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 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.

113 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.


  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.


    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:


      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.”

      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.”


      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:


            GUSTAVO BARJA
            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>>>

        • 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:


          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


      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


      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

        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.


  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

  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:

        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:

      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.


            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:

            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>>

        • 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??

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