214 replies to this topic

[DLR]

Thanks Evax for your explanation about immunity and CR. Talking about exercise, I thought most long-term CR practitioners exercise moderately. Most (if not all) books on CR emphasise the need to exercise. Is this something we all agree with?

[xEva]

Surely I even go a step further and claim that, in the long run, upping exercise may not necessarily increase the demand for calories (after the adaptation phase, which may be bumpy).

It was recently shown that, in humans, the levels of FGF21, a "starvation hormone" that extended life in mice by 30% without food restriction, are increased with regular exercise. FGF21 expression is induced in various tissues in response to fasting, exercise, and cold and leads to a very efficient management of resources, which includes upregulation of mitochondrial metabolism. This hormone may be the major player in paradoxical states in anecdotal reports characterized by low calories and high physical activity without the feeling of hunger.

The speculation is that FGF21 extended the lives of at-lib mice by reducing circulating concentrations of IGF-I by ~50% without causing a corresponding decrease in growth hormone concentrations.

For refs, see this thread: http://www.longecity...fespan-in-mice/

Edited by xEva, 28 October 2012 - 02:03 PM.

[xEva]

Cool! Michael just posted this on another thread:

FGF-21 (Fibroblast Growth Factor 21), a hormone shown to extend lifespan in mice by 30% without food reduction

Despite what both the popular press and even the abstract of the paper has said, the FGF21-Tg mice did, in fact, reduce their food intake: food intake is reported in g food/g mouse/3days, and is unchanged or even slightly increased in Tg vs WT mice -- but body weight was reduced by ~1/3 in males and by even more in females, so actual food intake was also cut by >30%. (Despite the widespread misunderstanding, long-term CR does not reduce food intake per unit of metabolic mass). And lifespan was increased by ~30%.(3)

As Alex Pickering has pointed out on the CR list, prima facie, a 30% reduction in food intake and a 30% increase in lifespan sure looks like (not-so-)'crypto-CR.' It's at least possible that this reduction in Calorie intake is entirely secondary to dwarfism imposed by overexpression of FGF21, and plays no role in its life-extension effect; it's also entirely possible that the reduction in Calorie intake is entirely responsible for the effect. Or, that 'crypto-CR' accounts for most of the benefit, with some additional effects specfic to the extra FGF21. But 'crypto-CR' is the null hypothesis, and this study is consistent therewith.


Reference
1: Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff
MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. elife.
2012;1:e00065. doi: 10.7554/eLife.00065. Epub 2012 Oct 15. PubMed PMID: 23066506;
PubMed Central PMCID: PMC3466591.

So, the mice have restricted themselves voluntarily in response to FGF21. Just as I have been saying all along: fasting and exercise in cold whether makes you feel energetic and takes away the hunger. What happens to the calorie count then?

[Brain_Ischemia]

Aren't Hispanics shorter on average? Naturally lower growth factors might have something to do with it.

FWIW, I am hispanic and 5'5"; some aspects of my pre-CR anthropometry are within 5th percentile of US adults (as per NHANES). Extended family has similar body type; history of deaths (@~median life expectancy) due to diabetes, alcoholism, cardiovascular disease (as opposed to cancer).

[Guest]

It's now a couple of month since the devastating preliminary results from the NIA-trials hit the news.

Michael - possibly the most knowledgeable authority in this regard - still did not post any analysis of the issue, and be it just a general direction or summary of which specific points prevent a conclusive evaluation at the moment. Therefore, in the light of the monkey-trials and the shocking silence of the CR-Society members (indicating their lack of comprehending the NIA outcome), I have to assume, that gerontologists were rigth: evolutionary, CRON is more a "survive a bad season" thing, which for long lived organisms does translate into a handful of month of live extension at best, while it prolonges the life of short lived animals considerably. The shorter the lifespan, the higher the gain in life expectancy percentage wise - so going from yest cells over fruit flies, mice and monkeys up to humans, CR becomes increasingly useless.

I can't understand how everyone just ignores the NIA-results. Following CRON has always been a matter of carefully analysing the scientific studies - that's how the effect was considered real and relevant in the first place. CRON-regimes were adjusted according to scientific findings, while ultimately it was unclear whether it prolongs life in humans or whether the gerontologists have a point - this uncertainty was part of the bet. To resolve the uncertainties the monkey studies where implemented. Today - decades after their start in the 1980s - we don't see the clear results most CRON adherents expected, to the contrary, we see no effect at all.

Don't get me wrong. I acknowledge of course that the effects on many biomarkers of health are real and despite not doing much for lifespan it can still increase healthspan. But personally I'm in it for the lifespan effect. If this effect is just not there it doesn't make sense for me to maintain my CRON-diet any longer. Of course I am not going to be overweight, but having flexibility in my eating patterns and not having to count every calorie adds to life quality considerably - especially if it doesn't matter for my life expectancy. At least the results indicate, that at BMI 22-23 I'am going to live as long as with BMI 18-19.

I am going to eat pizza tomorrow. On top of my (formerly) regular CRON-calory-budget. And I'll do it again and again (over a couple of days, that is).

[Nootropic Cat]

Hold on a second. The controls were on CR. The controls lived unusually long. Do I have this wrong?

[Guest]

Hold on a second. The controls were on CR. The controls lived unusually long. Do I have this wrong?

Yes, the NIA-researches stated, that measured against their initial baseline, monkeys in the control group started to eat less calories later in the trial. However, the CRON-monkeys were still considerably more caloric restricted than the controls - at the very least this says, that anything beyond slight CR has no additional effect in long lived species. If we consider this message to be inconsistent with prior positions (meaning that the level of CR should be related to the extend of the life span effect) it is easy to deduce that there is no effect of the slight CR to begin with.

Add to this the fact, that the diet in the Wiscon-study (the sister study to the NIA study) is crappy, basically sugar with vitamin pills, and add to this their (the Wisconsin guys) way of elminating half of the CRON-death from the statistic. Suddenly the life extension result the primate center reported seems questionable. Back then I gave it the benefit of a doubt, but considering the mortality in the NIA trial published in August it has become untenable to clinge to the notion of CRON in long lived species.

[scottknl]

Well, TFC, I have to say that I don't think your decision is a good one. CRON produces excellent results warding off diseases like heart disease, diabetes, stroke and cancer and seems to make a good firewall against alzheimers disease too. It's worth it just for those effects alone. As a treatment for those diseases it's more powerful than any drug known so far.

The NIA experiments appear to be poorly designed in many ways and the WNPRC study also has lots of flaws, so I guess we're not going to get any real answer from those. If you look on the good side, CRSociety members haven't been passing away. Most are in excellent health and will likely live very long lives even if they only hit the upper end of where the seventh day adventists (SDA) age range is. All in all many of them stand a chance to live long enough to hit the singularity even if only by the SDA measure of lifespan.

For anecdotal evidence, Matthew Lake seems to be retaining his youth as do several other CRONIES such as Joseph Cordell and David Fisher. And my own experience is that aging seems to have stopped for me. So I'd say the jury is still out.

[Guest]

To clarify, I am not going to be overweight now, but rather stay at the low-normal end of the BMI range (I was far from being overweight to begin with before CRON) and I am not going to engage in drinking soft drinks, highly processed/sugary food etc. . Also I do not smoke, get plenty of sleep, get daily exercise and I do not normally drink alcohol (though maybe I should start on that). Those factors alone put me into the 1% bracket of people with the most healthy - if you want: "anti aging" - life style. And I believe that most CRSociety members also follow this general life style, give or take the exercise, so it shouldn't be suprising seeing them as a healthy bunch of people.

Does CR give extra years on top of that in humans? The design of the studies seems to be flawed in some important respects. But still, given the theorised considerable contribution of CRON it is suprising not to see any effect at all in the NIA study. Nothing. Nada. It's just not there. The Wisconsin study had an effect after discounting half of the monkey death in their analysis, who may or may not be correctly labeled "age related" and "non-age related" - we would have needed a third party to evaluate the monkey bodies and their causes of death.

On the other hand the alternative theory, among others proposed by Aubrey de Grey, is the evolutionary "bad season" adaption, whereby long lived organism do not benefit from CRON in terms of (maximum) life span. This hypothesis has some plausibility and it takes experiments to test it. And given the decreasing effect of CRON we see in moving from yeast cells to fruit flies to mice, the monkey studies appear to imply that if you picture the relative CRON-lifespan effect against the normal life expectancy of organisms you will get a decreasing curve which bottoms out for long lived species.

It is now the duty of the CRON proponents to add to the disuccsion and refute this gerontologist's conclusion. But they are suprisingly silent.


If we would have to conclude, that the NIA/Wisconsin studies are worthless and should be discarded I have an alternative idea. We take an organisms with intermediate life spans (say, pigs), agree on the study design, choose 3 or 4 centers to conduct a large scale experiment each, and wait 7-9 years. If we see a further decrease in CRON-gains, which are compatible with the "bad season"-theory, I'd say that we do not need more monkey studies to conclude that CRON will be ineffective in humans. Pigs are cheaper to maintain than monkeys and runnning a study for 10 years is cheaper than a 30-year study - therefore funding it should be possible.

[scottknl]

TFC, as I noted before, the jury is still out on whether CRON adds the extra years in humans. I agree with your comments on the NIA and Wisconsin studies. Experiments have already been done with an intermediate species: dogs. It showed that CRON provided an extra 1.8 years in Labrador retrievers. It just wasn't done in a multi center setting at a large scale.

Effects of diet restriction on life span and age-related changes in dogs.

Kealy RD, Lawler DF, Ballam JM, Mantz SL, Biery DN, Greeley EH, Lust G, Segre M, Smith GK, Stowe HD.

Source

Pet Nutrition Research Department, Nestle Purina Pet Care Co, St Louis, MO 63164, USA.

Abstract

OBJECTIVE:

To evaluate the effects of 25% diet restriction on life span of dogs and on markers of aging.
DESIGN:

Paired feeding study.
ANIMALS:

48 Labrador Retrievers.
PROCEDURES:

Dogs were paired, and 1 dog in each pair was fed 25% less food than its pair-mate from 8 weeks of age until death. Serum biochemical analyses were performed, body condition was scored, and body composition was measured annually until 12 years of age. Age at onset of chronic disease and median (age when 50% of the dogs were deceased) and maximum (age when 90% of the dogs were deceased) life spans were evaluated.
RESULTS:

Compared with control dogs, food-restricted dogs weighed less and had lower body fat content and lower serum triglycerides, triiodothyronine, insulin, and glucose concentrations. Median life span was significantly longer for dogs in which food was restricted. The onset of clinical signs of chronic disease generally was delayed for food-restricted dogs.
CONCLUSIONS AND CLINICAL RELEVANCE:

Results suggest that 25% restriction in food intake increased median life span and delayed the onset of signs of chronic disease in these dogs.
PMID: 11991408 [PubMed - indexed for MEDLINE]

and more recently

Diet restriction and ageing in the dog: major observations over two decades.

Lawler DF, Larson BT, Ballam JM, Smith GK, Biery DN, Evans RH, Greeley EH, Segre M, Stowe HD, Kealy RD.

Source

2 Research South, Nestle Research Center St Louis (NRC-STL), Checkerboard Square, St. Louis, MO 63164, USA. dennis.lawler@rdmo.nestle.com
Erratum in

• Br J Nutr. 2009 Apr;101(7):1112.

Abstract

This report reviews decade two of the lifetime diet restriction study of the dog. Labrador retrievers (n 48) were paired at age 6 weeks by sex and weight within each of seven litters, and assigned randomly within the pair to control-feeding (CF) or 25 % diet restriction (DR). Feeding began at age 8 weeks. The same diet was fed to all dogs; only the quantity differed. Major lifetime observations included 1.8 years longer median lifespan among diet-restricted dogs, with delayed onset of late life diseases, especially osteoarthritis. Long-term DR did not negatively affect skeletal maturation, structure or metabolism. Among all dogs, high static fat mass and declining lean body mass predicted death, most strongly at 1 year prior. Fat mass above 25 % was associated with increasing insulin resistance, which independently predicted lifespan and chronic diseases. Metabolizable energy requirement/lean body mass most accurately explained energy metabolism due to diet restriction; diet-restricted dogs required 17 % less energy to maintain each lean kilogram. Metabonomics-based urine metabolite trajectories reflected DR-related differences, suggesting that signals from gut microbiota may be involved in the DR longevity and health responses. Independent of feeding group, increased hazard of earlier death was associated with lower lymphoproliferative responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen; lower total lymphocytes, T-cells, CD4 and CD8 cells; lower CD8 percentages and higher B-cell percentages. When diet group was taken into account, PWM responses and cell counts and percentages remained predictive of earlier death.
PMID: 18062831 [PubMed - indexed for MEDLINE]

Edit:
Also Pigs are not a good candidate for lifespan experiment because they also live rather long lives which means an expensive experiment. The average life span of a wild pig is 25 years. The life span of a domestic pig tends to be 10 - 15 years. With some CR, you could be close to 40 years again and no closer to determining that CR works in humans. Also pigs are classed as "highly intelligent" which means that you could have similar troubles as with the primates.

Edited by scottknl, 08 November 2012 - 06:09 PM.

[DR01D]

TFC

I practice CR for the healthspan effect. I have no intention of giving it up because I think it has a decent chance of getting me to 100 +/-.
However I own a landscaping company so I do LOTS of physical work. Plus I lift weights 5 days per week. So my version of CR includes enough calories for that level of activity. I call it CR because my body fat is 12%+/- and I'm hungry much of the time including right now. Most nights I go to bed a little bit hungry.

I would encourage you to keep doing CR. But eat enough to have a physically active life. Oh yeah and don't eat pizza. It's processed garbage!

Good luck with your decision!

[centagen]

Hasn't it been shown that CR does not really work except in those who consume a lot of unhealthy food and toxins? Less calories means less toxic build up. More recent studies seem to indicate that with an excellent diet CR will not help.

[nowayout]

I practice CR for the healthspan effect. I call it CR because my body fat is 12%+/- and I'm hungry much of the time including right now. Most nights I go to bed a little bit hungry.

I am wondering what CR really means in this context. Can it be reduced to a combination of BMI/fat percentage number? What of someone who has the same build and BMI and fat percentage as you do, but doesn't feel hungry as much as you - would you consider them to be on CR?

[Guest]

TFC, as I noted before, the jury is still out on whether CRON adds the extra years in humans. I agree with your comments on the NIA and Wisconsin studies. Experiments have already been done with an intermediate species: dogs. It showed that CRON provided an extra 1.8 years in Labrador retrievers. It just wasn't done in a multi center setting at a large scale.

[...]

Edit:
Also Pigs are not a good candidate for lifespan experiment because they also live rather long lives which means an expensive experiment. The average life span of a wild pig is 25 years. The life span of a domestic pig tends to be 10 - 15 years. With some CR, you could be close to 40 years again and no closer to determining that CR works in humans. Also pigs are classed as "highly intelligent" which means that you could have similar troubles as with the primates.

Unfortuantely I am not aware of a literature review that systematically evalutes the life span effect of CRON in a broad range of species, e.g. how does the effect compare between single celled organism over nematodes, to flies up to mice and long lived mammals. I remember that for simple and short lived organisms it was very significant (I believe more than doubling lifespan in nematodes). For rats it was up to 50% if you start early in life. A life extension of 1,8 years in Labradors is certainly less than 50% - maybe 15%. Also we have to bear in mind, that generally more complexe and longer lived species can not bear the same level of restriction as simpler ones. A mouse would die on the level imposed upon yeast and nematodes for optimal life extension. Also primates would not benefit from a level of CR optimal for rodent life extension.

This makes it difficult to define a common metric to compare interspecies CR-outcomes. Obviously the relative maximum life span gain (percentage wise) from the species-specific optimal level of CR is much smaller in very long lived organisms than in very short lived organisms. We knew this already, and it can be at least partly attributed to the fact, that simpler organisms can bear a higher level of CR. The question then is: how does the optimal level of CR for optimal life extension decline? Is 20% CR for primates - always compared to a normal lean monkey, not a sugar fed overweight one (!) - optimal or already to severe to extend life span? And will there be at least the 1,8 years seen in Labradors, even if no human starts CRON 8 weeks after being born, but normally after maturation - so at age 18 or older?

Put together the diminishing level of bearable CR in higher animals and by definition the late-onset CR (after maturation) in humans as opposed to mice and dogs, serious doubts about the CR-effect for us are justified, especially after the monkey studies, even as flawed as they are. Those dobust are justified even if we neglect the "bad season"-adaption argument from gerontologists.


Maybe it can work this way: take a fruit fly, rats and dogs and put them on the same level of CRON (the one optimal for dogs) and observe whether we see a diminishing response of CR-life-extension (%-wise) to "normal" life span. Then extrapolate and analyse what the effect would be for humans (hyothetically speaking, as we do not intentionally put Babies on CR). Given the outcomes we can('t) rule out the "bad season" hypothesis.

On top of that you have to consider, that optimal results in mice etc. are achieved when putting them on the diet soon after their birth and you are welcome to reflect upon what this means for humans.



I really wish that Michael could comment on this.


@DR01D: I practise a healthy life style for the healtspan effect. I am doing (or better: will have been doing) CRON to get life extension on top of that.

[nhenderson]

I can guess, but what exactly is the "bad season" hypothesis?

[scottknl]

TFC, Why would you expect 50% life extension in dogs that were only restricting their energy input by 25%? In general if you restrict calories by x% over a full lifetime, then you get x% increase in lifespan. Also if you start CR later in life, then your benefit is reduced as well by the proportion of your life already lived. I don't think anyone has made an organism live longer than twice it's normal lifespan by strictly using CR techniques although I'm not so sure in the yeast studies since they don't report %CR, but rather % of glucose in the growth medium.

As for the limit of tolerable CR, you can't hear the little yeast cells scream in hunger, so you can work it harder. It seems kind of cruel to try CR at 65% in a dog. 35% CR (my own usual target) is doable without too much drama in humans and animals, so 25% is a walk in the park.

Perhaps the key to figuring out how long something will live is in this:
"diet-restricted dogs required 17 % less energy to maintain each lean kilogram"
and the dogs lived ~18% longer.

[DR01D]

I practice CR for the healthspan effect. I call it CR because my body fat is 12%+/- and I'm hungry much of the time including right now. Most nights I go to bed a little bit hungry.

I am wondering what CR really means in this context. Can it be reduced to a combination of BMI/fat percentage number? What of someone who has the same build and BMI and fat percentage as you do, but doesn't feel hungry as much as you - would you consider them to be on CR?

CR isn't precisely defined or understood. For me it means eating just barely enough to keep myself working and active. No more, no less.

Before CR I was lean and very active and I still had high/normal blood pressure. If my numbers were just a few points higher I would have been on BP medicine. Last I checked my blood pressure was 106/72. So for that and other reasons I can say that eating just barely enough has a positive impact on health.

[Guest]

I can guess, but what exactly is the "bad season" hypothesis?

It's what you probably think it is (though gerontologists do not use that term). Basically it states, that the CR response is a response to famine situations, enabling organisms to endure e.g. a hard winter to procreate at a later date. For a more detailed outline of the argument see:

http://www.ncbi.nlm....d?term=15711074

Put simply: the CRON-proponents argue, that the relative (percentage wise) life extension we see in mice (e.g. 50%) at a certain level of CR largely translates to humans. The CRON-sceptics in turn argue, that the absolute level of life extension (e.g. 1-2 years) is the dominating effect.

Of course in case of humans we have to consider, that CRON is not started untill people are already grown up and the CR-level humans can endure (hypothetically speaking) is certainly less than 50% - compared to normal lean controls. Therefore, even if CRON-proponents are right, we won't see a 50% life extension in humans - this is what you can see at 50% CRON implemented directly after birth in rats. The Labradors had 1,8 years - or roughly 15% - life extension after 25% CRON implemented after birth. We don't know if they would hve lived longer at a higher level of CR, though arguably 50% CR right after birth would have been damaging (compared to normal lean controls).

So: are those 1,8 years relevant? or the 15% life extension?



@scottknl: I didn't said to expect 50% LE from 25% CR. I meant to say, that the optimal level of CRON in dogs likely won't be sufficient to extend their life 50%. Also 35% CRON (compared to normal lean humans) seems to be excessive. For a non-physically active human with a BMI of 22 who needs 2000 kcal a day, a 35% CRON translates to 1300 kcal a day. I doubt that this is life extending in the long run.

[scottknl]

Regarding the numbers from the study on Labrador Retrievers. I did a little figuring on how much the Labs should have lived. Starting at 8 wks and with the controls living 11.2 years, with a 25% DR one would expect a lifespan of 13.97 years. The study actually showed 13 years lifespan which is 93.1% of the expected lifespan. I found the numbers in this follow on study from the authors:http://jn.nutrition....136/7/1844.long

Regarding my CRON numbers, I do have a sedentary job as a computer jockey, so I don't need as many calories as you do. I do exercise regularly and have pretty good physical performance for my age. And I successfully maintain a BMI of 20 with a body weight of 155 lbs for my 6' 2" frame on a calorie intake of around 1750 calories per day. Metabolism does seem to vary widely from person to person, so one shouldn't expect everyone who's my height to do everything the same as I do. My experience with my health and parameters are typical of the most healthy CRON practitioners. I'll be happy if I can achieve even 75% of the predicted CRON life extension.

[Guest]

I take it that you imply, that generally a certain level-percent of CR could mean a certain percent of life extension, e.g. 50% CR = 50% life extension or 30% CR = 30% life extension.

Obviously this is not generally true for all species, though in lab mice the relationship roughly holds. Of course 100% CR does not mean 100% life extension even in mice - so, there are certain limits.

We simply do not know the general response to CR - is it indeed a percentage relation? Or more an absolute-number game? The 25% CR-from-birth-dogs lived 1,8 years longer; compared to 11,2 life span for the controls this is a 16% life extension (though the authors report median life spans, not average ones, which can blurr the true effect). Would dogs on 50% CR from birth would have lived even longer? There are reasons to assume that this would not have been the case (longer lived organisms seem to be unable to benefit, or just to survive, on the maximum benefical CR-level of shorter lived organisms).

Does this mean that 25% CR for humans from birth on leads to 16% life extension? We don't know. Does it mean that it leads to 1,8 years life extension? Again we are uncertain. The monkey-studies were supposed to clarify this. Both studies have serious problems.

The Wisconsin one had the controls likely somewhat overfed and the diet consists largely of simple sugar. So the CRed monkeys to some extend just avoided obesity (instead of being CRed compared to normal lean controls) and ate less of the crappy food. Still they had to discount a lot of the death to statistically obtain the life extension effect. Whether all death have been correctly labeled "ageing related" and "not ageing related" is a matter of debate and something we can not clarify. The NIA study has some strange biomarkers in the CR-group, which are partly inconsistent with what we know about the CR-response (and actually observe in rats, humans and short term monkey studies). Also the controls themselfs ended up eating less and effectively did a low level of CRON. This makes it hard to interpret the results. Still: there was no life extension effect in the CRON-monkeys at all.


Of course everyone is free to draw their own conclusions from this. I would be especially interested in the conclusions from Michael or maybe the Fontana-group. At the moment at least for me personally the NIA-study did shift the balance of evidence in favour of the CR-sceptics. I would likely return to CRON if someone makes a really compelling argument for it, particularly concerning the monkey-studies. Or maybe if in 10 years a follow up study in other organisms gives additional clues. Untill then I am upping my calories a bit and stop counting them. And I did eat Pizza today (this won't be a daily thing of course).

Edited by TFC, 10 November 2012 - 04:09 AM.

[Mind]

Sure there were flaws in the primate experiments, but I still figured there would have been some statistically relevant lifespan effects observed. There wasn't. The healthspan effect is certainly a good bonus to consider, but I am with TFC on balancing health and happiness. I am probably a little below the standard caloric intake (around 1800 to 2100 per day) and I am happy with the amount and variety of food I eat. Just 200 or 300 calories less and I am hungry and irritated at times through the day. I figure that for my age (41), there is high enough probability of technological (medical) progress for me to not do true CR, and instead rely upon a good nutritious diet, lower stress lifestyle, and the enormous health benefits of exercise for increases in healthspan. For me, exercise is a lot more fun than CR.

[pmcglothin]

Those who are following this topic may be interested in the CR Society response:

http://www.crsociety...ia_monkey_study

I hope you find it beneficial.

Paul

[DR01D]

I just read the response from the CR Society and I agree with this statment.

Exercise is not part of the regimen of the monkeys in any of the nonhuman primate studies examined here, even though moderate exercise is well documented to be important for health and long life in human primates¹¹. In fact, exercise activates the ancient energy sensor adenosine monophosphate kinase (AMPKinase)¹², a major facilitator of calorie restriction benefits¹³. The sedentary lifestyle of the rhesus monkeys in the studies would make activation of this biochemistry unlikely.

Living in a cage is unnatural and unhealthy. It's credible that this could counteract some or all of the benefits of CR.

[Guest]

Those who are following this topic may be interested in the CR Society response:

http://www.crsociety...ia_monkey_study

I hope you find it beneficial.

Paul

I miss a conclusion in the article. It appears to say inititally, that monkey studies conducted under the circumstances at Wisconsin and NIA deviate too much from "natural" conditions and therefore possibly can not tell much about CRON at all. The article proceeds by restating the facts already outlined in this thread without giving interpretations. Unfortunately this does not add to resolve our uncertainties.

I would be most interested in what in your opinion accounts for the DIFFERENCE in outcomes of the two studies. When the Wisconsin study arrived in 2009 it was hailed as evidence in favour of CRON (though Michael back then already pointed out some weaknesses). Without implying intent, it might appear, that as a response to the unfavourable NIA-study - which in principle is better designed that the Wisconsin one - both studies are now dismissed by the CR-society. This is the kind of selective perception already mentioned in this thread.

If the NIA-study would have reported a live extension-effect - would you have been equally critical about the study design and doubt its translatibility to humans based on housing conditions etc.? Or would you have hailed it as yet another proof that CRON works in long lived primates (aka humans)? Using a scientific mindset we have to take a neutral POV in assessing the methodlogy, irrespective of study-outcomes. I am not 100% certain that the discussion meets this standard.


Granted, given the biomarkers we know there is something odd going on in the NIA-monkeys. Still both, control and CR-monkey, have the same life style - so there would have been a factor that specifically affects the CRON-mechnism to offsett any CR-life extension effect, as both groups had the same life span. Or it could simply be, that CRON does not work in long lived primates. Your take. And remember to compare with normal lean controls with a healthy diet (say BMI 22 in human terms) and not overfed ones on a sugar diet.

[nowayout]

I just read the response from the CR Society and I agree with this statment.

Exercise is not part of the regimen of the monkeys in any of the nonhuman primate studies examined here, even though moderate exercise is well documented to be important for health and long life in human primates¹¹. In fact, exercise activates the ancient energy sensor adenosine monophosphate kinase (AMPKinase)¹², a major facilitator of calorie restriction benefits¹³. The sedentary lifestyle of the rhesus monkeys in the studies would make activation of this biochemistry unlikely.

Living in a cage is unnatural and unhealthy. It's credible that this could counteract some or all of the benefits of CR.

This is classical grasping at straws behavior on the part of the CR society.

[DR01D]

This is classical grasping at straws behavior on the part of the CR society.

I'm not part of the CR society. However Paul McGlothin's response was credible.

Sticking an animal in a cage all day (or sitting in front of a computer all day) could easily negate some or all of the benefits of CR.

Do some googling on "sedentary lifestyle" and "health". It's bad.

[Guest]

I'm not part of the CR society. However Paul McGlothin's response was credible.

Sticking an animal in a cage all day (or sitting in front of a computer all day) could easily negate some or all of the benefits of CR.

Do some googling on "sedentary lifestyle" and "health". It's bad.

Then how do you explain CR working in lab-mice? As of my knowledge they typically have only minor physical activity compared to wild mice.

Also it is fair to say, that we do not really understand the biochemical and metabolic pathways of the CR-response at the moment (therefore the Resveratrol/Sirtuin-disaster) - therefore claiming that lack of exercise specifically inhibits central CR-metabolic pathways is a very long shot based on superficial evidence, if any. Based on our knowledge (or lack of it) the statement "could easily negate some or all of the benefits of CR" is pure speculation and certainly not a reason to dismiss the studies.

[DR01D]

Then how do you explain CR working in lab-mice? As of my knowledge they typically have only minor physical activity compared to wild mice.

If lab mice had as much physical activity as wild mice CR would be even more effective.

It all comes down to evolution. Humans, monkeys, mice, etc. etc. were built to be physically active. A sedentary lifestyle is harmful.

We don't need a 30 year study to make that assumption. If you want to wait for that study to be published that's your prerogative.

In related news:
London will be final marathon for 101-year-old

Personally I think running 26 miles is kind of extreme. But this guy who also happens to practice CR is clearly pointed in the right, general direction.

Edited by DR01D, 20 November 2012 - 05:42 PM.

[Guest]

If lab mice had as much physical activity as wild mice CR would be even more effective.

It all comes down to evolution. Humans, monkeys, mice, etc. etc. were built to be physically active. A sedentary lifestyle is harmful.

We don't need a 30 year study to make that assumption. If you want to wait for that study to be published that's your prerogative.

You are specualting based on no evidence at all. Your are saying that lack of exercise SPECIFICALLY INHIBITS CR-METABOLISM. Remember, that both - CR-groups and control groups - had basically the same life style except amount of food consumed. Any harmful effects of sedentary lifestyle (which of course exist) would affect both groups equally and hence one would still expect to wittness a CR-lifespan effect.

That additional exercise would somehow enhance the global metabolic CR-response is at the moment highly speculative and it'll be hard to disentangle it from the positive normal-non-CR-related health benefit of exercise. On the other hand even without exercise we see 50% life extension in rodents - and considering rodents to be normally quite active species, the proposed specific anti-CR effect of non-exercise is apparently not that relevant.

Summary:

a) no one doubts, that lack of exercise is unhealthy

b) there is no conclusive evidence at all, that lack of exercise specifically inhibits CR-metabolism - so this argument shouldn't be used to dismiss the studies

[DR01D]

b) there is no conclusive evidence at all, that lack of exercise specifically inhibits CR-metabolism - so this argument shouldn't be used to dismiss the studies

Well... scientists somewhere in the world are devising a CR primate study that addresses the shortcomings in the latest studies. We'll get the results in another 20 or 30 years. In addition by then we'll have the results from dozens of other studies that will refine our understanding of how CR works.

In the meantime my money is on exercise + CR.

Why? Because evolution favored both.

If you want to do something different or wait for more research it's your prerogative.

Edited by DR01D, 20 November 2012 - 06:21 PM.