214 replies to this topic

[nowayout]

I have superimposed the 2 pictures you posted, showing the evolution of the percentage of the monkey population free of age-related disease:


... the smooth curves are the high-sugar Wisconsin study... impressively above...

So the Wisconsin CRed animals had better outcome than the NIA animals... am I reading it right?

Maybe antioxidants blunt the beneficial response to CR. There was indeed a rodent study (discussed here a few years back) in which a relatively short course of ALA early in life made the animals largely unable to derive benefit from CR, even long after the ALA was stopped. (We also know that antioxidants can blunt beneficial adaptations to exercise.)

Since the NIA animals had more antioxidants in their diet, maybe this could explain their weak response to CR.

[albedo]

.... There was indeed a rodent study (discussed here a few years back) in which a relatively short course of ALA early in life made the animals largely unable to derive benefit from CR, even long after the ALA was stopped. (We also know that antioxidants can blunt beneficial adaptations to exercise.) ...

Would appreciate if you can point us to that study. Thank you in advance.

[Hebbeh]

.... There was indeed a rodent study (discussed here a few years back) in which a relatively short course of ALA early in life made the animals largely unable to derive benefit from CR, even long after the ALA was stopped. (We also know that antioxidants can blunt beneficial adaptations to exercise.) ...

Would appreciate if you can point us to that study. Thank you in advance.

http://www.longecity...life-extension/

[Brett Black]

A pair of ragged claws, scuttling across the floors of silent seas. (Prufrock via Shaka)

But let's be careful. He may be scrawnier than me, but he's way, way smarter than I'll ever be. I really really want MR to comment on the paper.

So don't annoy he-who-will-not-have-his-initials-spelled-out.

MR phone home.

- cw

No offence/annoyance was intended; I'm keen to see Michael's analysis too.

[cesium]

I bet lab primates get fed better food in general than say rats, which get fed standard rat chow. This would point towards the ON being generally more important than CR as a part of CRON, and AgeVivo also noticed it.

I agree, unfortunately I was using CRON and CR interchangebly in my previous posts when I should have made the distinction.

[cesium]

I currently don't see any supps out there that have shown any credible evidence that they can lengthen max lifespan either. ... the buckyball experiment seems flawed

The problem that I worry about with fullerenes is exactly the same as what might be the case in this primate CR study: Long lived primates have better endogenous antioxidant defenses than rodents, so they aren't likely to see as much benefit from an antioxidant intervention, nor from CR, for similar reasons. Still, the Baati experiment worked better in rats than any supplement ever, OR CR (AFAIK). So where's the flaw? I fail to see it. Small N isn't a flaw, given the magnitude of the effect.

I shouldn't have used the word "flawed" since that implies that I was referring to a flawed methodology, which I didn't mean. But in addition to the n=6 there was the increase in maximum lifespan in the oo alone, but most remarkably the sheer magnitude of this extension. And mind you this magnitude was achieved with intermittent dosing on rats that were already aged, so presumedly if this was started on young rats at whatever the optimum dosage would be, the lifespan would be another order of magnitude greater. Instead of doubling their normal max lifespan it stands to reason it would triple it. Sorry that just seems pretty farfetched for any supplement to accomplish outside of some previously unknown mechanism like the 'resetting' thing Turnbuckle speculated on. I will say this however, that if this experiment can be reproduced, there is a good chance that Baati, et al would be inline to share in a future Nobel Prize for stumbling upon such a previously unknown mechanism. Catalytic antioxidant action alone just doesn't seem a feasible mechanism, especially when started in already aged animals.

[Mind]

Maybe the CR's monkeys were pissed off and threw their food because they weren't happy being starved (as seems to be the reason why most humans do not practice CR).

Edited by Mind, 02 September 2012 - 02:13 PM.

[Matt]

The control group were throwing away their food

Will copy and paste a message sent to the CR lists by Al Pater

"* The study incorporated monkeys that had previously been used in military research and 20 out of the 26 animals seemed to die before age of 12 years. Â In order not to taint the research, they tagged the results with an origin label and then adjusted to remove these animals. Â Could this have had an effect on the other animals too that was not controlled for?
Twenty of the 26 adult-onset females were obtained from a military research facility, and 19 of these monkeys developed severe and rapidly progressing endometriosis. The twentieth monkey of this group died at the age of 12 years from renal necrosis. It seemed apparent that this cohort was differentially affected in terms of long-term health, and thus, an indicator variable that designated the source of this monkey group as ‘Aberdeen’ was created and was included in most analyses to control statistically for the effects of these animals on the outcomes of interest.
* The animals didn't exhibit "CR normal" fasting blood glucose profiles vs age compared to prior CR animal studies.
* The animals didn't exhibit "CR normal" triglyceride profile vs age compared to prior CR animal studies. Â
* The female animals didn't live as long as the male animals in either CR or control groups. Â This is contrary to what we experience in humans where females average 5+ years more than males. Â

Edited by Matt, 02 September 2012 - 02:19 PM.

[Mind]

The control group were throwing away their food

Darn, sorry, my mistake then. Reading to fast.

[AgeVivo]

... the smooth curves are the high-sugar Wisconsin study... impressively above...

So would it be the NIA study that is impressively below in the graph, probably due to experiments they had in the military research? I guess we won't know what type of experiments it was? (survival from gas, radiations, infections... and then lifespan test )

Edited by AgeVivo, 02 September 2012 - 06:11 PM.

[Logan]

C60 might turn out to be that one supplement.

How about intermittent fasting? Doing this and maintaining just the right amount of calories/nutrients might give the same health enhancing benefits of CR, without compromising things like bone density.

Edited by Logan, 03 September 2012 - 08:46 AM.

[nowayout]

This may indicate a big problem with the CRON approach, at least with what we think of as ON.

The two studies seem to indicate:

CR alone = good results
CR + ON = bad results

The difference is in the ON, and seems to indicate that ON = bad, whatever ON meant in the NIA study.

[InquilineKea]

Hmm, what do people think of this quote on Reddit? (from http://www.reddit.co...primate/c616ybd )

This study is being severely misunderstood and misrepresented. What the study shows is that extreme calorie restriction in monkeys doesn't extend lifespan over that of monkeys with only moderate calorie restriction . This [1] NY Times article is more in-depth.
The control group already had a diet that was calorically restricted, so the test group had a diet that was restricted 30% beyond that. The test group monkeys were starved to the point where they were the monkey equivalent of a 6' tall man weighing between 120 and 133 pounds. We already knew that being extremely skinny is not the healthiest.
Also note that the starved monkeys in this study weren't compared to overweight monkeys. They were compared to normal weight monkeys with less of a calorie restriction, but still a calorie restriction.
The older University of Wisconsin study's result seem to differ primarily because they used a control group of monkeys who were allowed to eat as much as they wanted (no calorie restriction).

The key question is this: how do you "define" calorie restriction? How many rhesus macaque calories is approximately equal to 2000 human calories?

==

Also - I'll second the confusion on the females living shorter than the males in both the CR and control groups. Was this observed in the Wisconsin study too? Was it related to 20 of 26 adult-onset females being obtained from the military research facility?

Also, how do the survival curves of Wisconsin-CR monkeys compare with NIH-control and NIH-CR monkeys?

Carbohydrate content was also
notably different; although both diets had 57–61% carbohydrate by
weight, the NIA study diet was comprised primarily of ground wheat
and corn, whereas the WNPRC study diet contained corn starch and
sucrose.

How healthy is this, really? Ground wheat/corn is certainly healthier than corn starch and sucrose, but it still is far from ideal...

Edited by InquilineKea, 04 September 2012 - 12:42 AM.

[maxwatt]

Wild monkeys eat leaves, fruit, nuts, and whatever small animals they can catch. Or junk-food handouts from tourists. In Chinese parks this can include peanuts, cotton candy, dried fish seasoned with hot peppers, and any snacks they can steal.

[scottknl]

I also thought that monkeys often ate insects in the wild. I remember seeing a video of a chimp fishing ants out of a tree stump using a long thin branch and then eating them.

[maxwatt]

Insects, yes. Technically they are small animals. They eat each-other's fleas, too.

[Mind]

We already knew that being extremely skinny is not the healthiest.

Not so fast, SDR rats live 50% longer.

Which makes sense, with rats, in a lab. CR is essentially a method of slowing metabolism, slowing growth, lowering body temperature, reducing the rate of metabolic junk build up through life. Maintaining a bare minimum of calories to stay alive, restricting any nutrients that promote growth (stunting any possible growth), would extend life (if the damage theory of aging is substantially correct). For humans, if they plan on continually losing weight while on CR (losing muscle, bone mass, what-not, like the SDR rats), it would be good to live in a controlled environment with few exogenous threats.

[DLR]

Regarding the degree of restriction which may be beneficial for humans. I'm still very cautious, since as I have already mentioned, severe restriction does not extend life in wild mice according to some studies, and we don't know how much is 50 per cent restriction for a particular human being, or whether this is too much for a particular human. IMHO, major weight reductions that do not approach the low range of the healthy weight for humans (18 plus or minus 1 or so), might have increased risks for many people, given the genetic variability within human groups.

What do you think about this? After reading some articles, I'm starting to doubt whether the lab mice which many studies use are just too genetically predisposed to be fat and grow a lot, and therefore show even more longevity benefits when they are on Calorie Restriction

[Mind]

What do you think about this? After reading some articles, I'm starting to doubt whether the lab mice which many studies use are just too genetically predisposed to be fat and grow a lot, and therefore show even more longevity benefits when they are on Calorie Restriction

What do I think? I think you make a very good point. I don't think CR benefits will be as large in primates/humans because of our longer lifespan and varied genetics. Still, there certainly seems to be enough evidence to indicate solid gains in healthspan from limiting calories. If I was on CR (I am not), the two somewhat perplexing primate studies would not be enough to stop me from my CR.

[InquilineKea]

Hmm, Living the CR Way just posted this:

Calorie restriction lowers fasting glucose levels- Average glucose levels of the human CR cohort at Washington University were 81 mg/dl.¹ This makes sense since with less available energy from calories, cells burn serum glucose voraciously, causing glucose levels to fall provided that healthy, low GI carbohydrates are part of the protocol.
Calorie restriction lowers triglycerides - with less available energy, the body burns fat for fuel, so triglycerides fall. Average triglyceride level for the Washington University CR cohort was 49 mg/dL ²
Calorie restriction lowers IGF-I, Insulin-like Growth Factor, a hormone that's a major growth-driver. Ah, but this one is tricky: If protein levels are high, IGF-I stays high, whether calories are lower or not. ³ So if you want to turn down anabolic activity, a fundamental tenet of calorie restriction's effects, keep protein moderate.For anyone who doubts that calorie restriction has these effects - glucose, triglycerides and IGF-I are easy to test.

It should also go without saying that to conduct objective research on calorie-restricted humans, the subjects must not be ill nor be on medication to control an illness.
Does it not seem surprising then that the recently reported NIA study,
Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. (Nature. 2012 Aug 29. doi: 10.1038/nature11432. PMID: 22932268),

did not meet any of these criteria? These monkeys ate a high protein diet, likely to raise IGF-1 and their triglyceride and glucose levels were also uncharacteristically high. Further the cohort included previously used animals from a military research facility. Many of these animals died of illness unrelated to calorie restriction.

Thoughts?

Edited by InquilineKea, 05 September 2012 - 11:50 PM.

[nowayout]

Hmm, Living the CR Way just posted this:

Calorie restriction lowers fasting glucose levels
Calorie restriction lowers triglycerides
Calorie restriction lowers IGF-I, Insulin-like Growth Factor

Does it not seem surprising then that the recently reported NIA study, did not meet any of these criteria?

Not really, because it did meet those criteria in the late-onset CR group. (Or at least two of the criteria - I'm lazy to go back and look it up again.) Still, it did not extend their lifespan.

What is surprising to me is the expectation among people that early-onset CR animals should be healthier, given what we know about the long lasting deleterious effects of childhood malnutrition in humans.

Edited by viveutvivas, 06 September 2012 - 01:14 AM.

[scottknl]

Hmm, Living the CR Way just posted this:

Calorie restriction lowers fasting glucose levels
Calorie restriction lowers triglycerides
Calorie restriction lowers IGF-I, Insulin-like Growth Factor

Does it not seem surprising then that the recently reported NIA study, did not meet any of these criteria?

Not really, because it did meet those criteria in the late-onset CR group. (Or at least two of the criteria - I'm lazy to go back and look it up again.) Still, it did not extend their lifespan.

What is surprising to me is the expectation among people that early-onset CR animals should be healthier, given what we know about the long lasting deleterious effects of childhood malnutrition in humans.

CR != malnutrition both in humans and NIA Monkeys by definition.

CR has 2 main rules: 1) get full nutrition 2) cut calories
If you're not getting rule #1 then you're not doing CR.

Secondly, animals that have undergone CR have shown more robust health by all measures, even if they don't grow as large. So the expectation for good health was valid.

Just to be clear about what the NIA study showed was that both controls and CR group lived similar lifespans. CR animals in no way lived shorter or less healthy lives compared to the controls. In fact both groups appear to have set a new record for mean lifespan of m. mulatta. Of course, there's still data to come, so the final result isn't in, but isn't likely to change significantly.

[Luminosity]

When I've seen Calorie Restriction people on TV they look creepy. The theory sounds punitive and mad-scientistly. Look, life isn't a science experiment. You don't get some kind of prize for withholding a normal, healthy balanced diet from your body. You may not even get a prize for withholding occasional treats. Jean Calment ate a tremendous amount of chocolate. She was the longest lived person whose lifespan was unquestioned.

You have to listen to your body. You have to have some joy. You need a normal social life. You may need some fat reserves. I don't advocate extreme diets or deprivation of normal nutrients like carbohydrates or healthy fats. There's no historical basis for that.

I'm heavy but all my vital signs are perfect. I eat well and exercise. Doctors were always giving me a hard time because I was supposedly at risk for various health problems. It's been over twenty years and none of those health problems have appeared.

[Chupo]

When I've seen Calorie Restriction people on TV they look creepy.

How would you feel if I said, "when I've seen heavy people on TV they look creepy"?
You're a thoughtless ass!

[Luminosity]

How would you feel if I said, "when I've seen heavy people on TV they look creepy"?

You just did.

I've only seen a few CR people on TV but the ones I saw did look pale, and withdrawn and unearthly. Is that surprising? I wasn't trying to be insulting.

And in some cases, being deprived of nutrients seems to make some people quite irritable.

Have a chocolate won't you?

Edited by Luminosity, 06 September 2012 - 06:49 AM.

[Chupo]

I've only seen a few CR people on TV but the ones I saw did look pale, and withdrawn and unearthly. Is that surprising? I wasn't trying to be insulting.

I've only seen a few fat people on TV but the ones I saw did look bloated, and inflamed and swollen. Is that surprising? I'm not trying to be insulting.

Edited by Chupoman, 06 September 2012 - 07:57 AM.

[DLR]

I don't like the tone this discussion has taken in the last few posts. This post is not about how CR people or overweight or obese people look, nor is it about what people should do with their lives according to other people's subjective opinions.

The question is: is the evidence in this article powerful enough to make us think that CR may not be so beneficial in humans? In my opinion, there are many caveats that make this article look unreliable.

Does this mean that the results of extreme (let's say 60, 50 or even 40 per cent CR) CR in mice could be applied to humans yielding the same outcomes? Probably not, looking at the study of CR in wild mice (which as I already mentioned, show no benefit in lifespan extension and may be restricting too much if they eat 40 per cent less)

However, this doesn't mean that the current studies on human CR will not improve healthspan or lifespan (25-30 per cent is what many humans on CR practice, and only THIS (perhaps weak) study shows no improvement in lifespan (although they do find a better healthspan for monkeys on CR) in subjects with this kind of restriction.

Edited by DLR, 06 September 2012 - 10:56 AM.

[okok]

However, this doesn't mean that the current studies on human CR will not improve healthspan or lifespan (25-30 per cent is what many humans on CR practice, and only THIS (perhaps weak) study shows no improvement in lifespan (although they do find a better healthspan for monkeys on CR) in subjects with this kind of restriction.

I'm not knowledgeable on this topic, but if you accede the healthspan with no lifespan improvement, therefore obviating study design issues, then one could argue that's probably all there's to CR.

[DLR]

However, this doesn't mean that the current studies on human CR will not improve healthspan or lifespan (25-30 per cent is what many humans on CR practice, and only THIS (perhaps weak) study shows no improvement in lifespan (although they do find a better healthspan for monkeys on CR) in subjects with this kind of restriction.

I'm not knowledgeable on this topic, but if you accede the healthspan with no lifespan improvement, therefore obviating study design issues, then one could argue that's probably all there's to CR.

How can obviate study design issues? We only have two primate studies, one saying CR provides no lifespan extension, the other one saying it does, and both studies having serious methodological problems. Looking at mice studies, we have A LOT of studies saying there is lifespan extension, and very few saying it doesn't. The current state of knowledge suggests CR is more beneficial than detrimental to health and lifespan improvement. The problem is the degree of restriction which would yield benefits and when do we know that the line between CR for longevity and starvation has been crossed in humans?

Earlier it was thought that even 50 per cent was ok in mice, but that study in wild mice showed has 40 per cent might be too much for mice.

We shouldn't obviate the details of many studies to conclude whatever we like to think, and maybe experts reading these posts who've read the literature on CR more extensively might have a different opinion.

Edited by DLR, 06 September 2012 - 12:26 PM.

[nowayout]

What is surprising to me is the expectation among people that early-onset CR animals should be healthier, given what we know about the long lasting deleterious effects of childhood malnutrition in humans.

CR != malnutrition both in humans and NIA Monkeys by definition.

CR has 2 main rules: 1) get full nutrition 2) cut calories
If you're not getting rule #1 then you're not doing CR.

No, you are doing CR. You may not be doing CRON.

I don't think we know enough to be confident about what optimal nutrition, and therefore CRON, even is in humans, and probably not in monkeys. For example, there is increasing evidence that antioxidants, fish oil supplements, etc., may be counterproductive. In fact the Wisconsin monkey CR study seemed to work but not the supposed CRON study by the NIA. Also, in numans, there is no such thing as CRON in children. Optimal nutrition in children requires more calories than they would get from CRON, otherwise they will have lifelong mental and physical deficits, which will make a longer life beside the point. So severely restricting calories in children is by definition malnutrition (and child abuse) no matter how many vitamins you give them.

Edited by Michael, 19 September 2012 - 09:39 PM.