214 replies to this topic

[malbecman]

Interesting twist in the latest CR study of monkeys. This is from the National Institute of Aging study:

http://online.wsj.co...4017185860.html

[AgeVivo]

This is a big (bad) news for people practicing caloric restriction (CR).
Anyone sufficiently aware of the details of the CR monkey studies to guess why it extends lifespan at the university of Wisconsin in Madison, but not at the NIA?

[Mind]

The published research on the benefits of CR is vast. Non-beneficial outcomes are rare. The monkeys in this study did stay healthier longer, which is a good thing, and it seems to parallel health benefits seen in CR humans.

Is this one small chink in the CR research armor - sure.- but I doubt it will turn many CR practitioners back to more regular diets.

The most disconcerting thing I take away from this study is lower bone density. Late life bone fractures in humans are very challenging for longevity. Perhaps CRONies who get enough exercise will be able to maintain bone density.

Once again this reminds me of the perplexing population studies across several cultures on different continents showing slightly overweight people have a lower death rate on average. I speculated that it boils down to the human body having enough energy reserves to battle late-life diseases. A bit overweight people have energy stores to help recover. CRONies have none. This could be mitigated by aggressive supplementation and increased caloric intake by CRONies who happen to get infections or cancer late in life, but it might be difficult after a long time on CR. Just speculating.

[Chupo]

The NY Times says this about the Wisconsin study:

But even that study had a question mark hanging over it. Its authors had disregarded about half of the deaths among the monkeys they studied, saying they were not related to aging. If they had included all of the deaths, there was no extension of life span in the Wisconsin study, either.

I find it hard to believe they had the same rates of cancer though. The CR monkies should have had lower IGF-1. It makes me wonder if they were fed too much protein.

Edited by Chupoman, 29 August 2012 - 07:36 PM.

[Chupo]

Once again this reminds me of the perplexing population studies across several cultures on different continents showing slightly overweight people have a lower death rate on average. I speculated that it boils down to the human body having enough energy reserves to battle late-life diseases. A bit overweight people have energy stores to help recover. CRONies have none. This could be mitigated by aggressive supplementation and increased caloric intake by CRONies who happen to get infections or cancer late in life, but it might be difficult after a long time on CR. Just speculating.

It reminds me of this study:

Fat maintenance is a predictor of the murine lifespan response to dietary restriction.

Dietary' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/21388497']Dietary restriction (DR), one of the most robust life-extending manipulations, is usually associated with reduced adiposity. This reduction is hypothesized to be important in the life-extending effect of DR, because excess adiposity is associated with metabolic and age-related disease.

Previously, we described remarkable variation in the lifespan response of 41 recombinant inbred strains of mice to DR, ranging from life extension to life shortening. Here, we used this variation to determine the relationship of lifespan modulation under DR to fat loss. Across strains, DR life extension correlated inversely with fat reduction, measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63, P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan.

We identified two significant quantitative trait loci (QTLs) affecting fat mass under DR in males but none for lifespan, precluding the confirmation of these loci as coordinate modulators of adiposity and longevity. Our data also provide evidence for a QTL previously shown to affect fuel efficiency under DR. In summary, the data do not support an important role for fat reduction in life extension by DR. They suggest instead that factors associated with maintaining adiposity are important for survival and life extension under DR.

→ source (external link)

[AgeVivo]

The monkeys in this study did stay healthier longer

heathier longer but not lived longer => What did they die of, compared to the non-CR monkeys? I am always suspicious of health results when it is not a double blind study (treatment and health measures possibly involuntarily biased, I guess I'll have to find the time to read in details).

lower bone density. Late life bone fractures in humans are very challenging for longevity

Is low bone density and elevated risk of fracture recognised among CRONies?

[Vitor]

It would be very interesting to hear Michael Rae's opinion on this study.

[invictus8]

This is bad news... this study is better-designed than the U of W study (which removed half the monkeys in the sample).

[nowayout]

SOme other interesting quotes from the NYT article:

There were several differences between the studies that some have pointed to as possible explanations.
The composition of the food given to the monkeys in the Wisconsin study was different from that in the aging institute’s study.
The University of Wisconsin’s control monkeys were allowed to eat as much as they wanted and were fatter than those in the aging institute’s study, which were fed in amounts that were considered enough to maintain a healthy weight but were not unlimited.

...suggesting that there may be little benefit to reducing calories below that necessary to maintaining a normal weight.

The animals in the Wisconsin study were from India. Those in the aging institute’s study were from India and China, and so were more genetically diverse.

In those same years, though, studies in mice began indicating there might not be a predictable response to a low-calorie diet. Mice that came from the wild, instead of being born and raised in the lab, did not live longer on low-calorie diets. And in 2009, a study of 41 inbred strains of laboratory mice found that about a third had no response to the diets. Of those that responded, more strains had shorter life spans than had longer ones when they were given less food.
The response to that study was “absolute disbelief,” Dr. Austad said. “Even though the authors are well-respected calorie restrictors, people said the result was not interesting, that there was something weird about the mice.”

Possibly bad new for CR in people on average, given the large genetic diversity in humans. We are probably more analogous to wild-type genetically diverse mice/primates, in which CR does not appear to work on average.

As in inbred rodents, there is possibly a subpopulation of humans for whom CR will work very well, but of course we don't know who they are.

Edited by viveutvivas, 29 August 2012 - 09:12 PM.

[malbecman]

Once again this reminds me of the perplexing population studies across several cultures on different continents showing slightly overweight people have a lower death rate on average. I speculated that it boils down to the human body having enough energy reserves to battle late-life diseases. A bit overweight people have energy stores to help recover. CRONies have none. This could be mitigated by aggressive supplementation and increased caloric intake by CRONies who happen to get infections or cancer late in life, but it might be difficult after a long time on CR. Just speculating.

I think there is some truth to what you've said, Mind. My mother in law, while never a CRONie, has always eaten like the proverbial bird and been very thin. I"m guessing her BMI is ~16-18. Anyways, anecdotally, she
had a bad cold at age 68 which developed into pneumonia. She ended up so weak and thin that she had to go to the hospital and have an IV, etc. She didn't die but it was touch and go there for awhile and after it was all over, the
doctor told her to get rest, better and "go fatten herself up a little".

[stephen_b]

From Nature News: Calorie restriction falters in the long run.

One reason for that difference could be that the WNPRC monkeys were fed an unhealthy diet, which made the calorie-restricted monkeys seem healthier by comparison simply because they ate less of it. The WNPRC monkeys’ diets contained 28.5% sucrose, compared with 3.9% sucrose at the NIA. Meanwhile, the NIA meals included fish oil and antioxidants, whereas the WNPRC meals did not. Rick Weindruch, a gerontologist at the WNPRC who led the study, admits: “Overall, our diet was probably not as healthy.”

My goodness -- 28.5% sucrose?!

The article continues:

“When we began these studies, the dogma was that a calorie is a calorie,” Ingram says. “I think it’s clear that the types of calories the monkeys ate made a profound difference.”

Edited by stephen_b, 29 August 2012 - 10:37 PM.

[nhenderson]

Indeed it is bad news.

So basically we have the Spanish study in the 50's--elderly human population, and the two monkey studies. Probably the best study of the bunch is this last one. Any hot shot stat folks out there? Given the genetic variation, was the sample big enough?

Does anyone know of CR studies on longer lived mammals, say dogs?

[Lyle Dennis]

If anyone needs the full text reference, it is here:

http://extremelongev...oads/rhesus.pdf

I had a slightly bigger dinner than usual tonight

[scottknl]

I'd say the "Figure 3 | Incidence and estimated proportions of age-related diseases" tells the story here. Their diet was in some way causing poor cardio and glucoregulatory health in the animals. Overall it looks like between ages 13 and 26 were a high death period for the young cohort and 25+ was (as expected) a high deaths period for the older cohort. In the wild, one might expect the smaller animals to die when in a competitive environment with larger ones, but not in the lab surely?

Diabetes:
In other CR trials diabetes was non-existent yet in this one we have 2 young animals with diabetes before the age of 22. This should only be possible if the animals were stealing food or catching food from a cage above? Yet the diabetes performance was the best result from the 3 big disease causes.

Cardio:
Having 3 young CR animals with cardio problems between ages 18 and 25 is just crazy when the other studies have shown an almost complete immunity from CVD. I wonder if the same 2 animals with early diabetes also developed heart problems a year or so later?

Cancer:
It was completely prevented in the young CR animals so far which is a good performance, but wow --- look at how the old CR group are dropping like flies between 25 and 30 years of age from cancers. Must be too much protein or IGF-1 in the CR diet for those oldsters. Or there's a radiation source around the animal quarters somewhere!!! I would have expected about 1/2 as many deaths from cancer for CR based on the other animal studies where around 66% of cancers were prevented.

I suppose we won't have to wait much longer to see results from the WNPRC. I hope they don't also disappoint.

[niner]

Cancer:
It was completely prevented in the young CR animals so far which is a good performance, but wow --- look at how the old CR group are dropping like flies between 25 and 30 years of age from cancers. Must be too much protein or IGF-1 in the CR diet for those oldsters. Or there's a radiation source around the animal quarters somewhere!!! I would have expected about 1/2 as many deaths from cancer for CR based on the other animal studies where around 66% of cancers were prevented.

If the CR-induced suppression of cancer was seen in rodents or other cancer-prone animals, might it be the case that CR was correcting a defect in those animals that is taken care of endogenously in the much longer-lived primates?

[Guest]

IMHO this is a major blow to the CRON life extension theory. I will still put my pizza party on hold untill a full evaluation is provided, but things certainly do not look that good. On the other hand I am not so concerned about the wild-type vs. clonal type issue. To the contrary, for scientific validity you would want to have genetically identical animals - like putting identical twins on different diets to see who does better in terms of life expectancy, an effect that can be masked by good or bad genes in genetically diverse people. Only problem is, that most clonal types in mice are disease types, so dietary results can be biased.



@Michael: if you could summarize discussion results from the CR-society maillingslist it would be greatly appreciated

[Matt]

It's not that bad because many of us knew the issues in these studies years ago, which were brought up by the researchers themselves. I need to read the paper again and go over some things and I'll comment on it. Here's some comments from Fontana though;

""The old idea is that a calorie is a calorie. When you restrict it, you have a beneficial effect. Our data and other data suggests this isn’t the case. The quality of the diet matters,” Fontana continued."

“If you’re in a single cage for your whole life, and are a highly intelligent animal like a primate, deprived of contact with other peers, and on top of that you’re calorically restricted — can you imagine the psychological depression issues that will ensue?” said Fontana. “And we know the hypothalamus in the brain is a major regulator of many downstream metabolic factors.”

"Fontana pointed out that key hormonal changes found in both calorie-restricted mice and humans were not detected in either group of monkeys, an absence that he blames on their relatively high-protein diet.

also

"The female monkeys "P50.0276).Specifically, CR males had lower triglycerides than control males. By contrast, CR females
had higher triglyceride levels than control females""

The rate of age-related disease was very different in both rhesus monkey studies also. In the Wiisconsin the CR monkey appear to be healthier throughout their life.



Yeah it's disappointing... but it's not a surprise result either. Anyway I'll post properly on it later

Edited by Matt, 30 August 2012 - 03:27 AM.

[Chupo]

Alex Pickering's comments:

I just read the fulltext and here are my initial comments:

The conclusions being reported are in reference to the cohort that began CR at older ages. Older aged rats put on CR similarly do not live longer. The age-related survival curves for the monkeys that started CR either at young or adult ages are still all in the 60-80% range, which the authors acknowledge does not answer whether or not CR extends monkey lifespan when started early in life. However, there is no significant survival advantage for the CR group at the moment.

The monkeys are not an inbred strain: they are genetically heterogeneous. The authors acknowledge the recent results showing that certain strains of mice have shorter lifespans when put on CR.

Nothing that was immediately obvious to me (except possibly the above) suggests that the authors conclusions are questionable. The controls were not fully ad libitum - the design was more akin to Walford's studies in which the control group is slightly restricted and the CR group is fed 30% less than the control group. In terms of length of life comparison to the University of Wisconsin study:

"*In an estimate of NIA’s current data (as of 1 December 2011) to the published WNPRC data summarized as of 22 February 2008 and reported in ref. 5, NIA monkeys, both control and CR, may have a lifespan advantage comparable to the WNPRC CR monkeys*."

In other words, the authors report that the lifespans for their control and CR cohorts are comparable to the lifespan for the CR cohort from the Wisconsin primates. I have not personally verified this.

I'll leave you with the blurb given with regards to health parameters:

"*Although they eat less (Supplementary Table 2) and weigh less13, young-onset CR monkeys lack many of the expected CR benefits. Fasting serum glucose levels were not significantly lower in the CR monkeys compared to control (Fig. 2c), and only the CR males had somewhat lower triglycerides compared to respective controls (P = 0.051) (Fig. 2d). However, in a ligature-induced model of inflammation in the oral cavity1, we have shown an improved immune response in young-onset CR monkeys and beneficial effects in T cells isolated from adolescent-onset males2*.

*The incidence of cancer was markedly improved in young-onset CR monkeys (P = 0.028 compared to controls); in fact, neoplasia has not been identified in any monkey from this group (Fig. 3a). In contrast, five of the six cases in young-onset control monkeys were considered the cause of death with a mean age at diagnosis of 22.8 ± 1.7 years. Glucoregulatory function was also improved in CR monkeys (Fig. 3a). However, two cases of diabetes have been diagnosed in CR monkeys; thus, the prevention of obesity did not prevent the occurrence of insulin-dependent diabetes and further investigation of the aetiology of such cases is of interest. Interestingly, CR did not reduce the incidence of cardiovascular disease as was reported in the WNPRC colony. Our findings are based on tissue pathology because these diagnoses were identified after death*."

http://arc.crsociety...ad.php?2,211800

Edited by Michael, 01 September 2012 - 05:58 PM.

[AgeVivo]

CRON = CR + ON ≈ ON ?

[cesium]

If the CR-induced suppression of cancer was seen in rodents or other cancer-prone animals, might it be the case that CR was correcting a defect in those animals that is taken care of endogenously in the much longer-lived primates?

My guess would be that this study suggests that the endogenous antioxidant system in primates is already optimized to the point to where reducing ROS any further via CR isn't going to make much difference, as far as maximum lifespan is concerned anyways.

[Matt]

I need time to go over the paper again and review other papers related to the study. But just my initial thoughts on the study below:

Although they eat less (Supplementary Table 2) and weigh less13, young-onset CR monkeys lack many of the expected CR benefits. Fasting serum glucose levels were not significantly lower in the CR monkeys compared to control (Fig. 2c), and only the CR males had somewhat lower triglycerides compared to respective controls (P50.051)

"CR did not reduce the incidence of cardiovascular disease as was reported in the WNPRC colony"

"The incidence of cancer was markedly improved in young-onset CR monkeys (P50.028 compared to controls); in fact, neoplasia has not been identified in any monkey from this group"

"NIA diet formulation supersupplemented the control monkeys." (might contribute for little difference between survival).

"Although CR has not increased mean or maximum lifespan relative to control, 50% survival for the females is 27.8 years and 35.4 years for the males, exceeding the ,27 year median lifespan previously reported for monkeys in captivity"] (I found this interesting as it's usually females that live much longer).

Lack of activty/exericse might have also played a factor. CR'd males would have mroe muscle mass which might have accounted for better metabolic health, possilbly. The lack of certain changes that are seen in rodents and even in HUMAN studies suggest to me that not just the NIA study had problems (there was also some indications the monkeys were depressed and throwing their food way so the level of CR was decreased between the groups.). There was a difference also in how the both studies approached CR. The Wisconsin study they got each monkey's ad lib intake and restricted from there. With this study they lowered the control group Calories by 10% and then decreased the CR monkey's from there. There differences in age-related diseases is also striking between the both studies - with the wisconsin groups doing far better when it comes to CVD and Diabetes. CR is high effective in humans and it seems humans see a better response tha these rhesus monkeys had (both young-onset and old-noset CR. It was thought the maximum lifespan of a rhesus monkey was 40 years.

"Longevity under both conditions was above the norm, however. And four of the older animals in the calorie-restricted group and one from the control group have broken rhesus monkey longevity records by living beyond 40 years."

Both groups seem to be closer to that and quite a few monkeys living beyond it. I have a lot more to say but I need to read some of the papers of the NIA study, not just this one. I don't think people should jump off CR because of this result though.

I'm trying to get my head around the difference in health and ultimately lifespan between the Female and Male monkeys. I would expect females to have a longer lifespan!! females 27 years vs males 35 years is very surprising to me And I'm wondering if lower muscle mass causing metabolic problems in the females was the cause; due to low activity. You know exercise up regulates GLUT4 receptor in the muscle improving glucose uptake improving metabolic health. Less LBM higher risk of metabolic and other problems. Low levels of activity might have affected the female monkeys more than the males. I don't know... IGF-1 is an issue as well with cancer and the diet being I think 17%? proten. With CR'd females in some areas fairing worse than the controls I think raises some questions. The response to CR is far better in the wisconsin study and better still; humans.

Edited by Michael, 01 September 2012 - 06:02 PM.

[e Volution]

[cesium]

Lack of activty/exericse might have also played a factor. CR'd males would have mroe muscle mass which might have accounted for better metabolic health, possilbly.

I thought CR was associated with less muscle mass, at least in humans?

The lack of certain changes that are seen in rodents and even in HUMAN studies suggest to me that not just the NIA study had problems (there was also some indications the monkeys were depressed and throwing their food way so the level of CR was decreased between the groups.).

Seems like you're grasping at straws here.

The response to CR is far better in the wisconsin study and better still; humans.

What evidence exists for CR being effective for life extension in humans?

[DLR]

In those same years, though, studies in mice began indicating there might not be a predictable response to a low-calorie diet. Mice that came from the wild, instead of being born and raised in the lab, did not live longer on low-calorie diets. And in 2009, a study of 41 inbred strains of laboratory mice found that about a third had no response to the diets. Of those that responded, more strains had shorter life spans than had longer ones when they were given less food.
The response to that study was “absolute disbelief,” Dr. Austad said. “Even though the authors are well-respected calorie restrictors, people said the result was not interesting, that there was something weird about the mice.”


Possibly bad new for CR in people on average, given the large genetic diversity in humans. We are probably more analogous to wild-type genetically diverse mice/primates, in which CR does not appear to work on average.

As in inbred rodents, there is possibly a subpopulation of humans for whom CR will work very well, but of course we don't know who they are.

 Liao.pdf   48.34KB   1 downloads

The study by Liao et al (2009) you cite presents serious problems. Mice were fed in groups so that the aggressive mice would have eaten more food leaving the less aggressive ones even more restricted. In the end you'd get varying degrees of calorie intake: some mice would not have been restricted at all, and others may have been starving to death. This article provides no reliable evidence against CR.


On the other hand, severe CR may be detrimental for wild mice (this might be relevant for CR beyond the maximum 25 or 30 percent degree of restriction that most CRONIES practice), as has been shown in this study. In wild mice that eat 20 percent less than lab mice when they are ad lib, a 40 percent CR diet does not extend life span, but if we take into account that they are eating less than lab mice, this could even be considered to be at least 60 percent CR, and if you restrict just 10 per cent more, mice live less.
 CR2006.pdf   189.25KB   1 downloads
I'm no expert, but I in my searches I have found that there are not many articles that show that CR does not improve healthspan and lifespan that are well designed, compared to all the articles on CR that show this effect

Edited by DLR, 30 August 2012 - 12:49 PM.

[fql]

This was on slashdot:
http://science.slash...extend-lifespan

[e Volution]

Stephan from Whole Heart Source weighs in: Does Calorie Restriction Extend Lifespan in Mammals?

Last paragraph:

I think when you consider all the evidence to date, the take-away message is that eating a nutritious diet and staying relatively lean will probably prolong your life, while calorie restriction may or may not. It probably does reduce the risk of specific diseases however. Currently, a number people around the world are restricting their calorie intake in the hope of living longer. I wish these pioneers the best of luck. Hopefully we'll have the answer to this question eventually, but if I were a bettin' man I wouldn't put my money on the idea that calorie restriction will extend lifespan at this point.

[Mind]

In much the same way that primal/paleo/keto people pick apart negative findings surrounding fat/meat/protein intake, it is valid to scrutinize this current not-entirely-positive study about CR'd monkeys. CRONie humans are generally very meticulous about maintaining optimal health. Many of the aspect of human CRONies cannot be duplicated in other mammal studies. It seems the human sample is doing well (just as the primal/paleo/keto people are doing well), and it boils down to - if you feel good and look good - you are probably maintaining a good diet for your desired lifestyle, you are probably slowing the aging process, and warding off disease.

Interesting to note that some of the criticism of the UW-Madison study was that the monkeys were in a protected environment and thus not subject to the many fatal forces found in nature and thus lived longer, whereas in this study, someone mentioned that the monkeys were not stimulated enough like they would be in a natural environment and thus they DIDN'T live as long as one would expect (from other CR mammal studies). You can come away with polar opposite theories depending on how you look at it.

[cesium]

I think there is a fair amount of evidence that CR can have many beneficial health promoting effects like making the body resistent to early onset cancers, ect., but the bottom line for me is that now the evidence seems to point in the direction that CR is no more effective then taking various supps that also have been shown in numerous studies to do essentially the same thing. So why suffer with CR and not take supps instead.

For years I've watched the Cronies reporting on various internet forums every major study done (no matter how poorly designed) telling us supps were useless at prolonging lifespan, then suggesting that one couldn't be serious about life extension unless one embraced the 'only one true and proven thing' of caloric restriction. As far as I am concerned this evens the playing field between the two modalities as far as maximizing healthspan is concerned, and takes away the one thing that would make CR worthwhile - evidence that CR will increase maximum lifespan. So if any good is to come out of this disappointing study, it might result in more Cronies abandoning their sometimes dismissive opinions of supps and rekindle their interest in pursuing research into these compounds.

[Guest]

You are being slightly unfair to the CRON-crowd. Yes, there are people who overly embrace CR as "proven" means to extend life, but truth to be said, the most vocal proponents as Michael do emphasize the ON component extensively and are certainly not dismissive regarding supps. To the contrary, he has a quite extensively researched regimen which he posted in this forums. On the other hand more speculative supps such as Resveratrol, Rapamacyn or C60 do not exactly have a better scientific basis to warrant their consumption (at least not in real world applications and in primates).

Personally I hope that a positive results of a potential setback would be more interest in supporting biomedical research such as SENS, as sometimes you have the feeling that many CRON people (again, excluding some vocal ones as Michael) are to occupied with their diet, to realize that in the end the will have to rely on it to battle aging, illnes and death.

[cesium]

You are being slightly unfair to the CRON-crowd. Yes, there are people who overly embrace CR as "proven" means to extend life, but truth to be said, the most vocal proponents as Michael do emphasize the ON component extensively and are certainly not dismissive regarding supps. To the contrary, he has a quite extensively researched regimen which he posted in this forums. On the other hand more speculative supps such as Resveratrol, Rapamacyn or C60 do not exactly have a better scientific basis to warrant their consumption (at least not in real world applications and in primates).

Personally I hope that a positive results of a potential setback would be more interest in supporting biomedical research such as SENS, as sometimes you have the feeling that many CRON people (again, excluding some vocal ones as Michael) are to occupied with their diet, to realize that in the end the will have to rely on it to battle aging, illnes and death.

Didn't mean to single any individual out, actually I seldom even bother visiting those forums/threads (so don't know who is who on there) as I personally don't have the motivation/willpower to follow such a regimen unless there was definitive proof that it would increase maximum lifespan, especially somebody starting it at 50+. I would pop in occasionally to see if there was any new developments however, and was rather amused at some of the self righteous attitudes I would sometimes see. Apparently CR is serious business, while taking supps is child like foolishness to some of those guy, lol. And for what it's worth, I currently don't see any supps out there that have shown any credible evidence that they can lengthen max lifespan either. Res has long been debunked, the buckyball experiment seems flawed, and rapamycyn is too toxic at the effective dosage for humans. Existing supps look promising for increasing healthspan, I remain unconvinced of anything beyond that.