it>>>
            https://jefftbowles.com/why-80-of-us-are-deficient-in-magnesium/

        • Hi mark:

          I am not “espousing” any particular diet or lifestyle.

          I am simply passing along information and observations.

          You can correlate the information any way you wish.

          You are likely the best judge of what makes you feel healthy and what does not.

  8. I tried to post this before but it does not show up when I look at comments so apologies if this already read by you all…when studying the distribution of Covid-19 around the world and finding it occurs most in people and places where D3 levels are the lowest..

    I also discovered that you can explain the entire US obesity map that shows where obesity is the highest and lowest can all be explained by D3 levels in the population…You can explain the entire obesity pockets in the US by finding areas with people with darker skin that makes less d3 like blacks, hispanics and Indians ..there is also a fat pcoket in the Applachian mountains amongst whites..these are relatively low altiude mountains where the sun exposure is blocked during some portions of the day

    Then the really big clue was the fact that there are almsot no fat people in Colorado!!! or in the higher altitude plains states (except for Indian reservations) ..I could not initially figure this out I thought Colorado mountain shadows would cause widespread d3 defiiency…Ad then I found it…for every 1,000 feet increase in elvation the UVB level gets anywhere from 5 to 10% stronger. depending on who youi ask…!!! So at leadvill Colorado at around 10,000 elevation the sun is about anywhere form 50 to 100% stronger and better at making D3 than at sea level! And thus the ;population that lives in high altiudes has higher d3 levels and thus less obesity. even when living in the shadows of mountains.

    • Makes sense that less sunlight means cold, and cold means you need more fat to keep in the heat; lower Vit D is a useful mechanism to join the two. Africans (sub Saharan) tend to have long limbs to radiate maximum heat and this goes well with dark skin (low Vit D) and low body fat in the normal conditions they evolved in; but in darker, cold conditions this explains why African Americans easily put on weight, and perhaps why they are more likely to die from Covid-19.

    • Correlation is not causation. In Europe, the main driver of obesity is wealth and education regardless of the color of the skin. It seems to me that it is the same in the US. It is commonly known that african-american and hispanic people are in the average poorer than white people.

      • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

        Thanks Patritio. I had the idea (you say wrong) that wealthy people was better educated and were better informed on what is best to eat or to avoid eating, like in Manhattan (Woody Alllen guys type, or whatever…
        But I supposed it was the same in Europe and you say No.
        I am a biologist looking for erasing aging and found a couple of mitochondrial genes (ndufv2 st Complex I, and VDAC protein (part of the permeability transition pore up to our fibding implied only in partology) responsible for part of the AGING RATE. (ndufv2 involved in the mitROS production at CxI related to aging, other mitROSp sites at other Complexes are Not invokved in aging).
        See our recent paper: Mota-Martorell et al. Redox Biol. 2020 ( if you have to pay to get it just write me to : “gbarja@bio.ucm.es” and I will send you the paper.

        Coming back to the issue of obesity I never worked with human data. Only frogs, rats, mice, ….cow, horses, and birds pigeons, canaries and parakeets…
        Please send me the right paper to read that UE welthy people are more obese than the normal unwelthy (oposite to US), because I did not lnow that. Thanks Patricio.
        Now I understand…
        Many US Americans are naif, kind of innocent, whereas too many Europeans are Cynic (in the “bad” sense) due to the 6000 years of history on their backs. That is why I do not know any single UE gerontologist that does CR himself, whereas at USA I know many! ANYWAY,
        All the best

        • Sorry, I think you misunderstood me. When I said obesity was correlated with wealth and education, I didn’t mean that rich and educated people were more likely to be obese, but the opposite of course. I thought it was obvious…

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Ah! Ok Sorry Patritio. Everything is clear and makes sense to me now

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Patritio. I looked at your link and it is tge reverse The poor and ignorant eat worse not better than the wealthy ones. Just the same as in Manhattan. Makes sense.
            Read the title. It is in French. I am fluent on it.

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Half obesity in high white collars executives than in workers, peasants etcetera. I am directly translating from French to English

      • Europe is a big place. It would be interestingly to look at the differences in obesity and race between Scandinavia and the Mediterranean area. That might tell us if my theory has any merit.

        • Hi Mark:

          If you do some research you will see that cold weather, and cold environments in general, stimulates brown fat.

          Brown fat is thermogenic so it produces heat, but people with a lot of brown fat are much slimmer. The thermogenic brown fat keeps people warm even if slimmer.

          High altitudes over 5,000 feet, reduce hunger and cold weather stimulates brown fat production. Both tend to stimulate weight loss.

          People living in Colorado tend to be slim. It always makes the list of the slimmest state. Look it up.

          • It could be the cold weather..But I used to live in Steamboat Springs through entire winters I was never cold…When I went outside I had some really good down coats and moon boots…When I skied I often would be sweating under my clothes. My houser and car were alwasy warn…
            What was happneing is I was exposd to a much stronger UV-B sun rays at the 8000 foot altitude anywhere from 50 to 80% stronger and able to make much more vitamin D3 thean the sun at sea level at an equal latitude. I believe the people in Colorado are skinny due to having high d3 levels most of the year. I present a lot of eviudence for this in my book about Covid-19 which was banned by Amazon but I am giving away free as a pdf…16 Fascinating Covid-19 and Spanish Flu Mysteries Solved. send me an email at jeffsbandn@gmail.com for a free copy

          • Jeff, please send me your book (free you say) about COVID. I am very interested

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Thaks a lot Jeff

        • Confoundng Variables…
          Scandanavians supplement with alot of vitamin D3 in their foods, cod liver oil use is high as well…and the Norweigiens eat tons of coldwater fush that are high in D3..
          Italians and Spaniards live in the shadows of low altitude mountains which makes them somehwat Vitamin D3 deficient..
          If Vitamin D3 levels are the cause or prevention of obesity….then we won’t learn much from a study like this unless you control for d3 levels…

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Jeff, In Spain 50% of people 65 years old or older are vitamin D3 deficient. Studies performed by doctors or the Spanish Ministry of Health. However there has never been launched any campaign of vitD3 supplementation here. Neither the political Right nor the Left (now in power) has ever done it!
            Concerning mountains we have many but we have also lots or plains: The Two Castillans Communities and part of Aragon Community (“States”). These plains are likely 40% or more of Spain surface and pretty sunny uncloudy skyes except a norrow area in the North.

            But A) we do not walk nude in the street, B) Most Spaniards expend most of the 24 hours of each day indoors (working in odfices or at home in small apartments 60 to 80 square meters most of them and C) The angle of incidence in winter in Spain and other North World areas is so small that A+B+C = vitamin D3 deficiency in half of the old

        • Here is some research for you:

          https://www.bmj.com/content/368/bmj.m1101/rr-10

          Inhabitants of Swedish-Somali origin are at great risk for covid-19

          ‘Vitamin D status is strongly related to low sun exposure and dark skin. In two different studies, the great majority of Swedish women of Somali origin had very low levels of S-25(OH)-D (< 25 nmol/l).[3,4] In Finland, Somali women required more than twice the amount of vitamin D in order to maintain recommended vitamin D status.'

  9. Josh what counts is not BMI but the muscle mass. The more muscle mass some one have relative to the total weight the more healthy one is. I’ll be curios to see a study that measure the percentage of muscle mass. vs the health
    One can think that bodybuilders live longer. Unfortunately most bodybuilders take anabolica and after a certain age stop training.
    One must look at the hobby natural bodybuilders who continuously train until old age but not for performance. Those are the most healthy people on earth (save the illnesses that are genetically conditioned)

    I have myself experimented this. I had 20 years a chronic inflamation. I tried everything which helped me more or less. Since 3 years I began bodybuilding at 50 years old. After a few months the inflamation dissapeared and now I am feeling again as I am im my 30s.

    As about Corona virus and muscle mass. I read that not a single active bodybuilder (amateur or profesional) at any age who test positive have any symptoms. There are also active bodybuilders who are in their 70s

    • @Florentin

      My own experience aligns very well with your observation. I’m not considering myself a bodybuilder. I started resistance exercise at the age of 58 and 8 years later I’m lean with considerable muscle mass but not bulky (more like Michelangelo’s David).

      The thing is, naturally gaining muscle mass is an individual effort and commitment, and for most older people a no-go. Scientists know that and focus their research on exercise and CR mimicking drugs (Rapamycin, Metformin) or diets (V. Longo). Which I consider a waste of resources.

      Another example is the hype about NAD+. A couple of years ago Sinclair and others convinced me to go for it. Over 18 months, I tried 2 different commercial NAD+ precursor brands. It was a waste of money, no difference at all. Just learned that exercise and fasting, which I do too, increase NAD+ levels naturally, even in older people.

      • Interesting observation Stephan, and fits very well with my own experience. I’ve skipped expensive (and sometimes dangerous) drugs and replaced them with exercise and fasting. Most people won’t believe they can run 5K after 20 hours without food, but they can. Lack of discipline and willpower are their only limitation.

        • You are right Ole! When I hit the gym or go hiking in the mountains I haven’t eaten for at least 16 hours. My amateur hypothesis is that my body is then in Ketosis and is burning fat only, which provides more energy than burning carbs or proteins.

          Also, I do a water fast every third month for 4 days which feels like a battery recharge.

    • The photo shows Jim Morris, his figure is excellent, but all physiological systems correspond to 77 years. What does this match mean? Information space diagnostics (dyagtor.kom.ua) determines all parameters of a person from a photo. So with aging, after 20 years, epithelial and connective dense tissues increase; loose connective tissue, blood and lymph decreases; cartilage, bone, nerve and hair roots are partially embalmed. Embalming is the transition of a part of tissue from a living state to a non-living state with a 50-fold decrease in mass. Therefore, the reserves of Jim Morris are small, despite the excellent view. There are now two anti-aging products available. It is an energetically stabilized malic acid that stops the aging of internal organs with a daily intake of this acid of 100 milligrams. Also, energetically stabilized galactose has been obtained, which, when consumed daily in 50 milligram doses, stops the aging of the skin, hair and teeth. Stabilization is a process of informational logical action associated with the technology of information fields of the Universe.

    • I’m just not sure. These studies don’t guard against reverse causation – it could just be that those who are better able to exercise feel like doing it.
      It is certainly difficult to unpick the lifestyle and genetic elements.

      I personally prefer weight lifting to endurance, but I can see the benefit to both, and clearly endurance is better for weight control, as is pertinent to this article.

    • Interesting study.

      IMO, it is extremely important to maintain muscle mass. Building muscle releases beneficial hormones and speeds up the metabolism to burn fat. Also good muscle tone prevents falls and back issues from lifting small items around the home.

      Aerobic activity alone is also good for burning fat. Thus some aerobic activity is a good choice coupled with strength training. But if a person had to choose one, IMO, it should be strength training.

      My personal observation regarding runners, that do not strength train, is that they appear very fragile and some runners that do not supplement properly are even bent over, likely from osteoporosis.

      Some runners refuse to strength train because they want to remain slim and light weight. To their minds, strength training may cause them to bulk up and slow down their running speed.

      • The real question for me is how much of a choice is it to maintain muscle mass and how much deterioration happens outside of our control. At some point even bodybuilders have to retire.

        The wasting that occurs at advanced age is in many cases not reversible with weight training (and there are papers to prove this), due to the chronic activation of ROS sensitive inflammatory cytokines, and these have to be addressed first. Even then the root cause of aging has not been addressed.

        This is not to suggest that appropriate lifestyle and supplements cannot postpone the point of tissue wasting, only to highlight that weight training is no panacea.

        • There is definitively no panacea for aging at this point. At least not one that is commercially available to humans.

          Still, sarcopenia is typically related to a disease state or process, sometimes co-morbid with cardiac cachexia, cancer, hormonal disruptions, or PERHAPS stimulated, or worsened, by inactivity or poor nutritional states.

          —————————————-
          “Sarcopenia is a type of muscle loss that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors.

          The muscle loss is related to changes in muscle synthesis signaling pathways. It is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although both conditions may co-exist.

          Sarcopenia is considered a component of frailty syndrome. Sarcopenia can lead to reduced quality of life and disability.”
          ———————————————————————————————–

          Also, some people in their 90s can not stand up on their own or walk on their own, but others can.

          So, all things being relative, If a 98 year old is still able to walk and stand on his or her own without a walker or assistance, that indicates that they have excellent muscle mass……. for their age, of course.

          We can not yet reverse the aging process. Alas that is true. We also can not prevent all diseases or disorders even with good nutrition and exercise.

          There is evidence, however, that we can slow the process some. Still, we can not stop it completely, or reverse it, yet.

          Nevertheless, using strength training and nutrition as a way to attempt to slow the process is an inexpensive approach.

          If it works…..Yay!!!!!!!!

          If it doesn’t…Oh well you tried.

    • Not discounting skeletal muscle mass and longevity associations (and there is good biology as well to support), but there is a vast quantity of research showing quite conclusively, that high CRF (cardio respiratory fitness) is associated with reduced all cause mortality, ie, extended lifespan.

      Here is just one example:

      Association of Cardiorespiratory Fitness With Long-term Mortality
      Among Adults Undergoing Exercise Treadmill Testing

      https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2707428

      Look at figure 2. Can someone show me a lifestyle intervention in HUMANS that is PROVEN to extend lifespan as much?

      I run 4km/day, moderate heart rate zone (125 bpm), as well as do another 30-45 minutes of resistance exercise daily. Doing half marathons here and there, but don’t push the envelope. I am 56, very fit, lean, and muscular. Have to be 1% percentile amongst my peer group in fitness. I also am strict ketogenic, OMAD (one meal a day) for last 5 and 3 years, respectively. I am under the care of a FMD, take testosterone, DHEA, and handful of some key supplements (zinc, magnesium, Vitamin D, B vitamins, fish oil), as well as many anti-inflammatory supplements. I also donate blood every 8 weeks to dump iron. Started on 4mg/week Rapamycin 3 month ago.

      My first epigenetic blood test last year showed I was 4 yrs younger than chronological.

      I don’t which, if any, of these interventions will help extend healthspan/lifespan, and MOST IMPORTANTLY, I am not stressed about any of the things I am doing, they are all part of a VERY happy disposition. My dad passed with Parkinsons (also had prostate cancer), and mom has advanced AD. Do I have some wonky hardware genes? Can I explain (I call it rationalization) their fate based on lifestyle factors, most definitely, but I have no way of knowing. But I am not rolling the dice…pulling the epigenetic levers to try and change my trajectory.

    • Indeed, another paper showing strength training and reduced cancer and CVD.

      Modified aging of elite athletes revealed by analysis of epigenetic age
      markers

      https://s3-us-west-1.amazonaws.com/paperchase-aging/pdf/EXQLAZn4sSz2Cguic.pdf

      Although somewhat counterintuitive in that elite strength trained athletes have higher DNA age vs controls. In fact, in this paper, endurance athletes had even higher epigenetic age than controls! Wow, so all this endurance and resistance training is actually blunting my DNAage result? Clearly, a confounder since there’s no doubt that highly fit persons have longer healthspan/lifespan than sedentary controls.

      “Most studies have indicated longer life expectancy in top athletes compared to the general population and our finding of an accelerated epigenetic age of elite athletes seems to contradict these results. However, careful inspection of the molecular nature of TRIM59 and KLF14 might reveal their specific impact on aging processes in these athletes. TRIM59 has recently emerged as a powerful oncogene involved in induction of cellular senescence. Recent findings showing the role of KLF14 in chronic inflammatory responses and the pathogenesis of atherosclerosis may be particularly relevant to this finding [The modified methylation of TRIM59 and KLF14 in top athletes may be accounted for by the biological roles played by these genes. Their known anti‐tumour and anti‐inflammatory activities suggests that intense physical training has a complex influence on aging and potentially launches signalling networks that contribute to the observed lower risk of elite athletes to develop cardiovascular disease and cancer.”

      • HI intreresting…

        by the way FYI it is KL4 not KL14

        KLF4 – Wikipedia
        https://en.wikipedia.org/wiki/KLF4

        Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancer

          • Treat epigenetic aging measures carefully – the test you got is not necessarily the same as that used in the study you quote. One cannot read across from the methylation of certain important gene promoters to the epigenetic age reported from looking across 100s of sites, other than in a rough correlational sense; indeed aging clocks can easily not overlap with each other at all for the sites they look at.

            I get methylation age tests and telomere tests. But I also assess my health through biomarkers such as HRV, BP, etc., and standard blood panels, as well as just general subjective well being. I am sure you do the same.

            ps KLF14 and KLF4 are not the same thing, although they are both in the same family. KLF4 is the more famous gene, being one of the original 4 Yamanaka reprogramming factors for somatic cells to return to being pluripotent stem cells.

          • Thanks for pointing out the nuance and important distinction trying to cross associate DNA methylation testing. Some recent work by Horvath on specific epigenetic interventions and methylation age have not found a strong connection to “exercise”, but the studies are underpowered as it relates to high performance fitness individuals.

            And yes, I do extensive biomarker testing, as part of a holistic well being protocol. DNA methylation testing is more a scientific curiosity, albeit another plus in the anti-aging column. Since I started on Rapamycin, without having other easily measurable pro longevity proxies, DNA methylation is a simple global checkpoint.

  10. weight and aging: a paradox, maybe, but I strongly feel that this is just one more confirmation that aging is programmed.

  11. Off topic:
    Here is a new paper that looked at the different statins effect on neurodegenerative diseases and found 96 and 98% less Alzheimer’s and cognitive decline in users of pitavastatin. It is interesting that the different statins behaved so much differently on the different neurodegenerative diseases.

    I don’t need a statin but will start taking pitavastatin and rotate perhaps monthly with pravastatin because pitavastatin shows possible increased ALS risk and pravastatin has the lowest ALS risk but not as good for cognitive decline or Alzheimer’s.

    https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12108

  12. Greetings,
    search “Seventh-Day Adventists BMI” large studies one for men one for women that dispenses with the idea that increasing BMI decreases mortality

      • Yes, there might be fewer confounding factors in this study. In the population as a whole skinny people tend to have health problems or be smokers, but vegetarians are likely to be both skinny and healthy (provided they get enough B12), so the study results are not unfairly biased against being skinny.

        Here is my take (speculation) on the wider issue… if you are young and skinny mother nature assumes times are hard and slows down your aging so that you have a better chance to survive to a better time to have babies. On the other hand, if you are old (beyond your reproductive years) and skinny, mother nature still assumes times are hard, but worries that you might be competing with your younger relatives for scarce resources, so ages you faster to get you out of the way. By “mother nature” I mean evolutionary pressures, of course.

  13. I’m still not confident CR will have a lower effect in humans than in other animals. Even long lived dogs experienced substantial life extension under very moderate CR. There were many issues with the primate studies.

    Also higher level of CR some articles have suggested can lead to significant bone loss in longer lived humans. So if that is true supplements or drugs to counteract the bone loss would be required to test whether it would affect lifespan and to what degree.

    The thing is even in short lived animals it is said CR requires adequate micronutrient intake, and CR was shown to work even at 65% restriction, iirc. A level of restriction where the animal would not have enough energy to scavenge for food, and if the environment was so harshly affected the little food found would be unlikely to contain high enough micronutrient density. It is said that without adequate micronutrient intake CR does not provide life extension, iirc.

    That is CR works even outside the parameters of what could occur during a normal famine. Also I’ve heard it is said CR has to be introduced gradually if it is in adulthood, sudden CR is said to not provide any life extension, iirc. If that is true, can we truly expect famines to occur gradually in nature, or more sudden?

    The fact CR works to extremes of 50%-65% restriction yet requires dense micronutrient food, something unlikely to occur in nature during famines. The fact it seems it needs gradual not sudden entry into CR, also something I doubt to occur in natural famines. All that leads me to believe CR life extension might be a quirk of the metabolic systems, and unlikely to be significantly diluted regardless of species lifespan.

    I expect a proper CR test on primates to exhibit significant life extension. Of course higher levels of CR might require some form of drug or supplement to counter increased bone loss, and any other issue that may emerge. I also expect a grimage test of CR society members who’ve been on moderate to high CR to hint at this being the case. Although the high CR might be inaccurate, if it shows significantly lower risk of death, due to increased bone loss unless that was compensated for.

    • Actualy famines might be gradual as most famines are caused by droughts. As the drought kills off plants and animals one by one there will plenty of food to eat for awhile..So this suggests that if drought precedes famine there should be a much better form of life extension caused by water restriction. And indeed I ran an experiment in the late 90’s in my closet with 10 rats 2 WR rats 8 controls…and I got one of the WR rats to set the world record for its type for extension of maximum lifespan (Sprague Dawley female) when I looked through all the CR studies using them and some studies had 1000+ rats. Here is a youtube link to a little video I shot>>>>you will notice that the WR rat goes wild for a piece of water soaked celery>>> https://youtu.be/skLVAQgWx60

      • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

        Jeff,
        It is not strange to me that water restriction increases longevity. Please go to the left of my Fig. 2 in Barja Exper. Gerontol. 2019 Towards a Unified Theory of Aging.
        Many afferent stresses (CR, PR’ MetR or WR) on the left part of the figure (A) will stimula the Nuclear Aging Program (B) to decrease the aging rate (C).
        CR and WR are hormetic responses to steess?

        • HI there

          My thoughts on this is that at least CR and WR are
          evolved repsonses to famine and drought
          this might be a rare case of true group selection
          because when two different groups are starving they stop reproducing so there will be no gene transfer between the groups during the selection event.
          the group with the best famine defenses of aging reversal and reproduction postponement survives / the group that does not have such good famine defense goes extinct. The fact that CR shuts down reproduction suggests it is an evolved adaptation- it hasnt been studied but I woujld expect WR will also shut down reproduction. Other forms of stress probably don’t shut down reproduction…but who knows?

          • JEFF, you said: “..here will be no gene transfer between the groups during the selection event”.

            But, what about horizontal gene transfer? Je je !!

      • If there are plenty of animals around to eat, at least to begin with, then we should expect a low carb diet, aka keto, to be beneficial against aging, as this is also a signal of famine. Looking into this further, many of the cellular ‘rejuvenation’ pathways seem to involve a switch to burning fats rather than carbs. One of the most noticeable metabolic things about old people as compared to the young, is that they have impaired fat burning in their mitochondria.

        • Good Point..
          So the question is in the begining of a famine are there more dead plants or dead animals to eat? And which will provide more water to get through the famine..Probably the dead animals..but dead fruits and vegetabes might also provide water.

          • Mark:

            There could be a evolutionary genetic variations in those tribesman that allows them to survive on less water.

            Likely somewhere along the evolutionary track, the tribesmen who were able to survive, on less water, lived to breed, whereas the others, who could not survive on less water, died out or were too weak to breed.

          • Heather,

            Yes, similar to how agricultural cultures developed alcohol, and from there it became a selective advantage to be able to metabolise alcohol efficiently, as an alternative to drinking often contaminated water.

          • Caloric restriction dramtically alters hormones to the point where ti shuts down female fertility. Melatonn the anti aging hromone goes way up during fasting adn caloric restriction. They can use mealton at 76 mg per night for birth control in women. Not having children in a famine surely makes it more likely a female will survive than is she had a child to feed and care for when there is no food. Hormones might be altered to rejuvenate starving individuals so that if the famine was a long one, there wold at least be one fertile mating pair to reconstitute the group when the famine ends. Long live the king! There is a study of some navy men who were fasted with no calories for 5 straight days. They had dramatic changes in many hormones some up some down. DHEA + 100% , LH and FSH down 67% Testosterone down 50%

          • HI there
            Just like testostewrone in men , I think estrogen would go down in females during fasting. Melatonin was not measured in the fasting men. But in other animals fasting causes melatonin to increase quite a bit. If melatonin is the famine protection hormone it would make sense that during fasting it goes up and suppresses testosterone in men and probabaly estrogen and progesterone in women. Both hormone changes are designed to suppress reproduction during a famine. Another intersting point is that the DHEA levels doubled while testosterone was halved >> the exact same move just in reverse. My thinking – DHEA is men’s non sexual form of testosterone designed to maintain muscle mass without encouraging reproduction. Melatonin is apprently evoluton’s birth control (and anti aging) hormone in both men and women at high doses.

    • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

      I have done many (all of them published) experiments of CR (and PR and MetR. In all cases doing it WITHOUT any micronutrient supplementation it allways lowers mitROSp and oxudative damage to mitDNA
      Thats a mechanism by which these CRs increase longevity and the decrease in mitROSp has nothing to do with micronutrients.

      • “I have done many (all of them published) experiments of CR (and PR and MetR. In all cases doing it WITHOUT any micronutrient supplementation it allways lowers mitROSp and oxudative damage to mitDNA”

        Interesting, because I thought the Roy Walford book and the CR society both were in agreement that adequate micronutrient intake is necessary for CR to extend life.

        If you used food pellets and assuming they came fortified perhaps no additional supplementation was necessary.

        But there are cases of even 68% CR extending life, iirc. Surely lifelong 68% CR would result in micronutrient deficiencies and pathologies if not supplemented.

        Again perhaps famines can be gradual. But unless micronutrient needs are met, I think there could be issues. Perhaps CR did evolve to deal with famines, but even if that’s the case it works far beyond what is possible in a natural environment(60+% restriction while meeting micronutrient needs)

    • Darian:

      I am a vegetarian. I do eat eggs and cheese but no flesh foods. I also take supplements.

      I self experimented with CR and quite honestly I experienced absolutely no beneficial effects from CR.

      My blood parameters which were already in the healthy range. Remained the same.

      The one effect I did experience was negative. It was weight gain. When I returned to my meatless, Mediterranean-diet style of eating, I lost the weight.

      My guess is the weight gain may have been because my body went into starvation mode and held onto fat instead of releasing it.

      Every human has a unique biochemistry .

      Maybe it is what a person eats, not how much they eat.

      • Could be issues with genetics, but from what I gather many CR society members have been tested and shown extensive benefits to blood parameters. Not only that but their blood pressure became those of a ten year old.

        I’m a believer in programmed aging. But I also think that the longer lived a species is the closer it is to simply having negligible senescence, the fewer mutations or changes needed to allow it to reach such.

        As João Pedro de Magalhães pointed, iirc, in his website or one of his articles, there are closely related species were one ages and one does not. I can bet you a genome analysis will show small genetic differences if they are closely related.

        Aubrey’s view seems to imply that the longer lived a species is the more the easy gains have been exhausted, and extensive engineering needed for any further gains. But even in primates, primates with half or less the lifespan of humans are about 99~% similar to us, and most of the small difference is likely unrelated to lifespan.

        My view is that even mice neurons can live twice as long as mice, and researchers have commented potentially indefinitely in the right host. Nature found a way to make cells ageless, even non-dividing cells with some of the highest metabolic rates. This occurred as early as the evolution of rodents, given neurons needed to last a lifespan at high metabolic rate, it seems nature made them able to last indefinitely. But such solutions couldn’t be shared with the rest of the body, lest the animal become an impediment to future generations.

        The body has the ability to last indefinitely, at least at the cellular level it does. But this ability has to be hamstrung for the benefit of the next generation.

        Rather than CR(which as I commented earlier works outside parameters possible in nature, tested at up to 68% CR. Protein restriction experiments with 4% protein are said to imply even 80% might extend maximum animal life, but probably with additional death rate in the population) having lower effects in humans, I suspect the effects could even be greater, if issues like bone loss or other problems that emerge can be dealt with.

        Blood factors, nutraceuticals, CR, future antiaging drug combinations, in a species with a century+ maximum lifespan, one that should be closer to negligible senescence, might have benefits that exceed expectations in my opinion.

        Now as to why don’t single mutations confer as great lifespan the longer lived animals are? Well the aging program is tighter in longer lived animals, as said even mice have the key to ageless biologically immortal cells. Similar to the incest avoidance genes, one or two mutations will not knock it out. If incest avoidance was knocked out, it could poison the gene pool with significant damage. Similar happens to aging, normally knocking it out has grave consequences, so it has significant multigene mechanisms to ensure it is not that easy to knock out.

        • Darian:

          You said: “Blood factors, nutraceuticals, CR, future antiaging drug combinations, in a species with a century+ maximum lifespan, one that should be closer to negligible senescence, might have benefits that exceed expectations in my opinion.”

          Agreed, Darian.

        • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

          For PR in humans see the excelent work of
          Luigi Fontana. Excellent results.
          He emailed me many years ago and said : “Gustavo, I got in humans exactly the same results you are obtaining in Methionine Restricted (almost the same as PR I think) rats”.
          He wanted me to ask for money to the UE but everything went wrong because I had a too strong personal problem and could not meet with Luigi at Madrid as we had planned together before….Too bad, I tried later but I think Luigi lost his confidence on me….

          Concerning Aubrey do not listen to him if you do not want to be cheated. I was cheated by him gor 15 years starting st 2000 when he came to see me the 1st time at Madrid. I helped him s lot. He dined st my house twice with my 1st wife and son.. Last time I presented his dirty nonsense 2nd book (the 1st one at Landes wss wonderful) at UCM . I filled the room emailing 2000 UCM Professors when he stsrted to lie concerning CR . It is recorded with cameras. You can still watch it on internet.
          He is a fake. Most intelligent guy but sn absolute fake. He only wants your money to rob you. Must have big account at some Fiscal Parsdise. He only loves himself, to drink as s drunkard anf fuck as many wonen as he can.
          Shit of man Aubrey is. He captures minds of the too many silly american sheeps.
          Now we have the UE ‘ S Aubrey copy. A Spanish Youtuber. He got 10 million visits saying exactly tge same stuff as Aubrey. Right stuff “money to aging not to the cirrupted medical doctors and Big Pharma ” but he tskes it from you for his own pocket. You are warned twice by Gustavo. An honest man. Now it is your choice to be cheated or not…
          I stop. Speak against this smart thief no more….He cheated and abused my friendship 15 years but…not a single more minute , NO!

      • @Heather

        A daily 18:6 intermittent fasting became part of my lifestyle and I’m living on a mostly Paleo-style diet for over 25 years. My blood values only improve significantly if I do a 4 days water-only fast. I do that every 3 months.

        In my case, intermittent fasting probably doesn’t equal CR. I don’t count calories but protein intake due to my high level of rigorous exercise. It is at least 1.2 g/kg.

        In regards to life extension, I’m wondering whether the benefits come only from reduced calorie intake or the level of physical activity and the number of calories burned?

  14. Here is a hypothesis to explain why we might not expect life extension in humans given an alternate day feeding CR regime. The idea centers on a well known systems effect called incommensurate scaling.
    I have heard that rats can only go two or three days without food before they die. On the other hand I have heard that humans can safely do 22 day fasts with no ill effects. That suggests that the bodily stress of an alternate day feeding regime for rats is much more extreme than the stress of alternate day feeding for humans. The biological mechanisms which slow ageing under caloric should be conserved between species, but there is no reason to expect that those mechanisms activate at times like “after 1 day” with out food between species.
    A data point which may suggest this possibility is the work of Dr. Longo which tries to improve health markers with a fast mimicing diet. My understanding is that his research indicates that fasting needs to continue for at least 3 days for health marker benefits to be observed after breaking the fast. One day is not enough.
    The link to the idea of incommensurate scaling is that systems as they are scaled up or down behave very differently despite the physical laws governing them remaining the same. For example, in ship design one would not expect a 1/50 scale model of a full size ship to behave the same in water as the full size ship even though sizes and materials were scaled exactly. To get model data that applies to a full size ship, one would scale the model exactly and also maintain invariant the dimensionless constants involved in the pysical effects being investigated. This would usually involve a selection of different materials to build the model from and a liquid different from water to float it in. Similarly rats and humans are related systems governed by the same biochemical laws of aging but to use rat data to predict effects in humans we need to scale with just a little more sophisication.

    • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

      Marco.
      1-Your reasoning is OK. However’ I think your conclusion (on top) is wrong.
      To understand why please se left side (A) of Fig. 2 in Barja (2019) Towards a Unified Theory of Aging Exper. Gerontology

      Even in humans (which do resist much longer than rars without eating anything due precisely,’ as you correctly say, to scaling see Schmidt Nielsen: “Sacaling Why is animal size so important? Cambridge UP “past century book, soft cover) CR arrow will impact on the Nuclear Aging Program (B)gene expression modifying hundreds of efector proteins (C) coordinately to slow down aging.(Section 4 explains…)

      2. Evolution is much more than just natural selection. Please read Chapter 5 (of Longevity and Evolution Barja-G’, Nova New York, 2010) containing a Scheme with around 10 additional known mechanisms of biological evolution on sddition to natursl selection
      Every body uses reasonings based on the believe that Neo Darwinian Synthesis from 1930’s is right. But it is absolutely outdated (already has 90 years of delay without incorporation of any of the new discoveries of molecular genetics and others….I call it “The Old Lady”. Dogmatism of Neodarwinian “priests” at US AND UK is responsible for this aSientific full wrong situation in Evolutionary Biology.

      The book is expensive 180 US$ NOVA CHEATED ME. I ASKED THEM PUT THE BOOK AT 20 US $!
      But if you write me to gbarja@bio.ucm.es I will send you a pdf containing same as it is.

  15. Will add have come up with a hypothesis on why CR might have had less benefits on primates.

    Most animals synthesize vitamin c. Primates have a defect that they dont. Heard, but need to confirm, that animals that produce vitamin c live 8-12x their age of maturity also heard animals that dont only live 2-3x age of maturity. Also heard when an animal is stressed vitamin c production significantly increases. I suspect CR being a constant strong stressor might be drastically increasing vitamin c production, though need to check literature to see if anyone has checked.

    Very high vitamin c might be the missing ingredient that yielded subpar cr results in primates

    • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

      I demonstrated in my 1st longlife study in frogs that stressed lived 100% longer in MEAN lifespan and 0% longer In Maximim longevity and they Induced Ascorbate (yes), GSH, SOD (these by 100%) and GSH-REDUCTASE (by 1,000%) in 4 organs and this is only what we measured…of course a battery of hundreds of protective substances of different kinds were induced too. That had been discovered in bacteria earlier by Gabriela Storz? (Science paper? Ig my memory does is traitor to me..
      We published around 6 papers on this 3 year long duplicated study in 220 adult frogs.
      We discovered with that lifelong aging experiment what one decade afterwards everybody called “HORMESIS” but nobody recognized us nor gave any attention to this most interesting aging experiment that started in 1988 my research on ROS and aging because: 1) We did not put a name (hormesis) to what we observed and 2) We are Spanish all the signers of these papers in FRBM, J. Neurosci. Research and Mech. Ageing Development if I remember well.

      • As Josh has pointed out repeatedly, no single substance will significantly increase max lifespan. In that case, we would have heard about it a long time ago.

        But take a person from the CR society and give that person daily IV infusions of L-ascorbic acid and we shall see…….

        • “As Josh has pointed out repeatedly, no single substance will significantly increase max lifespan. In that case, we would have heard about it a long time ago.”

          Vitamin c wasnt discovered till like a century ago, iirc, and megadose vit c only became widely available like after the second half of last century.

          If anyones going to live significantly longer we will have to wait 50+ years to find out.

          CR + high dose Vit C, which some models suggest should be taken in multiple doses throughout the day, could not be practiced until recent history. It will be awhile before we can tell if it has significant effect on lifespan

          • Linus Pauling must have been one of the worlds earliest adopters of a calorie restricted diet combined with high doses of vitamin C.

            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238903/

            I don’t think we have any reason to doubt that Linus did not comply with a calorie restricted diet, since switching back to ad libitum feeding would inevitably have caused worsening of his kidney disease.

            93 years of age isn’t bad for a man who had suffered from a kidney disease, since he was 40, but still pretty far away from the longevity benefits achieved in rodents.

          • >93 years of age isn’t bad for a man who had suffered from a kidney disease, since he was 40, but still pretty far away from the longevity benefits achieved in rodents.

            Single subject died from cancer. Yet was quite lucid if I’m not mistaken. Also if he practiced CR it probably was moderate, as some people with high CR have suffered severe bone loss to the point of disability, iirc.

            Not only that but If I remember my research correctly Both of linus parents were quite short lived, so pretty impressive he got to live substantially longer. Also lets not forget Linus didn’t start megadose vitamin C at birth, he probably did late in his life. A late life intervention is not as effective as a full life intervention.

            Also the dynamic flow model of vitamin C suggests taking it multiple times throughout the day every few hours. If pauling only had one or two big doses, most of that was likely excreted, and he likely had suboptimal levels throughout a lot of the day.

            What is now been suggested by some is vitamin c every 5-6 hours, and even right before bed time, and upon waking. To keep a constant level of vitamin C at a high level as if we did not have the mutation.

            Sadly the mouse experiment only had two vitamin C levels, enough to prevent death, and high enough to cause blood levels akin to an animal able to produce vitamin c. We do not have results from intermediate levels.

          • You may very well be right Darian, but how are we ever going to find out?

            Who wants to starve themselves from the time of maturation and the rest of their lives with all the known side effect like bone loss, loss of libido, fatigue, constant hunger etc.

            Perhaps a FMD approach is more realistic, but still…..

          • No single substance?
            Rapamycine Harrison et al. Science 2009!
            Very small effect (much than that of CR) but triplicated done in parallel at 3 labs under NIH ITP? Program.
            See also Martinez Cisuelo et al. 2016 100% back to young levels in mice! (Done by us, so…well done!

        • Ole:

          I agree with josh that no single substance will significantly slow aging or increase life span.

          Likely because each human/animal has a unique biochemistry.

          This is the same reason why prescription drugs work for some humans/animals and fail for others.

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Josh,
            What about rapamycin (Harrison et al. Science 2009. Three independent labs. In parallel and good longevity of control mice.
            Very small effect but still significant.
            And see impressive results to me: “Matinez Cisuelo et al. Exper. Gerontol. 2016. 100% back from old to young control levels for mitROSp etc. mtDNA fragments included!
            And we used exactly the same dose and form (encapsulated rapamycin imported from USA with the generous help to us of Richard Miller.

          • Well Bill Sardi is kind of controversial but his argument suggests there is promise assuming the information he brings is accurate.

            1. Mice were engineered to have a similar mutation as humans that causes a lack of production of vitamin c, low vitamin c supplementation resulted in significantly lower lifespan than normal mice without mutation. Very high dose oral resulted in similar blood vitamin c as normal mice and they lived just as long 3X as long as mice with similar vit c mutation as humans on low vit c dose(a dose lower than many humans but still resulting in blood levels similar to those seen in millions of humans).

            2. Animals with the ability to produce vit c live 8-12x as long as their time of maturation, don’t know if true. While multiple animals with the vit c defect mutation live only 2-3x as long as time of maturation. That to me suggests that the evolved compensation mechanisms for inability to produce vit c, cannot fully compensate and do not restore longevity to that of most animals. Again I will need to check if these claims are true.

            Given that stressed animals are said to produce even more vitamin c, I think vitamin c sounds like a very promising compound.

  16. Some interesting info on Vit C, very useful…

    Why Animals Don’t Get Heart Attacks but People Do, Fourth Revised Edition (Englisch) Taschenbuch – 1. August 2003
    von Matthias Rath (Author)

    Ten Years That Changed Medicine Forever (Cellular Health Series) (Englisch) Taschenbuch – 1. Januar 2002
    von Matthias Rath (Author)
    on Amazon…

  17. My N=1 experience
    Was born underweight and remained underweight all my life despite a diet of 3 donuts plus multiple cookies and other sweets per day.
    At 62 diagnosed with prostate cancer and have gotten rid of sugar and focused on health since but as Josh indicated, never had a need or desire to do CR

  18. True paradox or inconsistency with antagonistic pleiotropy theory and “U” shape correlation of IGF-1 plasma levels and life span in humans?

    Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Renehan AG, Zwahlen M, Egger M, Dekkers OM. Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. J Clin Endocrinol Metab. 2011 Sep;96(9):2912-20. doi: 10.1210/jc.2011-1377. Epub 2011 Jul 27. PMID: 21795450.

  19. programmed aging hypothesis

    The epigenetic aging graph of humans is tracking DNA modifications of certain group of genes from birth till death, which encompasses growth, maturity and aging.
    This graph does not track a proposed hypothetical group of genes(Group A) from birth till onset of puberty/maturity, whose DNA modification might be changing/activated from birth till onset of puberty at the growth rate of a particular species and reversal/deactivation on onset of puberty.
    This graph also does not track a proposed hypothetical group of genes(Group B) from onset of puberty till death whose DNA modification might be changing/activated from onset of puberty at the aging rate of a particular species.
    The hypothesis is that a certain Group A genes are activated at the end of morphogenesis and under their control body growth takes place at the species rate of growth and upon reaching a growth milestone (puberty) Group B genes are activated and control of Group A genes and the rate of growth/maturity/aging is passed on to them.
    Thus on puberty Group B genes are the master regulators of maturity/aging in the body and exercise control over all the genes being tracked in the epigenetic age graph, they control the aging rate/clock of the species.
    The epigenetic age graph has three distinct parts, the rapid rate of change(Group A), the gradual change in rate(Control is passed from A to B), which is the knee and constant rate of change which is aging(Group B).
    The hypothesis also is that DNA modification at a particular age corresponds to the level of expression of Group B genes.
    When young blood plasma is injected in an aged organism, the level of the Group B gene product is diluted, which changes the DNA modification towards a younger profile.

    • It can also be hypothesised that the Group A genes responsible for growth, are not hidden and they are being tracked in the epigenetic age graph and once control passes over to group B genes, the DNA of the Group A genes are modified at the aging rate rather than at the growth rate.
      In this case introduction of the young blood plasma in an aging body will dilute the Group B factors and in turn decrease the inhibition of the Group A factors, which can lead to growth signalling.

      • You can see what happens when the Transcription factors that turn off the non-Group A genes during Group A development and the non-Group B genes in Group B from of develpomnet in the rpaid aging diseases of progeria (kicks in at birth) and (kicks in at puberty) Werner’s Syndrome…
        Check out the updates in this blog post>>
        https://jefftbowles.com/aging-is-programmed/

        • Jeff, the whole epigenetic aging theory not focussing on the onset of puberty, is the single biggest missed opportunity for aging research according to me.
          Tracking epigenetics from birth till death for a particular set of genes and not focussing on the major turning point/onset of aging on the graph itself is the real tragedy

          • I’ve looked into this in some detail, and we now know that errant methylation can downregulate important genes like GDF11, Oxytocin receptors and other things like glycine synthesis. All crippling over time. The most recent work by Horvath on his pan-species clock seems to be suggesting (thanks to Josh for his great post on this) that it is methylation not demethylation in general that is ‘driving’ this clock (and potentially aging). It appears methyl transferases are relative constant with aging, but de novo methylation is upregulated. I’m agnostic on whether this is programmed or just accidental or a reaction to something else that is causing aging. But it does seem to be a quick win in terms of trying it out and actually discovering if this can reverse aging in vivo the same way it does in single cells.

          • From the paper

            Universal DNA methylation age across mammalian tissues

            ‘These results reinforce the association between development and aging. This may appear counterintuitive but finds support from the fact that mice with compromised development following ablation of growth hormone receptors (GHRKO), exhibit significant slowing down of their aging process 8. We demonstrated that the universal epigenetic clocks are slowed in cortex, liver, and kidneys from GHRKO mice ‘

            Compromised development can lead to the sexual maturity milestone not being reached in time, which possibly delays the start of the aging process.

          • It appears that the de novo methylase Dmnt3a is critical. Loss in hematopoietic stem cells leads to their immortalisation, but at the cost of differentiation and the formation of new red blood cells. So we may be seeing a conflict between proliferation and differentiation. Either way too far in either direction and we get aging.

  20. If we infuse young blood plasma in an aged individual and expect it to reverse age because of the abundance of growth factors in it, but that same individual had far higher levels of growth factors in his blood during youth and that did not stop them from getting older. That probably is the reason, the positive effect of infusion of young blood plasma is because of the dilution effect of certain aging factors which have not been accounted for.

  21. The epigenetic aging graph shows that DNA modification curve rapidly rises after birth and at a certain point the curve starts to bend. At that bend, which probably is the onset of puberty, certain factors, I will call them Aging factors for now, start influencing the rate of modification, which starts moderating and eventually transforms in to a steady rate of change.
    Is it possible, if these aging factors were to be completely inhibited and the modification curve brought to the same stage at which the curve starts to bend, would growth resume again.
    Is it possible that the partial reprogramming factors discovered recently, are doing the same thing i.e inhibiting the aging factors to a point where they are completely inhibited and growth resumes.

    • HI there Kunal

      Have you seen the Conboy experiment where they rejuvenated old mice by removing half their blodd plasma and replacing it with saline and albumin??

      • Yes, I have seen it and that is why I feel, the rejuvenation is taking place due to the dilution of some unidentified aging factors. However it is not so simplistic, because the rejuvenation by young blood plasma due to presence of growth factors may be much stronger.

        • Yeah there are two things going on the Comboys have identified the increaser of bad stuff in the blood. And Harold Katcher has proved that there are good things missing from the blood… Ying and Yang

          So a good question to ask is do the good things missing form the blood shut down the production of the bad things? Or do the bad things in the blood shut down the good things in the blood…Is one system dominant? If so , Which system is dominant ..If I had to guess I woudl guess that the good things in the blood system is dominant.

          • I would say the good things are dominant till onset of puberty and thereon the bad things. The bad things are good during youth, cause the growth arrest has to take place, runaway growth cannot continue indefinitely.

          • IIRC, Hatcher gave an initial treatment of good stuff to rodents, and it shortly started aging fast again, but I think he commented after a subsequent treatment not only was rejuvenation achieved again but the rate of aging changes seemed to be slowed to be similar to what it is for younger animals.

      • I also think that the partial reprogramming method and the young blood plasma experiment are linked in some way, because I feel,the aging process is far too robust to have alternate pathways.
        My theory is that, some of the elite transcription factors(homeobox, heatshock) which are in charge of the development process after birth and are in control of a gene network which acts systemwide are inhibited at puberty. Due to this the hierarchy of the gene network changes and the leadership is passed to some other transcription factors such as NfKb, Myc etc. A gene network changes personality when its leadership changes, some downstream genes are transcribed but their gene product is inhibited and with so much redundancy built in, the system works.
        I feel this new gene network is in charge of the aging process and the partial reprogramming method changes leadership of this gene network again and we see age reversal.

      • I don’t think the removal of bad actors or the addition of good ones is a different approach; they appear to be doing the same thing.

        There was a recent paper where they just gave mice infusions of pristine albumin and increased their lifespan.

        All biomolecules (with the exception of DNA) are created, damaged during their normal operation, and broken down ready for replacement. With age we just have more of these biomolecules in a damaged state.

        You could remove them at a greater rate, or simply add more fresh molecules and let natural turnover cause the percent of good molecules to rise (as with the albumin experiment).

        You could also argue that all the interventions that have extended lifespan to date are in some way increasing this biomolecule turnover process – CR, autophagy inducers, targeted antioxidants, telomere enhancers, etc.

        • To your thinking Mark re “young/new/diluted/refreshed” aka “pristine” proteins milieu, recent paper by Tony Wyss-Coray, using blood proteonomics:

          Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681068/pdf/ACEL-19-e13256.pdf

          “We previously identified 529 proteins that had been reported by multiple different
          studies to change their expression level with age in human plasma. By performing
          machine-learning modelling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries”

          A couple of notables for my takeaway (2 of my core interventions. I also donate blood every 8 weeks, and although a positive signal, a lesser impact):

          “Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. The predicted age difference between aerobic exercise-trained and sedentary individuals was 5.43 years”

          “Interestingly, our “innate immune system” Reactome clock was almost as predictive as our “immune system” clock, despite containing 438 fewer SOMAmers. This would suggest that the innate immune system is especially pertinent to human aging.
          With these data in mind, it is quite intriguing that one of the most effective anti-aging drugs capable of extending life span and health span in mice is Rapamycin which is clinically used as an immunosuppressant. Thus, clinical therapies that correct immune dysfunction may be particularly capable of improving human health span”

          Thoughts on this clock vs DNA methylation??

          • Hard to say with confidence what clocks are better.

            The innate immune system just attacks stuff in an unhelpful way as you get older, so suppressing that is generally good (within reason). But not really causal. But rapamycin may also be upregulating autophagy, which is increasing turnover of damaged molecules. It also alters signalling, possibly suppressing the movement of the methylation profile of cells towards a more aged/cancerous prone state.

            Defeating aging will involve allowing sufficient growth for tissue replacement, whilst simultaneously preventing the cells we have given such licence from epigenetically drifting into an unhelpful state (and being selected by growth signalling into becoming cancer prone). Hopefully we can find the right balance of signals to get the balance just right and remain perpetually youthful.

          • We need an aging clock for all the transcription factors, I feel that is when the mystery of aging will unravel. I think aging is caused by a gene network same as a metabolic network, a renal network, a neural network,and this aging network is assembled at the onset of puberty.

        • ‘You could remove them at a greater rate, or simply add more fresh molecules and let natural turnover cause the percent of good molecules to rise (as with the albumin experiment).’
          But the natural turnover will also cause the bad molecules to rise and the bad molecules have been in command since aging commences after maturity.
          This could only mean the bad molecules are rising at the aging rate and when dilution takes place, the good ones raise their levels at a higher rate in spite of being subordinates to the bad ones.

          • This could only mean the bad molecules are rising at the aging rate and when dilution takes place, the good ones raise their levels at a higher rate in spite of being subordinates to the bad ones, because the concentration of the in command bad molecules has dipped.

          • Dilution reduces the concentration of bad molecules, adding good molecules decreases the ratio of bad:good molecules. In either case there is a benefit. Of course there is more to aging than this, but a successful treatment for aging must keep this ratio in a youthful balance.

          • ‘Dilution reduces the concentration of bad molecules’
            i agree, but why would good molecules increase at a higher rate than bad molecules on dilution by albumin, unless the rate of increase is different for both. And if the rate of increase is different, what explains it.

          • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

            Hello Kunal.
            I have been reading many of your comments on this blog and many of them (concerning heterochronic parabiosys and/or blood exchange) are interesting to me, and I am copying and pasting all (from you or others interesting ones in this blog) on a single Word file. I will use it to update my written 2nd part “review” like (really theoretical proposal 2nd part paper written on 2015 and censored at many USA nice IF aging journals at USA), only because, contrarily to Ch. Darwinn, the “pig” Neo Darws Bosses in Evo- power at Anglo imposing earth their competitive hate theory (mainstream full wrong Neo Darw Modern synthesis from the 1930’s.. same as Called by GB. “The Old Lady” that refused to incorporate all the new genome derived most of them new mechanisms of evolution (TEs, HGT, Hybridization, gene and full genome duplications, symbiogenesis, etc.).

            Most of these mechanisms, additional to natural selection (COMPETITION-ONLY-BASED hypothesis of ONLY!! plus randomness evo-mechanism , favored by miope anglo-ideology prejudices; if your theory is “Randomness” ot is the same as saying “I do not have the smallest idea of what are the causes of the evolution facts!!) are, deep in essence, different forms of COLABORATION.

            I EXPLAIN ALL THIS at my book ” Longevity and Evolution, Chapter 5 ( Evolutionary Mechanisms in general and a strong critic destroying full wrong for SURE! absurd nonsense non updated ridiculously called today “Modern Synthesis”. (Chapter 6 deals with Evolution of Aging a much less important subject. Non-PA absurd nonsense 3 mainstream ¿?¿?¿ theories” of evolution of aging (no theories only full wrong hypotheses) denying a role fir natural selection!!! (Neo Darws in this reach paroxysm denying natural selection!!! They are agaibst it and us the “revokutionary 7 mafnificient worldwide are fir it! (Schizofrenic Neidarw minds but tgey have no other iotion to be able to use tgeir prejuduce to denye tge evident (both lab. And field studies shiw mainstream 3 tgeories are wrong absokutely 100% wrong Medawar’s and stupid Tom Kirkwood (he did not spoke about its iqn tgeory even on his first 1970’s Nature paper proposing it!!! Incredible. Please read that bullshit. He dedicates roughly 20% if his 1st Nature DS theory proposal paper (1970’s) to speak about DS, and most of the paper (more than 50%) to “leak the ass” -showing his absolute lack of Ethics (he is English culturally after alll…Drake tge pirate robbing the gokd was Minister of Queen Elisaberth tge 1st the virging queen who Felipe 2nd teyed to kill with the Armada Invencible but Mother Nature bug storm was on the English side so Spain lost that battle to not raise head ever again…) to the big Evo-guys of the time including Robin, who he thougth ,miserously, that they could promote him to what english culture? calls “sucess” (to win no matter what one has to do to win. Theor only moral is just money money money…Cabaret-like what un-ethical ideology…

            In summary Ken. I will update my 6 years already maliciosly delayed ms. with many important things published in the last 1,5 years or so, but in your case (perhaps I add some sentences or a paragraph? I do not know now but your reasinings are appealing and seem weel based to me. But…there are no citations on this blog.
            I always like to cite anyone (of course including even English people! Even anticolaboration Brexit English People) who says something that I could mention in my next ms.

            I do not want to appropriate any idea. I want to cite you if I include something from you on my next fully tgeoretical paper (same style ss Barja Exper. Gerontol. 2019 but mainly on extracellilar coordination of programmed of course AGING.

            SO, MY EMAIL ADRESS IS: gbarja@bio.ucm.es
            Could you please write to me to that address? You could send me yor papers or indicate please (I amm too time pressed) in what of your papers pages/paragrafs do you say the interestubh ideas about co boys and the dilution or not of young/old factors in parabiosys experiments or analogous ones?

            Thank you. Of course I can send you for free to your email my Longevity & Aging Nova NY 2010 book and sime key recent papers from 2019-2021.

          • @Gustavo Barja

            sorry for replying so late to your comment on appreciating my hypothesis on aging. I am no scientist, but a layman following the anti aging field for the last 10 years.
            Here is my take again.
            Multi cellular organisms are governed by gene networks right from embryogenesis till death. I say death because i feel aging is also controlled by a gene network, which comes in to being at puberty. I also feel that morphogenesis does not end at birth, it continues till the end of the pubertal phase. Morphogenetic pace not phase varies across species with varying intervals of growth pace.
            A gene network has function not individual genes, an individual gene can be part of many gene networks in the same organisms(for e.g serotonin). it is the gene network that morphs at various tissue growth milestones or organ boundary milestone and acquires different forms and function at those milestones. It does this by inhibiting some of its member genes and/or adding new genes to its network.
            Aging is one such network which is activated at the morphogenetic milestone of puberty. The activation of this network, results in a program which controls
            1 :the repair functions of the cell at the individual level, such as autophagy,dna repair, protein digestion, mitochondria repair etc.
            2: the recruitment of the immune system in response to cell damage and
            3: the renewal provided by resident stem cells.
            The gene network which was in control of the above functions during the growth and the final morphogenetic turn at puberty, is modified by activation of some unidentified genes, which in turn inhibit some genes, which played a key role in the previous iteration of the network. Due to this, the whole network modifies itself to implement the aging program.
            And therefore, various genes which were found to be beneficial in the previous avatar of the network turn deleterious in the new network, leading to the so called phenomenon ‘antagonistic pleiotropy’.
            Various supplements which have proven to be beneficial are just perturbing small parts of the overall network. However, with the epigenetic clock showing lock step epigenetic modification across various organs and tissues in the organism, the presence of signalling factors in the communication medium can be hypothesized. Hence plasma exchange/dilution are probably effective because the perturb the whole network.
            Also according to me partial reprogramming is an unnatural way of changing the dynamics of the aging gene network by introducing elite transcription factors, which supersede the key transcription factors controlling the aging network.
            I would really like to know your thoughts/critic on the above.

          • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

            Kunal:

            Concerning the gene network role, together with Epigenetics, relationship to it, I agree.

            I have published an ms. dealing in detail exclusively with that genetic “network” (to me. it must necessarily be a hierarchically organized one) including drawing a likely hypothetical scheme of it already 13 years ago (Barja G. The Gene Cluster of Aging
            Bioerontology (2008).

            Concerning your list ON RELEVANT AGING-RELATED FACTORS I THINK IT IS INCOMPLETE. I agree with it but the real one is much longer and needs additions/modifications which I summarize in capital letters (For details see Barja, G.Towards a Unified Theory of Aging. Gerontology, 2019,

            1 :the repair functions of the cell at the individual level, such as autophagy, dna repair, protein digestion, mitochondria repair etc.
            BIUT, CONCERNING DNA REPAIR PLEASE NOTE THAT:

            A) THE CYTOSOLIC OR TOTAL CELL OR NUCLEAR (GENOMIC) BASE EXCISION REPAIR (BER) ONE IS NEGATIVELY CORRELATED WITH LONGEVITY IN COMPARISONS BETWEEN MAMMALIAN SPECIES (SO, NOT RELEVANT TO DETERMINE LONGEVITY).

            B) UNSCHEDULED DNA SYNTHESIS IN FIBROBLASTS IN RESPONSE TO UV-INDUCED DAMGE IS POSITIVE WITH LONGEVITY , BUT THIS REFERS TO EXOGENOUS DAMGE (AGING IS OF ENDOGENOUS ORIGIN) AND ONLY AFTER HIGHER THAN NORMAL STRESS (ANIMALS AGE EVEN IF PUT INSIDE AN BUNKER ISOLATED FORM UV RADIATION OR OTHER ENVIRONMENTAL AGGRESSIONS. ANSD 3RD, THIS AFFECTS SKING FIBROBLASTS ONLY, NOT SHOWN ON NEURONS OR CARDIOMIOCYTES OR SKELETAL MUSCLE CELLS, THE MOST RELEVANT ONE FOR AGING.

            C) HOWEVER, WE HAVE RECENTLY SHOWN THAT MITOCHONDRIAL BASE EXCISION DNA REPAIR (mitBER) IS POSITIVELY CORRELATED WITH SPECIES LONGEVITY IN MAMMALS (GREDILLA ET AL, Geroscience (2020) Mitochondrial base excision repair positively correlates with longevity in the liver and heart of mammals), and this is EXACTLY THE OPPOSITE OBSERVED FOR NUCLEAR (GENOMIC) DNA BER (lack of or negative correlation). THEREFORE, LACK OF APPROPRIATE CORRELATION WITH LONGEVITY IN PAST STUDIES SEEMS TO BE A MATTER OF NOT TAKING INTO ACCOUNT CELLULAR COMPARTMENTATION. THESE NEW DATA ADD TO MANY PREVIOUS ONES INDICATING THAT MITOCHONDRIA ARE MOST IMPORTANT FOER AGING, AND THAT DISCARDING MFRT AT THE BEGINNING OF THE PRESENT CENTURY BY TOO MANY USA RESEARCHERS HAS BENN. A HUGE MISTAKE

            2: the recruitment of the immune system in response to cell damage and
            THIS REFERS TO THE SUB-ARE OF INFLAMMAGING. BUT IT IS SCARCELY SAID BY PEOPLE WORKING IN THAT AREA WHERE INFLAMMATION COMES FROM, EXCEPT AS THOSE SAYING IT OCCURS “RANDOMLY” WHICH TO ME IS THE SAME AS SAYING “WE DON´T KNIOW EHERE DOES IT COME FROM.

            I HAVE MY OWN ANSWER: TO ME INFLAMMATION IS A WHOLE ORGANISM COORDINATOR OF AGING AND ITS SOURCE IS THE AGING PROGRAM LYING IN THE NUCLEUS OF MOST CELLS IN THE BODY. AN EXAMPLE ARE DAMPS (names can hide things too..) BECAUSE PART OF THESE DAMPS AT LEAST ARE MITOCHONDRIA-DEPENDENT SINCE PART OF DAMPS ARE:

            -A) CELL FREE MITOCHONDRIAL DNA (cp-mtDNA) TRAVELLING IN THE BLOOD

            -B) mtDNA FRAGMENTS IN THE BLOOD

            THESE TRAVEL IN THE BLOOD TO COLLABORATE TO COORDINATE AGING AT WHOLE ORGANISM EXTRACELLULAR LEVEL. THEREFORE, the mtDNA fragments produced at mitochondria by mitROS producing DSBs in mtDNA, travel to 2 main sites:

            A) AND INSERT INTO THE NUCLEAR DNA OF THE SAME CELL INTEGRATING ON IT IN ALL ARAMS OF ASLL HUMAN CHROMOSOMES INDUCING AGING AND ALL THE DEGENERATIVE DISEASES INCLUDING CANCER (CARO ET AL., MITOCHONDRION 2010 AMND TOTHER VARIOUS PAPERS IN MICE, RATS AND YEAST REVIEWED IN: “BARJA G. EXPERIMENTAL GERONTOLOGY 2019”.

            B) they are RELEASED THE EXTRACELLULAR space and enter the bloodstream to help to loosely coordinate aging at whole organism level

            THE INCLUSION OF ALL THESE mtDNA-related molecules as part of “DAMPS” (Damage associated Molecular Patterns) BY THE PEOP,E WORKING IN THE INFLAMMAGING AREA OF AGING DOES NOT HELP TO SEE THE EXTENT TO WHICH MITOCHONDRIA ARE RELEVANTLY CONTRIBUTE TO THE DETERMINATION OF THE TOTAL AGING RATE. ON THE CONTRARY, IT HELPS TO HIDE OR AVOID SEEING BY READERS TO WHAT EXTENT THERE ARE MANY KINDS OF RELEVANT EVIDENCES CONCERNING MFRTA (THE MITOCHONDRIAL FREE RADICAL THEORY OF AGING) AND WHY DISCARDING IT FOR THE WHOLE OF THIS CENTURY HAS BEEN A HUGE MISTAKE THAT HAS PRODUCED A STRONG DELAY IN SOLVING THE AGING PROCESS (I FELT TOO ALONE CONTINUING THAT MITOCHONDRIA-AGING RELATED WORK ALMOST UNACCOMPANIED AL THESE LONG DECADES…)

            3: the renewal provided by resident stem cells.

            (Yes KUMAL, but obviously only very relevant in highly mitotic tissues, which precisely are the LESS RELEVANT for aging. IN NATURAL CONDITIONS THERE IS VERY SMALL CELL RENEWAL IN NEURONS, CARDIOMYOCITES AND SKELETAL MUSCLE CELLS,, THE MOST RELEVANT ONES FOR AGING (SAME PROBLEM APPLIES TO THE TELOMERE SHORTENING- AND HAYFLICK´ S-LIMIT HYPOTHESES OF AGING.

            FINALLY, MAY OTHER FACTORS ARE LIKELY INVOLVED IN DETERMINATING THE FINAL AGING ERATE AND LONGEVITY OF EACH ANIMAL SPECIES. LIKE :

            -HIGH REDUNDANCY OF CELLS, ORGANELLES, MTDNA COPIES OF GENES ETC (SEE THE GAVRILOV´´S IMPORTANT CONCEPT ALTHOUGH ALMOST NOBODY PAYS ATTENTION TO IT

            -HIGHER RESISTANCE OF CELLULAR MEMBRANES TO ROS-INDUCED LIPID PEROXIDATION IN LONG-LIVED ANIMALS DUE TO THEIR LOWER CONTENT OF DOUBLE BONDS (LESS UNSATURATED MEMBRANE FATTY ACIDS IN LONG-LIVED ANIMALS). IT IS STRIKING TO ME HOW VERY LITTLE OR NO ATTENTION TO THIS IS PAID BY MOST AUTHORS IN SPITE OF EXiSTING NO EXCEPTION TO THIS MOST IMPORTANT TRAINT DEMONSTRATED IN AROUND 30 PUBLICATIONS STARTING AT 1996 (MAD PAPER IN RATS AND PIGEONS AND COMING FROM TWO DIFFERENT RESEARCH GROUPS: FIST US AT SPAIN (MADRID AND LLEIDA R PAMPLONA AND OUR GROUP IN COLLABORATION), AND TONY HULBERT´ S GROUP MUCH LATER BUT ALSO OFFERING LARGE EVIDENCE IN AUSTRALIA. IN ADDITION, VARIOUS OTHER GROUPS HAVE SHOWED SUPPORT TO THIS LONGEVITY ADAPTATION IN INVERTEBRATES (BIVALVES, SOCIAL INSECTS, NAKED MOLE RATS ETC)

            -THE RATE OF mItROS PRODUCTION . MOST IMPORTANT, A LOW RATE OF mtROS production in LONG-LIVED as well as in CR, Protein Restricted and Methionine restricted -longer-lived rodents. THE Tables 2 and 3 in our last review “Pamplona et al FEBS J (2021) Is the NDUFV2 subunit of the hydrophilic complexes I domain a key determinant of animal longevity?” LIST 72 published different investigations AMONG WHICH 66 OF THEM OF THE DEMONSTRATED THAT a LOW rate of mitROS production EXISTS in long-lived animals (both between, and inside-CR and the like, SPECIES), ONLY IN 6 INVESTIGATIONS NO SIGNIFICANT DIFFERENCES WHERE REACHED, AND NOT A SINGLE CASE OF HIGH mitROSp in long-lived animals was found. DUE TO THIS HUGE EVIDENCE WE CONSIDER IT NONSENSE HARD EFFORTS TO CONSIDER MFRTA “FLAWED OR DEAD…OR …IN PAPER TITLES”. WHAT ARE FLAWED IN OUR HEAVILY DATA AND EXPERIMENTAL EVIDENCE SUPPORTED OPINION ARE SOME WRONGLY DESIGNED EXPERIMENTS OR MODELS (LIKE TO USE VERY POORLY SPECIFIC BIOCHEMICAL METHODS LIKE TO USE KITS, OR TBARS, TO ESTIMATE LIPID PEROXIDATION OR OXIDATIVE DNA OR PROTEIN DAMAGE, INSTEAD OF MUCH MORE ACCURATE AND SPECIFIC CHROMATOGRAPHY, HPLC-CL, OR MASS SPEC DETECTION ETC; AND TO PERFORM -EARLY XX CENTURY WIDE AND EXPENSIVE RESEARCH IN MICE- OVER-EXPRESSING CYTOSOLIC OR TOTAL CELL INSTEAD OF MITOCHONDRIAL ANTIOXIDANTS WHEN TRYING TO CLARIFY IF THEY HAVE OR NOT A ROLE IN AGING (AGAIN A PROBLEM, IT SEEMS, OF COMPARTMENTATION, LIKE IN THE mitBER vs. nuclear BER, WE HAVE NEW EVIDENCE COMING CONCERNING THIS MOST RELEVANT PROBLEM…

            -APOPTOSIS, AND CELL DEATH

            -SENESCENT CELLS,
            -BLOOD FACTORS (RELEASED BY CELLS AND THEIR AGING PROGRAM-DEPENDENT TARGET GENES EXPRESSED AS AGING EFFECTORS) RESPONSIBLE FOR HETEROCHRONIC BLOOD EXCHANGE RESULTS,

            -OF COURSE EPIGENETICS WHICH IS FUNDAMENTAL FOR CONTROL OF GENE EXPRESSION OF THE AGING PROGRAM ACTION AT DIFFERENT AGES OCCURRING AT A DIFFERENT PACE IN EACH SPECIES

            -SUPRACELLULAR HIERARCHICALLY HIGHER ORDER AGING CLOCKS?

            OF COURSE NOTHING OF ALL THIS IS DUE TO RANDOM CAUSES AND THAT IS THE DEEP REASON WHY ALL THE NON-PROGRAMMED THEORIES OF AGING ARE NECESSARILY WRONG:

            GIVEN THAT EPHEMERA INSECTS CAN LAST ONLY 1 DAY AND SOME SPONGES CAN LIVE 13,000 YEARS WITH THOUSANDS OF EXAMPLES OF INTERMEDIATE LONGEVITIES BETWEEN THEESE TWO EXTREME EXAMPLES, WHEREAS, HOWEVER, MOST ANIMALS ARE ESSENTIALLY COMPOSED (WITH SOME EXCEPTION LIKE THE DBI OF MEMBRANE FAs) BY THE SAME BIOCHEMICAL MACROMOLECULES , wear and tear based mechanistic hypothesis of aging must be surely flawed.

            -ONE SHOULD ADD TO ALL THAT THE MANY MECHANISMS OF AGING (AGING EFFECTORS IN BARJA EXP GERONTOL. 2019) STILL TO BE DISCOVERED…

            THESE, PLUS THE NUCLEAR AGING PROGRAM, PLUS THE SIGNALS FROM THE EXTERNAL AND INTERNAL ENVIRONMENT REACHING IT (SEE FIG. 2 IN BARJA 2019 EXP GERONTOL.) CAN BE RECONCILED ALL OF THEM WITHIN MY PROPOSAL MENTIONED ABOVE OF A SINGLE UNIFIED THEORY OF AGING. THE RELEVANCE OF THE NUCLEAR AGING PROGRAM IS EVIDENT LOOKING AT THAT FIGURE WHEN INE REALIZES THAT:

            A) ONLY ACCEPTING THE EXISTENCE OF THE NUCLEAR AGING PROGRAM CAN THE PREVIOUSLY CONSIDERED SEPARATE “THEORIES OF AGING” BE UNIFIED INTO A SINGLE THEORY. WITHOUT THE AGING PROGRAM, THE UNIFICATION FALLS APPART AND ALL THE AGING EFFECTORS SEPARATE AS DIFFERENT “AGING HYPOTHESES” or hallmarks of aging without connection to each other. it is the aging program what unifies and connects all of them giving them sense within organism aging.

            YOU HAVE A DETAILED DESCRIPTION OF ALL THIS AND MORE ON MY REVIEW BARJA G EXPERIMENTAL GERONTOLOGY (2019) TOWARDS A UNIFIED MECHANISTIC THEORY OF AGING

        • Many elderly people suffer from Hypoalbuminemia, even if their protein intake is adequate, and sometimes independent of a disease process.

          Therefore, replacing albumin will likely extend health and thus lifespan.

          • @ kunal

            ‘why would good molecules increase at a higher rate than bad molecules on dilution by albumin, unless the rate of increase is different for both. And if the rate of increase is different, what explains it.’

            Albumin is a specific case; we are not ‘diluting by albumin’ we are adding fresh albumin, which is undamaged, hence you are increasing the ratio of good: bad albumin. As Heather points out albumin concentration falls with age (this is at least partially due to increased rate of catabolism of oxidised albumin), and indeed adding albumin extending the lifespan of mice.

            But we could extend this to a more general case of other blood proteins.

          • From the conboy paper
            ‘ Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE’
            It should be clarified by the researchers whether the lab mice used for their experiment had faulty albumin.

          • In any case, the primary function of albumin is transport and therefore infusing fresh albumin will also improve the transport of the negative factors similar to the positive factors.

          • conboy paper

            ‘To start dissecting the possible mechanisms by which exchange of old mammals with saline plus albumin exerts these rejuvenative effects, we examined whether ectopic albumin (human serum albumin, HSA) might be a determinant. First, we performed HSA dose curve, which demonstrated that ectopic albumin does not promote myoblast proliferation

            We also looked at the antioxidant properties of PreTPE versus PostTPE serum. Albumin has antioxidant activity [16], and thus we tested if Post TPE serum might promote myogenic cell proliferation simply through improved antioxidant properties. Interestingly, we did not find antioxidative difference between Pre and PostTPE serum
            These results establish that NBE and TPE have positive effects on adult myogenesis and that ectopic albumin does not rescue the old serum-imposed inhibition of myogenic proliferation.’

          • Positive effects of albumin – Conboy paper
            ‘To continue the study with ectopic albumin, we performed BrdU proliferation assay with neural precursor cells, NPC, which provide a good in vitro correlation to the efficiency of hippocampal neurogenesis [15, 28]. Interestingly, in contrast to the lack of effects on myogenic cells, ectopic albumin enhanced NPC proliferation by itself – in the absence of serum and improved NPC proliferation when old serum was present in the cultures (Supplementary Figure 3B). These results agree with previously published enhancement of proliferation of retinal precursor cells by albumin [29] and with efficient proliferation of human iPSC-derived NPCs on electrospun serum albumin fibrous scaffolds’

          • Effects of albumin on the brain – conboy paper

            ‘However, the body of published work consistently demonstrates that albumin is a negative factor for brain health. With respect to reaching neural cells in vivo, Blood Brain Barrier becomes leaky with age [31, 32] and serum albumin crosses it and is found in cerebro-spinal-fluid of older individuals in a positive correlation with age and with certain types of dementias [33]. Moreover, in direct test, infusions of albumin into the brain were deleterious: causing neuro-inflammation, excessive TGF-beta1 and neuronal dysfunctions ‘

          • Kunal, you can write as much as you want about Albumin from the Conboys – you and they are still wrong. Albumin is an important determinate; this can be seen in two ways 1. It DOES decline with age, in fact you could make a very accurate aging clock with just serum albumin concentration; 2. Adding pristine albumin in regular infusions increased the mean and max lifespan of mice.

            As to your assertion that albumin would also carry ‘bad’ actors around the blood, this is simply not the case – oxidation, glycations, etc., impairs the ability of albumin to carry out its transportation function.

          • You mean to say that conboy is lying when she says the following

            ‘we examined whether ectopic albumin (human serum albumin, HSA) might be a determinant. First, we performed HSA dose curve, which demonstrated that ectopic albumin does not promote myoblast proliferation (Figure 2F). Based on this dose-curve, we added 4% HSA to our myoblast proliferation assay (where cells were cultured with 4% Pre versus Post TPE human serum). Interestingly, while there was consistently better myoblast proliferation with PostTPE serum as compared to the PreTPE, HSA neither rescued the proliferation of PreTPE myoblast cultures, nor added to the proliferation of the Post-TPE cultures’

          • ‘oxidation, glycations, etc., impairs the ability of albumin to carry out its transportation function.’

            Fresh albumin infusion would have the same effect on its transport function for both positive and negative factors, as it would not have oxidation, glycations, etc to impair its primary function.
            That there is rejuvenation, hints at a faster rate of recovery of the positive factors as compared to the negative factors and there is no current evidence to explain this.

          • However, it can also be said that fresh undamaged albumin can contribute to rejuvenation by infusion because of the dilution of the plasma, which cannot be shown by only using albumin in vitro. Instead the paper should have infused isolated albumin from aged rats to carry out the dilution to isolate its effect.

          • The Conboys looked at one particular aspect of rejuvenation, which fresh albumin had no benefit for, they didn’t prove it has no benefits.

            Obviously replacing albumin is not the whole story – but it is part of it as the more recent study shows.

            As to your repeated assertion that fresh albumin would also carry bad actors around (better than damaged albumin), this is pure speculation and contrary to the evidence.

          • Let us separate the facts and speculation if any,
            Conboy publishes a peer reviewed paper which shows that dilution of blood plasma by saline and albumin leads to rejuvenation in aged rats. Rejuvenation through the above can happen in only one way(whichever way you look at it), i.e Imbalance between the concentration of the pro aging and anti aging factors tilted towards the anti aging factors, because if concentration of both remains the same, it is back to square one.
            This is precisely what happens, with the concentration of the anti aging factors higher than the pro aging factors, when compared prior to infusion.
            This leads to the conclusion(no speculation), that dilution leads to anti aging factors being generated at a higher rate than the pro aging factors.

            Rest is speculation

  22. With a thousand Horvath samples along with the peptides, we could solve for the effect of many of these 529 peptides on aging

  23. Research paper
    ‘Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial’ April 2021.

    Research paper
    ‘Endurance Exercise Mobilizes Developmentally Early Stem Cells into Peripheral Blood and Increases Their Number in Bone Marrow: Implications for Tissue Regeneration’ Nov 2015

    Prolonged Endurance Exercise on a Treadmill Increases the Number of VSELs Circulating in PB as well as Residing in BM. This increase in the number of VSELs circulating in PB correlated with an increase in expression of mRNA for VSEL markers such as Oct-4, Sox2, and Nanog.

    Is the effect of exercise similar to partial reprogramming.

  24. Check out my two new updates for my aging blogpost>>>
    link>> https://jefftbowles.com/aging-is-programmed/
    title >> NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING-AND REVEALS THE NEW: PROGRAMMED LOSS OF CELLULAR DIFFERENTIATION THEORY OF AGING

    Updtes>>> the coolest one first>>>
    Update #13

    I wrote in my 1998 paper > ” Cancer, in a broad sense, may simply be a cell returning to its earlier, primitive, immortalized, state. It should not be very surprising that a mortal life form that evolved from a previously immortalized life form could spontaneously become immortalized through loss of some type of control. However, if the mortal life form had evolved from mortal ancestors, spontaneous immortalization would seem to be quite a miracle indeed.” see comment in full context at the end of this update .

    Well, well, well>> I have been reading all the abstracts in Pub Med that contain the term “Yamanaka Factors” and what have I found? The cancer cells are basically just malfunctioning de-differentiated embryonic stem cells. And yes it seems very likely they are simply a reemergence of our oldest ancestors…Single cell life that lived before the age of oxygen. Both cancer cells and embryonic stem cells can dviide indefinitely (immortal). Both of the them do not use oxygen for energy even when oxygen is present but rather switch to an anaerobic form of glycolysis for energy ! What follows are the interesting abstracts that show how this view of cancer being a reversion of cells to their most primitve state seems to be correct:
    The role of pluripotency factors to drive stemness in gastrointestinal cancer

    Abstract

    A better molecular understanding of gastrointestinal cancers arising either from the stomach, the pancreas, the intestine, or the liver has led to the identification of a variety of potential new molecular therapeutic targets. However, in most cases surgery remains the only curative option. The intratumoral cellular heterogeneity of cancer stem cells, bulk tumor cells, and stromal cells further limits straightforward targeting approaches. Accumulating evidence reveals an intimate link between embryonic development, stem cells, and cancer formation. In line, a growing number of oncofetal proteins are found to play common roles within these processes. Cancer stem cells share features with true stem cells by having the capacity to self-renew in a de-differentiated state, to generate heterogeneous types of differentiated progeny, and to give rise to the bulk tumor. Further, various studies identified genes in cancer stem cells, which were previously shown to regulate the pluripotency circuitry, particularly the so-called “Yamanaka-Factors” (OCT4, KLF4, SOX2, and c-MYC). However, the true stemness potential of cancer stem cells and the role and expression pattern of such pluripotency genes in various tumor cell types remain to be explored. Here, we summarize recent findings and discuss the potential mechanisms involved, and link them to clinical significance with a particular focus on gastrointestinal cancers.

    The oncogene c-Jun impedes somatic cell reprogramming

    Jing Liu 1, Qingkai Han 1, , Duanqing Pei 2

    Oncogenic transcription factors are known to mediate the conversion of somatic cells to tumour or induced pluripotent stem cells (iPSCs).

    EMBO Rep

    . 2014 Mar;15(3):244-53.

    Dedifferentiation and reprogramming: origins of cancer stem cells

    Abstract

    Regenerative medicine aims to replace the lost or damaged cells in the human body through a new source of healthy transplanted cells or by endogenous repair. Although human embryonic stem cells were first thought to be the ideal source for cell therapy and tissue repair in humans, the discovery by Yamanaka and colleagues revolutionized the field. Almost any differentiated cell can be sent back in time to a pluripotency state by expressing the appropriate transcription factors. The process of somatic reprogramming using Yamanaka factors, many of which are oncogenes, offers a glimpse into how cancer stem cells may originate. In this review we discuss the similarities between tumor dedifferentiation and somatic cell reprogramming and how this may pose a risk to the application of this new technology in regenerative medicine.

    J Cell Sci

    . 2013 Aug 15;126(Pt 16):3638-48.

    The reprogrammed pancreatic progenitor-like intermediate state of hepatic cells is more susceptible to pancreatic beta cell differentiation

    Abstract

    Induced pluripotent stem cells (iPSCs) hold great promise for cell therapy. However, their low efficiency of lineage-specific differentiation and tumorigenesis severely hinder clinical translation. We hypothesized that reprogramming of somatic cells into lineage-specific progenitor cells might allow for large-scale expansion, avoiding the tumorigenesis inherent with iPSCs

    Expert Rev Anticancer Ther

    . 2021 Apr 8.

    Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer

    Abstract

    Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.

    Biochem Biophys Res Commun

    . 2019 Sep 17;517(2):324-329.

    Silencing of the transcription factors Oct4, Sox2, Klf4, c-Myc or Nanog has different effect on teratoma growth

    Abstract

    Induced pluripotent stem cells (iPSC) have a great potential, but their clinical application depends on finding strategies to abolish their tumorigenic potential. The use of Oct4, Sox2, Klf4, c-Myc and Nanog to generate iPSC demonstrated the already known importance of these genes to maintain stemness. Therefore, the presence of these genes is responsible for iPSC-derived teratomas. Similar to iPSC, P19 teratocarcinoma cell line also has characteristics of embryonic carcinoma cells and the ability to differentiate into many cell types. We separately silenced the transcription factors Oct4, Sox2, Klf4, c-Myc and Nanog in P19 cells and measured the impact of this silencing in vivo. All silenced cells generated tumors when injected in immunosuppressed mice, but silencing of Oct4, Sox2 and Klf4 generated mainly teratomas with mesoderm tissue. Our results suggest that downregulation of these transcription factors is not enough to avoid the formation of teratomas, but their silencing affect their differentiation potential.

    Oncogene

    . 2019 Aug;38(34):6226-6239.

    Epigenetic reprogramming of primary pancreatic cancer cells counteracts their in vivo tumourigenicity

    Abstract

    Pancreatic ductal adenocarcinoma (PDAC) arises through accumulation of multiple genetic alterations. However, cancer cells also acquire and depend on cancer-specific epigenetic changes. To conclusively demonstrate the crucial relevance of the epigenetic programme for the tumourigenicity of the cancer cells, we used cellular reprogramming technology to reverse these epigenetic changes. We reprogrammed human PDAC cultures using three different techniques – (1) lentivirally via induction of Yamanaka Factors (OSKM), (2) the pluripotency-associated gene OCT4 and the microRNA mir-302, or (3) using episomal vectors as a safer alternative without genomic integration. We found that induction with episomal vectors was the most efficient method to reprogram primary human PDAC cultures as well as primary human fibroblasts that served as positive controls. Successful reprogramming was evidenced by immunostaining, alkaline phosphatase staining, and real-time PCR. Intriguingly, reprogramming of primary human PDAC cultures drastically reduced their in vivo tumourigenicity, which appeared to be driven by the cells’ enhanced differentiation and loss of stemness upon transplantation. Our study demonstrates that reprogrammed primary PDAC cultures are functionally distinct from parental PDAC cells resulting in drastically reduced tumourigenicity in vitro and in vivo. Thus, epigenetic alterations account at least in part for the tumourigenicity and aggressiveness of pancreatic cancer, supporting the notion that epigenetic modulators could be a suitable approach to improve the dismal outcome of patients with pancreatic cancer.

    Methods Mol Biol

    . 2019;1916:249-261.

    Reprogramming of Human Melanocytes and Melanoma Cells with Yamanaka Factors

    Abstract

    The expression of Yamanaka factors (Oct3/4, Klf-4, Sox-2, c-Myc) can reprogram cancer cells to a pluripotent stage. This may cause the removal of their epigenetic memory and result in altered tumorigenicity. Various studies in the literature have shown that cancer cell reprogramming is a potential tool to study disease progression or discover novel therapeutic or diagnostic markers in cancer research. In this chapter, we aim to introduce the cancer cell reprogramming protocol in detail by using human melanocytes and melanoma cell lines, and Sendai viral vectors encoding Yamanaka factors have been used to reprogram cells. Representative results are discussed and important notes have been summarized in order to point out important steps during cancer cell reprogramming.

    J Biomed Sci

    . 2018 Jul 19;25(1):57.

    Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype

    Abstract

    Background: Induced pluripotency in cancer cells by ectopic expression of pluripotency-regulating factors may be used for disease modeling of cancers. MicroRNAs (miRNAs) are negative regulators of gene expression that play important role in reprogramming somatic cells. However, studies on the miRNA expression profile and the expression patterns of the mesenchymal-epithelial transition (MET)/epithelial-mesenchymal transition (EMT) genes in induced pluripotent cancer (iPC) cells are lacking.

    Methods: iPC clones were generated from two colorectal cancer (CRC) cell lines by retroviral transduction of the Yamanaka factors. The iPC clones obtained were characterized by morphology, expression of pluripotency markers and the ability to undergo in vitro tri-lineage differentiation. Genome-wide miRNA profiles of the iPC cells were obtained by microarray analysis and bioinformatics interrogation. Gene expression was done by real-time RT-PCR and immuno-staining; MET/EMT protein levels were determined by western blot analysis.

    Results: The CRC-iPC cells showed embryonic stem cell-like features and tri-lineage differentiation abilities. The spontaneously-differentiated post-iPC cells obtained were highly similar to the parental CRC cells. However, down-regulated pluripotency gene expression and failure to form teratoma indicated that the CRC-iPC cells had only attained partial pluripotency. The CRC-iPC cells shared similarities in the genome-wide miRNA expression profiles of both cancer and pluripotent embryonic stem cells. One hundred and two differentially-expressed miRNAs were identified in the CRC-iPC cells, which were predicted by bioinformatics analysis be closely involved in regulating cellular pluripotency and the expression of the MET/EMT genes, possibly via the phosphatidylinositol-3 kinases-protein kinase B (PI3K-Akt) and transforming growth factor beta (TGF-β) signaling pathways. Irregular and inconsistent expression patterns of the EMT vimentin and Snai1 and MET E-cadherin and occludin proteins were observed in the four CRC-iPC clones analyzed, which suggested an epithelial/mesenchymal hybrid phenotype in the partially reprogrammed CRC cells. MET/EMT gene expression was also generally reversed on re-differentiation, also suggesting epigenetic regulation.

    Conclusions: Our data support the elite model for cancer cell-reprogramming in which only a selected subset of cancer may be fully reprogrammed; partial cancer cell reprogramming may also elicit an epithelial-mesenchymal mixed phenotype, and highlight opportunities and challenges in cancer cell-reprogramming.

    Biochim Biophys Acta Rev Cancer

    . 2018 Jan;1869(1):1-10.

    Deubiquitylating enzymes as cancer stem cell therapeutics

    Abstract

    The focus of basic and applied research on core stem cell transcription factors has paved the way to initial delineation of their characteristics, their regulatory mechanisms, and the applicability of their regulatory proteins for protein-induced pluripotent stem cells (protein-IPSC) generation and in further clinical settings. Striking parallels have been observed between cancer stem cells (CSCs) and stem cells. For the maintenance of stem cells and CSC pluripotency and differentiation, post translational modifications (i.e., ubiquitylation and deubiquitylation) are tightly regulated, as these modifications result in a variety of stem cell fates. The identification of deubiquitylating enzymes (DUBs) involved in the regulation of core stem cell transcription factors and CSC-related proteins might contribute to providing novel insights into the implications of DUB regulatory mechanisms for governing cellular reprogramming and carcinogenesis. Moreover, we propose the novel possibility of applying DUBs coupled with core transcription factors to improve protein-iPSC generation efficiency. Additionally, this review article further illustrates the potential of applying DUB inhibitors as a novel therapeutic intervention for targeting CSCs. Thus, defining DUBs as core pharmacological targets implies that future endeavors to develop their inhibitors may revolutionize our ability to regulate stem cell maintenance and differentiation, somatic cell reprogramming, and cancer stem cells.

    Biochim Biophys Acta Mol Cell Res

    . 2017 Jul;1864(7):1359-1369.

    Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences

    Abstract

    Reprogramming, or generation of induced pluripotent stem (iPS) cells (functionally similar to embryonic stem cells or ES cells) by the use of transcription factors (typically: Oct3/4, Sox2, c-Myc, Klf4) called “Yamanaka factors” (OSKM), has revolutionized regenerative medicine. However, factors used to induce stemness are also overexpressed in cancer. Both, ES cells and iPS cells cause teratoma formation when injected to tissues. This raises a safety concern for therapies based on iPS derivates. Transdifferentiation (lineage reprogramming, or -conversion), is a process in which one mature, specialized cell type changes into another without entering a pluripotent state. This process involves an ectopic expression of transcription factors and/or other stimuli. Unlike in the case of reprogramming, tissues obtained by this method do not carry the risk of subsequent teratomagenesis.

    Iran J Basic Med Sci

    . 2016 Oct;19(10):1131-1135.

    Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma

    Abstract

    Objectives: Similar characteristics of molecular pathways between cellular reprogramming events and tumorigenesis have been accentuated in recent years. Reprogramming-related transcription factors, also known as Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC), are also well-known oncogenes promoting cancer initiation, progression, and cellular transformation into cancer stem cells. Long non-coding RNAs (lncRNAs) are a major class of RNA molecules with emerging roles in stem cell pluripotency, cellular reprogramming, cellular transformation, and tumorigenesis. The long intergenic non-coding RNA ROR (lincRNA-ROR, linc-ROR) acts as a regulator of cellular reprograming through sponging miR-145 that normally negatively regulates the expression of the stemness factors NANOG, OCT4, and SOX2.

    Stem Cells

    . 2016 Nov;34(11):2613-2624.

    Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer

    Abstract

    The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.

    Stem Cell Reports

    . 2016 Jul 12;7(1):1-10.

    MiR-31/SDHA Axis Regulates Reprogramming Efficiency through Mitochondrial Metabolism

    Abstract

    Metabolism is remodeled when somatic cells are reprogrammed into induced pluripotent stem cells (iPSCs), but the majority of iPSCs are not fully reprogrammed. In a shift essential for reprogramming, iPSCs use less mitochondrial respiration but increased anaerobic glycolysis for bioenergetics. We found that microRNA 31 (miR-31) suppressed succinate dehydrogenase complex subunit A (SDHA) expression, vital for mitochondrial electron transport chain (ETC) complex II. MiR-31 overexpression in partially reprogrammed iPSCs lowered SDHA expression levels and oxygen consumption rates to that of fully reprogrammed iPSCs, but did not increase the proportion of fully reprogrammed TRA1-60(+) cells in colonies unless miR-31 was co-transduced with Yamanaka factors, which resulted in a 2.7-fold increase in full reprogramming. Thus switching from mitochondrial respiration to glycolytic metabolism through regulation of the miR-31/SDHA axis is critical for lowering the reprogramming threshold. This is supportive of multi-stage reprogramming whereby metabolic remodeling is fundamental.

    Cancer cells exhibit aerobic glycolysis. This means that cancer cells derive most of their energy from glycolysis that is glucose is converted to lactate for energy followed by lactate fermentation, even when oxygen is available. This is termed the Warburg effect.

    Full context extrtact from my 1998 paper>>>

    “So, if mitochondria existed as separate organisms prior to their merging with the drifting Archaea, then it might be expected that they had evolved their own separate aging system. Once the two life forms merged and the larger, combined, life form was completely dependent on the mitochondrial energy source, whenever enough mitochondria in the cell had died, the cell itself would also die. If the mitochondrial imposed death occurred before death caused by telomeric shortening, two aging systems could exist in the same organism, one dominant and one vestigial. Mitochondrial aging will be referred to as Aging System #2 or (AS#2).

    The next step in evolution would likely have been the vast colonization of the oceans by these photosynthetic Archaea. (We will now refer to them as algae). With the sun providing unlimited energy and the ocean an unrestricted habitat, evolution would select for maximal reproductive potential and therefore maximal life spans. The first two aging systems, therefore were likely deactivated. The symbiotic mitochondria could simply evolve longer life spans, and the telomeric aging system could be deactivated by the creation of telomerase which rebuilds the ends of the chromosomes after each round of replication. Also, to counter the effect of the sun’s deadly mutating UV, Gamma, and X rays ( referred to herein as solar radiation) a DNA repair system had to evolve that could excise damaged base pairs and replace them with the proper ones. Additionally, to protect against the free radicals generated by the oxygen produced from photosynthesis and solar radiation, an antioxidant protective system had to evolve as well. After a billion years of this selection pressure it could be expected that the algae evolved into non-aging, rapidly-reproducing organisms with perfect DNA repair and free radical defense systems. Is there any evidence that single cell organisms were once immortal? Many cell-types with the proper manipulations can become immortalized cancer strains and reproduce indefinitely as a culture. Cancer, in a broad sense, may simply be a cell returning to its earlier, primitive, immortalized, state. It should not be very surprising that a mortal life form that evolved from a previously immortalized life form could spontaneously become immortalized through loss of some type of control. However, if the mortal life form had evolved from mortal ancestors, spontaneous immortalization would seem to be quite a miracle indeed.

    Update #12 >>>
    Update #12 Turns out lamin A is missing in undifferentiated embryonbic stem cells and is defective in the rapid aging disease of progeria :

    Efficient induction of pluripotent stem cells from granulosa cells by Oct4 and Sox2

    Jian Mao 1, Qian Zhang, Xiaoying Ye, Kai Liu, Lin Liu

    Abstract

    Various types of somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells. Somatic stem cells exhibit enhanced reprogramming efficiency by fewer factors, in contrast to fully differentiated cells. Nuclear Lamin A is highly expressed in differentiated cells, and stem cells are characterized by the absence of Lamin A. Granulosa cells (GCs) and cumulus cells in the ovarian follicles effectively and firstly generated cloned mice by somatic cell nuclear transfer, and these cells lack Lamin A expression. We tested the hypothesis that GCs could be effectively used to generate iPS cells with fewer factors. We show that iPS cells are generated from GCs at high efficiency even with only two factors, Oct4 and Sox2, like the iPS cells generated using four Yamanaka factors. These iPS cells show pluripotency in vitro and in vivo, as evidenced by high expression of pluripotency-associated genes, Oct4, Nanog, and SSEA-1, differentiation into three embryonic germ layers by embryoid body formation and teratoma tests, as well as high efficient generation of chimeras. Moreover, the exogenous genes are effectively silenced in these iPS cells. These data provide additional evidence in supporting the notion that reduced expression of LaminA and stem cells can improve the reprogramming efficiency to pluripotency.

  25. The latest and greatest anti-aging intervention?

    Glycine and N-acetylcysteine (GlyNAC) supplementation in
    older adults improves glutathione deficiency, oxidative
    stress, mitochondrial dysfunction, inflammation, insulin
    resistance, endothelial dysfunction, genotoxicity, muscle
    strength, and cognition: Results of a pilot clinical trial

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/pdf/CTM2-11-e372.pdf

    “GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation”

    Thought the oxidation theory or aging was dead? Non essential amino acids having profound anti-aging benefits?

    For a 70kg person, 7g glycine/day and 9.3 g NAC/day.

    • Well the strict oxidation hypothesis is clearly wrong as that would imply higher metabolism would inevitably result in lower lifespan. But there are known exceptions to this rule. What is now known I think goes by the name membrane pacemaker modification, or something like that, it shows that the peroxidation index of membranes is modified in species with longer than expected lifespan for their metabolism. Species make membranes more oxidation resistant if they are longer lived for a particularly high metabolism.

      I think this is also the case in insects, when comparing long lived queens vs short lived workers. Queens membranes are more peroxidation resistant than worker membranes. Keep in mind that some insect colonies are rumored to have up to 100x difference in lifespan between queens and workers, despite having identical genomes. Showing how changes to regulation of gene expression can lead to vast differences in lifespan.

      What I’d need to research is how it works for neurons, given I’ve heard they tend to have a lot of polyunsaturated lipids in their membranes, which would presumably be easily oxidable and a very bad idea given their extremely high metabolism. Yet neurons are said by some to be biologically immortal in the right environment. They live as long as the animal lives without dividing at extreme metabolic rates, how they accomplish this is a good question.

      How a body can have immortal nondividing cells at high metabolism yet the rest of the dividing mostly lower metabolism body ages, aka less oxidation and damage due to lower metabolism, is a good question.

      • Darian it is you who is wrong whe you ignorantly critizize MFRTA, because you are assuming that FRL% is a constant which is not, absolutely not!!!!!. I wrote a whole paper (Barja Rejuv. Research 2007) to explain this to those who do not understand how the mitochondrial electron transport chain works, the 100% of scientists at USA since Britton Chance (PA) died. It is clear that you are one more if those ignorants. It is terrible how much ignorance pervades USA science due to you being dominated by FASHION!. SCIENCE IS NOT FASHION. AND BRITTON WAS A GOD. YOU LODT HIM AND YOU WERE LEFT IN ABSOLUTE IGNORANCE ON MITICHONDRIAL FUNCTION. I SPEAK OF FUNCTIONAL WELL COUPLED (ALIVE!!!) RESPIRING MITOCHONDRIA. CHRISTOPH RICHTER A GERMAN TAUGHT ME HOW TO OBTAIN THEM FROM FRESH TISSUE IN 1994. AT THAT TIME NO ONE IN THE WHOLE USA KNEW HOW TO BREAK THE CELL AND TAKE OUT OF IT WELL COUPLED FUNCTIONAL MITOCHONDRIA. NOW YOU HAVE AT BUCK INSTITUTE ANOTHER EUROPEAN (OF COURSE!!!) WHO KNEW HOW TO DO THAT, THE KING OF H+ LEAK MARTIN BRAND FORMERLY PROFFESSOR OF BIOCHEMISTRY AT CAMBRIDGE UNIVERSITY UK. YOU BOUGHT HIM WITH YOUR VALUE: DOLLARS (HE RENOUNCED TO HIS CAMBRIDGE PROFESSIRSHIP!). HE WILL RETURN TO ENGLAND WITH HIS MILLIONAIRE RETAIRMENT. THAT IS WHAT HE WANTED FROM YOU IN INTERCHANGE FOR WHAT HE GAVE YOU CONCERNING FUNCTIONAL MITOS. I HELPED MARTIN TO LEARN HOW TO PROPERLY MEASURE MITROSp (I SENT MY STUDENT SUSANA CADENAS WHO DID HER PhD with ME AT MADRID TO DO A 4 YEARS LONG PISTDOC WITH MARTIN AT CAMBRIDGE UK….

        • What are you talking about?

          Mitochondria free radical has an effect. But it has clearly been seen that altering membrane composition to reduce oxidation is enough to essentially do away with the issue. Humans are said to have even more oxidation resistant mitochondrial membranes, iirc.

          Now some species essentially show little to no signs of aging, and then drop dead, probably due to programmed death program. Others even have unlimited lifespans as far as we can tell. Is there a movement of additional mitochondrial genes to the nucleus, not as far as I know.

          Our rodent ancestor likely had a lifespan of a few years, or primate ancestor a few decades at most, yet we live over 115 years. Few genetic mutations allowed this.

          With regards to the brain with 115+ year long lived cells, that can probably last for centuries while keeping high metabolism, maybe their mitochondrial membranes are even more oxidation resistant than other tissues. Their external membranes are said to have lots of polyunsaturated lipids, iirc. Maybe they have protections for that. But perhaps they deal with the issue by dealing with the mitochondria membrane.

          Know this mice neurons last OVER TWICE AS LONG AS MICE THEMSELVES DO when transplanted into another host, and researchers have speculated these cells to be biologically immortal.

    • 9.3 grams of NAC per day seems like an awful lot, especially when we keep in mind that NAC has pro-oxidant effects at large doses. It’s certainly an interesting study and the results cannot be ignored.

      • …in addition, we need to see the same study conducted on HEALTHY AND FIT OAs without insulin resistance.

        I’m wondering, if changing diet, incorporating exercise and fasting would have led to similar health benefits, considering that the room for improvement is so vast for these individuals.

        • No it doesn’t – the inflammatory cytokines caused by elevated ROS mean you can’t gain muscle without first lowering ROS (if you are in that aged state). But it is a fine balance, too low ROS and autophagy doesn’t work.

          It is a mystery why to me why this paper has got so much attention. Wulf Droge (RIP) was talking about this in the early 2000s.

  26. The recent paper on albumin

    Young and Undamaged rMSA Improves the Longevity of Mice

    ‘125 mg/mL of rMSA dissolved in saline was i.v. injected slowly. Mice were weighed before each injection to calculate the dosage, with saline served as the negative control. Mice were injected with 1.5 mg rMSA per gram of mouse body weight and isometric saline every 3 weeks as indicated.’

    Actuals according to various papers

    average body weight of mice 30 g
    average plasma volume of mice 1.6 ml
    average concentration of Albumin in mice 25 mg/ml
    average total albumin in mice 40 mg

    The paper also does not mention clearly the total volume of saline with albumin injected per mouse. It mentions 125 mg/ml was injected, whereas average concentration of Albumin in mice 25 mg/ml. But in the same paragraph it mentions ‘Mice were injected with 1.5 mg rMSA per gram of mouse body weight’, which comes to average 45 mg albumin injected.
    Whereas 125 mg/ml concentration comes to 187.5 mg total concentration in plasma of 1.5 ml.

  27. @Gustavo Barja

    sorry for replying so late to your comment on appreciating my hypothesis on aging. I am no scientist, but a layman following the anti aging field for the last 10 years.
    Here is my take again.
    Multi cellular organisms are governed by gene networks right from embryogenesis till death. I say death because i feel aging is also controlled by a gene network, which comes in to being at puberty. I also feel that morphogenesis does not end at birth, it continues till the end of the pubertal phase. Morphogenetic pace not phase varies across species with varying intervals of growth pace.
    A gene network has function not individual genes, an individual gene can be part of many gene networks in the same organisms(for e.g serotonin). it is the gene network that morphs at various tissue growth milestones or organ boundary milestone and acquires different forms and function at those milestones. It does this by inhibiting some of its member genes and/or adding new genes to its network.
    Aging is one such network which is activated at the morphogenetic milestone of puberty. The activation of this network, results in a program which controls
    1 :the repair functions of the cell at the individual level, such as autophagy,dna repair, protein digestion, mitochondria repair etc.
    2: the recruitment of the immune system in response to cell damage and
    3: the renewal provided by resident stem cells.
    The gene network which was in control of the above functions during the growth and the final morphogenetic turn at puberty, is modified by activation of some unidentified genes, which in turn inhibit some genes, which played a key role in the previous iteration of the network. Due to this, the whole network modifies itself to implement the aging program.
    And therefore, various genes which were found to be beneficial in the previous avatar of the network turn deleterious in the new network, leading to the so called phenomenon ‘antagonistic pleiotropy’.
    Various supplements which have proven to be beneficial are just perturbing small parts of the overall network. However, with the epigenetic clock showing lock step epigenetic modification across various organs and tissues in the organism. the presence of signalling factors in the communication medium can be hypothesized. Hence plasma exchange/dilution are probably effective because the perturb the whole network.
    Also according to me partial reprogramming is an unnatural way of changing the dynamics of the aging gene network by introducing elite transcription factors, which supersede the key transcription factors controlling the aging network.

  28. In stem cell therapy adult stem cells often get harvested from fat tissue. I don’t know why fat seems to have a higher stem cell concentration but it could perhaps help explaining the BMI paradox. The net effect of (a) the risks associated with a higher BMI and (b) the renegerative benefits of the stem cell population is positive.

    • Josh,
      at your bottom line you said:
      ” I don’t know why the robust association of caloric restriction with longevity doesn’t lead to a clear longevity advantage in humans for a lower BMI”
      I do not say what follows is correct but, what about the De Gray published claim aroun 2007 that selection for the CR adaptation to famine depends on the relative length of famines in the wild (rarely longer than one year or two) vs. the life span of the species considered, which would explain why CR clearly (no reasonable doubt after 90 years of experimentation specially from the 1970’s mainly at Texas medical? center) increases longevity in (short-lived species) rodents but not in (long-lived species) humans?

      The solution to this problem CANNOT BE studies in humans. You will lose your peecious time and money studying humans with their too many confounding factors impossible to statistically eliminate (those who claim they do are lying fakes only due to own corporative interests, medical drs., big pharma in health issues, same for fake siciologists or economists etc who say their disciplines are “scientific”! But they are not! There are only 4 Sciences:
      2 BEST HARD ONES: PHYSICS AND CHEMISTRY
      and Two Less Hard and derived from the 2 first ones: GEOLOGY and BIOLOGY

      Coming back to CR, then, how to solve Josh’s dilemma?
      In my opion the best is to go to intermediate longevity species….and that huge effort has already been done and WILL NEVER BE REPEATED ( concernibg rhesus this last sentence is rge only thing in which I agree with the clearly biased for his e onomic interests in 2013 Aubrey declared at Madrid Phylosophy Faculty UCM invited by me extending his presentation to 2,000 UCM Proffessors!

      CR in rhesus macaques (max. longevity around 35 years), 2 experiments published years ago
      1. Aubrey (scandalously biased) only considered Mattison et al. Nature 2012 (GOVERNMENTAL CONTROLLED NIH STUDY).
      2. Richard Weindruch Wisconsin University Primate Center directed experiment (I consider Richard the highest scientific “authority” worldwide withou any discussion posible): Coleman et al. Science (2009)

      Both studies agree that CR in Rhesus significantly decrease/delay incidence of degenerative diseases. But only Richard experiment showed inprovement in longevity (experiment not finished to max. In Coleman Science 2009.).
      I suggest you to read both papers plus a third one (in 2014) signed by both Coleman and Mattisson trying to ascertain why longevity outcome was different in both studies.
      After your detailed reading FROM TOP TO BOTTOM. Please read both papers IN FULL , NOT ONLY THE ABSTRACT! (you will not be so tired it is only 2 papers: I read 10,000 IN FULL in my whole life and perhsps that is why finally I discovered the gene ndufv2 responsible for mitROSp and around 1/3? Zof aging rate?
      I did read Mattison and Coleman papers in full and more than once in my life. In my opion both experiments have design problems but….if I must choose one…..I CHOSE COLEMAN .
      The implication is that in my opion the Aubrey de Grey argument about CR impossibly selecting for increased human longevity is flawed.
      No doubt De Grey is intelligent enough to understand that he must dismiss/ignore Coleman’ s paper (as he scandalously did at Madrid even after me -co Chair and co-organizer of the of his talk recorded in TV still now available on the web) . If he considers Coleman, then his ONLY THEORETICALLY BASED prejudice falls down.
      And do not forget that Aubrey de Grey IS NOT A SCIENTIST he is, as he always claimed while (unfairly) despising both geriatricians and GERONTOLOGISTS! , AN ENGINEER!
      Of course he is that! And that is why he is so wrong about Aging, an obiously biological and thus scientific subjetc

      Engeneers please better stay doing radios, bridges and the like but not give opiion on animals which they absolutely ignore how ate they builded up inside. (Aubrey is an ignorant without even a biology degree. Do not give money to that cheater. That is my uninterested advice.

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