• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Differences Between People and Animals on CR


  • Please log in to reply
16 replies to this topic

#1 Johan

  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 25 September 2008 - 11:54 AM


http://www.scienceda...80924151018.htm

Differences Between People And Animals On Calorie Restriction

ScienceDaily (Sep. 24, 2008) — Calorie restriction, a diet that is low in calories and high in nutrition, may not be as effective at extending life in people as it is in rodents, according to scientists at Washington University School of Medicine in St. Louis.

Previous research had shown that laboratory animals given 30 percent to 50 percent less food can live up to 50 percent longer. Because of those findings, some people have adopted calorie restriction in the hope that they can lengthen their lives. But the new research suggests the diet may not have the desired effect unless people on calorie restriction also pay attention to their protein intake.

In an article published online this month in the journal Aging Cell, investigators point to a discrepancy between humans and animals on calorie restriction. In the majority of the animal models of longevity, extended lifespan involves pathways related to a growth factor called IGF-1 (insulin-like growth factor-1), which is produced primarily in the liver. Production is stimulated by growth hormone and can be reduced by fasting or by insensitivity to growth hormone. In calorie-restricted animals, levels of circulating IGF-1 decline between 30 percent and 40 percent.

"We looked at IGF-1 in humans doing calorie restriction," says first author Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University and an investigator at the Istituto Superiore di Sanità in Rome, Italy. "For years, we have been following a cohort of people from the CR Society who have been on long-term calorie restriction. We found no difference in IGF-1 levels between people on calorie restriction and those who are not."

The CR Society members, who call themselves CRONies (Calorie Restriction with Optimal Nutrition), had been on a calorie-restriction diet for an average of seven years when Fontana did the measurements, but their IGF-1 levels were virtually identical to sedentary people who ate a standard, Western diet.

Because calorie restriction is linked to extraordinary increases in maximal lifespan in rats and mice, Fontana and colleagues at Washington University, including principal investigator John O. Holloszy, M.D., professor of medicine, have been involved in a scientific study that compares calorie restriction to exercise and measures many biological factors linked to longevity and health. Called the CALERIE study (Comprehensive Assessment of the Long term Effects of Reducing Intake of Energy), the project randomly divided 48 people into three groups: Eighteen cut their caloric intake by 25 percent for one year. Another 18 started exercising to increase their energy expenditure by 25 percent for a year. A third group of 10 people didn't change anything.

At the end of that year, the investigators measured IGF-1 levels in all three groups. Again they found no reductions in the group on calorie restriction.

"That was puzzling because it was the first time we hadn't seen agreement between mice and rats on calorie restriction and humans on calorie restriction," Fontana explains. "But we know there are two major influences on IGF-1 levels: calorie intake and protein intake. So we decided to look at the influence of protein."

Again, Fontana had a ready-made study group. His team has been following a population of strict vegans for several years. They tend to eat less protein than the CRONies from the CR Society, so he compared IGF-1 levels between the two groups.

"The vegans had significantly less circulating IGF-1, even if they were heavier and had more body fat than CRONies," he says. "Protein in the diet seemed to correlate with the lower levels of IGF-1. The strict vegans took in about 10 percent of their total calories from protein, whereas those on calorie restriction tended to get about 23 or 24 percent of calories from protein."

The investigators wanted to take one more look at the relationship between dietary protein and IGF-1, so Fontana asked a group of CRONies to eat less protein for a few weeks. He says it was not easy to cut protein because those on calorie restriction have to do a lot of calculating and juggling to ensure they take in very few calories and still get adequate nutrition. Increasing dietary protein is one way many CRONies guard against becoming malnourished.

"But six of them agreed to lower their protein intake," Fontana explains, "and after three weeks their circulating IGF-1 declined dramatically."

Previous research from Fontana's group had found that a diet lower in protein might protect against some cancers. These more recent findings suggest lowering protein also might be important to longevity. Fontana admits his evidence is preliminary, but the findings suggest that when people adjust their diets to improve health and lengthen life, they should control not only calories and fat but also keep an eye on protein.

Fontana isn't proposing radical low-protein diets. Instead, he is suggesting the current recommended daily allowance (RDA) for protein, which is 0.82 grams of protein per kilogram of body weight, or about 56 grams of protein for an average, adult man and 46 grams for an average, adult woman. Most people, including CRONies, consume much more protein than the RDA recommendation.

"It's much easier to restrict protein than to restrict calories," he says. "If our research is on the right track, maybe humans don't need to be so calorie restricted. Limiting protein intake to .7 or .8 grams per kilogram per day might be more effective. That's just a hypothesis. We have to confirm it in future studies."

Until then, Fontana suggests people might want to look at protein consumption and tailor it to RDA recommendations. Traditionally, he says, nutritionists have not worried about people eating too much protein, but these findings suggest perhaps they should.


What does this mean for those of us (including me) who follow a Zone-type CRON diet (i.e. 30% of calories from protein, 40% from carbs, and 30% from fat)? Should we decrease our protein intake?

I know Michael Rae has extensively argumented for Zone CRON, and that's partly why I follow that diet. Perhaps he can chime in on this?

#2 Matt

  • Guest
  • 2,862 posts
  • 149
  • Location:United Kingdom
  • NO

Posted 25 September 2008 - 01:10 PM

Haven't got time to write a big reply here, I hope Michael can share a few of his links where he's already been through this discussion before. It seems as you increase protein in CR'd mice their longevity within the CR group itself increasesl. Same for fat to a certain extent. I wonder with increasing protein intake in the mice does it also attenuate the normal reductions in IGF1 that you usually see?

As for this being a major setback in whether or not CR will work in humans, no, it is certainly not.

#3 luv2increase

  • Guest
  • 2,529 posts
  • 37
  • Location:Ohio

Posted 25 September 2008 - 04:02 PM

I hope Michael can share a few of his links where he's already been through this discussion before.



This is dated yesterday; isn't it something new? How can someone have gone over something before if it is just new?

#4 Matt

  • Guest
  • 2,862 posts
  • 149
  • Location:United Kingdom
  • NO

Posted 25 September 2008 - 04:51 PM

I hope Michael can share a few of his links where he's already been through this discussion before.



This is dated yesterday; isn't it something new? How can someone have gone over something before if it is just new?


Because the people at the CRS are the ones involved in the study

So anyway, I managed to do a quick search and came up with something might be worth a read
http://www.caloriere...3992#msg-183992

#5 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 25 September 2008 - 05:00 PM

So anyway, I managed to do a quick search and came up with something might be worth a read
http://www.caloriere...3992#msg-183992

That's a great find, Matt. Michael's posts are always very informative. ;)
Still, it's going to be interesting seeing where this low(er)-protein thing is heading.

Oh, and congrats on becoming a Navigator. When did that happen?

#6 Heliotrope

  • Guest
  • 1,145 posts
  • 0

Posted 25 September 2008 - 10:51 PM

Wow Matthew Lake , Navigator, yeah when did that happen?

I still think of my body as developing so I don't voluntarily practice CR, though i like to read about CR and maybe easing into it some years in the future, but I find CR is certainly very easy to do with stimulants.

I've tried caffiene and adrafinil (quite a few years of experience w/ caffiene, only days of experience w/ adrafinil), and when on the stimulanting supplements, I find that I simply don't eat as much, don't have that much appetite can even skip like 4 or 5 meals straight, it's almost like involuntary CR for me. I usually remind myself and force myself to at least something, getting healthy snacks and have nice meals somewhat often.

#7 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 26 September 2008 - 05:34 AM

I still think of my body as developing so I don't voluntarily practice CR, though i like to read about CR and maybe easing into it some years in the future, but I find CR is certainly very easy to do with stimulants.

I've tried caffiene and adrafinil (quite a few years of experience w/ caffiene, only days of experience w/ adrafinil), and when on the stimulanting supplements, I find that I simply don't eat as much, don't have that much appetite can even skip like 4 or 5 meals straight, it's almost like involuntary CR for me. I usually remind myself and force myself to at least something, getting healthy snacks and have nice meals somewhat often.

You may need to be careful with stimulants if/when you're starting CR, though - Matt said in another thread somewhere that CR might enhance the effects of stimulants as well as medications. I recently had a bout with dark chocolate, that may have been because of caffeine and increased sensitivity due to CR.

Edited by Johan, 26 September 2008 - 05:37 AM.


#8 JLL

  • Guest
  • 2,192 posts
  • 161

Posted 26 September 2008 - 11:08 AM

So their theory is that reducing IGF-1 is the key to longevity and eating less protein is the key to reducing IGF-1? Wouldn't we then have seen studies saying vegetarians live longer?

Yet as far as I know, that is not the case. OK, we have the Okinawans who probably eat less protein than other people, but they're doing CR too.

#9 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 26 September 2008 - 11:22 AM

So their theory is that reducing IGF-1 is the key to longevity and eating less protein is the key to reducing IGF-1? Wouldn't we then have seen studies saying vegetarians live longer?


Yes, that seems to be their hypothesis. The article doesn't mention anything about looking at biomarkers other than IGF-1, though. It would have been interesting to know if lower IGF-1 causes other biomarkers to improve in mice and rats, and if those biomarkers are improved with CR in humans, even though IGF-1 levels stay the same.

#10 kismet

  • Guest
  • 2,984 posts
  • 424
  • Location:Austria, Vienna

Posted 26 September 2008 - 11:28 AM

I hope Michael can share a few of his links where he's already been through this discussion before.

This is dated yesterday; isn't it something new? How can someone have gone over something before if it is just new?

He gets to see unpublished and as of yet not published studies, corresponds with scientists, etc. It's his job to be proactive about that stuff.

Is igf-1 signalling the only mechanism of action by which CR extends life span? I don't think so..
In this post, even though it was focused on methionine restriction MR mentions that the epidemiological data (e.g. nurses health study) does not support low protein diets.

#11 Shepard

  • Member, Director, Moderator
  • 6,360 posts
  • 932
  • Location:Auburn, AL

Posted 26 September 2008 - 05:20 PM

This is dated yesterday; isn't it something new? How can someone have gone over something before if it is just new?


Fontana has talked about protein intake for years, so there has been time for others to put up counter-arguments.

#12 Michael

  • Advisor, Moderator
  • 1,293 posts
  • 1,792
  • Location:Location Location

Posted 28 September 2008 - 03:53 PM

ScienceDaily (Sep. 24, 2008) — Calorie restriction, a diet that is low in calories and high in nutrition, may not be as effective at extending life in people as it is in rodents, according to scientists at Washington University School of Medicine in St. Louis.

Previous research had shown that laboratory animals given 30 percent to 50 percent less food can live up to 50 percent longer. Because of those findings, some people have adopted calorie restriction in the hope that they can lengthen their lives. But the new research suggests the diet may not have the desired effect unless people on calorie restriction also pay attention to their protein intake.


They have, with respect, shown neither of these theses. Their study in no way demonstrates that protein limits health; they have shown that protein consumption limits CR-induced IGF1 reduction.

This is the same nonsense we previously had to deal with on SIRT1. Once again: this is a surrogate outcome, based on a mechanistic hypothesis. When you actually feed animals CR diets, they live at least as long -- and often longer -- on a high-protein as on a low-protein regimen. actively cutting protein for animals on CR shortens their LS. And in humans, high-protein (but healthy -- including, eg, low in saturated fat) diets reduce risk factors and incidence of chronic disease.

Read this first:

http://www.caloriere...3327#msg-183327

Then, for scattered but extensive documentation:

http://health.groups...ty/message/4224
http://www.caloriere...1409#msg-111409

(today, I'm a bit embarrassed by some parts of the above (the infamous "Albatross"), which is sorely out of date and sometimes poorly reasoned -- but the protein info is largely solid). For more recent, or otherwise not included, documentation:

http://www.caloriere...7327#msg-147327
http://www.caloriere...7356#msg-147356
http://www.caloriere...2596#msg-142596
http://www.caloriere...3924#msg-183924
http://www.caloriere...9317#msg-179317
http://www.caloriere...2200#msg-182200

Also,

In an article published online this month in the journal Aging Cell, investigators point to a discrepancy between humans and animals on calorie restriction. In the majority of the animal models of longevity, extended lifespan involves pathways related to a growth factor called IGF-1 (insulin-like growth factor-1), which is produced primarily in the liver. Production is stimulated by growth hormone and can be reduced by fasting or by insensitivity to growth hormone. In calorie-restricted animals, levels of circulating IGF-1 decline between 30 percent and 40 percent.



On IGF1 itself:
http://www.caloriere...8804#msg-188804

It's also worth noting that while "In calorie-restricted animals, levels of circulating IGF-1 decline between 30 percent and 40 percent" -- yet their maximum LS is indistinguishable from that if IGF1R knockout mice, and CRing the GHRKOs (which of course cannot further reduce their nonexistent IGF1) still further extends their lives:

Posted Image

(AL 1,163 ± 38 d, CR 1,363 ± 20*, GHRKO 1,362 ± 11†, GHRKO-CR 1,468 ± 15‡) - Table 1 of (1)), despite the fact that the knockouts have circulating IGF-1 is indetectable (see Table 2 in (2)).

(but note that there was a gender disparity: the female IGF1Rs seemed to benefit more than the males -- which is consistent with the results in the similar human mutation, referenced in one of the links above). This shows at the very least that IGF1 is not the only factor in CR-induced longevity -- and it may indicate that it's just not involved.

Until someone takes a two cohorts of CR mammals (not, eg, fruit flies, which age differently from mammals and in whom reducing protein extends LS even with no CR at all, for reasons involving female fertility), feeds one a high-protein diet and one a low- , and shows that the latter live longer and healthier than the former -- ie, until someone shows the exact opposite of what has consistently been found in available studies to date -- people should simply eat the evidence-based, "high-protein" (Zonish ) CR diet (which, NB, because of the reduction in total Caloric intake, actually means high in percentage protein but pretty average in absolute protein grams), and forget about (or otherwise modulate) their IGF1.

-Michael

References
1: Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A.
Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7901-5. Epub 2006 May 8.
PMID: 16682650 [PubMed - indexed for MEDLINE]

2. Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A.
Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction.
Endocrinology. 2005 Feb;146(2):851-60. Epub 2004 Oct 21.
PMID: 15498882 [PubMed - indexed for MEDLINE]

Edited by Michael, 29 September 2008 - 01:12 AM.


#13 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 11 October 2008 - 07:31 PM

Here is a paper by Fontana et al. on CR and IGF-1 levels. I haven't had the time to read it myself, but I thought some of you might be interested.

#14 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 16 October 2008 - 05:41 PM

After reading The CR Way by Paul McGlothin and Meredith Averill, I read one of their referenced studies, in which it is reported that higher IGF-1 levels attenuate the activation of mammalian SIRT1 in CR rats and human cells treated with serum from those animals. In the below study, 429 ng/ml of IGF-1 was supplemented. I don't know what level of IGF-1 in humans this translates to, but since higher amounts of dietary protein increases IGF-1, this could be important to us. The study is from 2004, so I expect that more experienced Zone CRONies, like Matt and Michael Rae, have already read (and refuted?) this study.

Here is the abstract of that study:

1: Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17.
Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA.

Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.

PMID: 15205477 [PubMed - indexed for MEDLINE]


And here is the full-text paper:

Edited by Johan, 16 October 2008 - 10:01 PM.


#15 VictorBjoerk

  • Member, Life Member
  • 1,763 posts
  • 91
  • Location:Sweden

Posted 17 October 2008 - 07:52 AM

I think i read somewhere that a zone diet is recommended not restricting proteins.They seem to conclude that there is little evidence of the benefits to cut down on protein, In the CR way however they suggest that you should have a comparable low protein intake.

If I remember right this story was on the CR society mailing list which I occasionally read.

Edited by VictorBjoerk, 17 October 2008 - 07:54 AM.


#16 Johan

  • Topic Starter
  • Guest, F@H
  • 472 posts
  • 9
  • Location:Sweden

Posted 17 October 2008 - 11:11 AM

I think i read somewhere that a zone diet is recommended not restricting proteins.They seem to conclude that there is little evidence of the benefits to cut down on protein, In the CR way however they suggest that you should have a comparable low protein intake.

If I remember right this story was on the CR society mailing list which I occasionally read.

I'm not talking about restricting protein, but increasing it beyond a "standard" CR diet. Zone-level protein intake is 30% of daily calories. For me, that's 130 g (2.35 g/kg, or 1.08 g/lb). The question is really how big of a role IGF-1 levels play in human aging.

#17 Michael

  • Advisor, Moderator
  • 1,293 posts
  • 1,792
  • Location:Location Location

Posted 23 October 2008 - 09:37 PM

After reading The CR Way by Paul McGlothin and Meredith Averill, I read one of their referenced studies, in which it is reported that higher IGF-1 levels attenuate the activation of mammalian SIRT1 in CR rats and human cells treated with serum from those animals. In the below study, 429 ng/ml of IGF-1 was supplemented. I don't know what level of IGF-1 in humans this translates to, but since higher amounts of dietary protein increases IGF-1, this could be important to us. The study is from 2004, so I expect that more experienced Zone CRONies, like Matt and Michael Rae, have already read (and refuted?) this study.

First: this argument and many others like it, are preemptively refuted by Walford's chapter on "The Nature of Evidence," which every life-extensionist (and particularly anyone looking at supplement promotional material), should read and re-read until it is embedded in hir mind as an established bullshit filter.

This is mechanistic speculation, being advanced on the basis of an hypothesis about how CR works, here backed by a test-tube study, not in vivo lifespan results which (as I've previously posted) clearly refute the implication that eating more protein will interfere with the youth-extending benefits of CR; indeed, empirically, quite the reverse is true.

On the specific question: the whole CR/SIRT1 thing is tenuous at best and likely bunk, as I've posted extensively on the Methuselah Foundation forums -- but even if it were much more credible (like the IGF-1 hypothesis), it's still bad reasoning to jump from this to what you should actually do in the real world. You want to look at in vivo studies with interventions and clinical outcomes, not effects on surrogate markers (IGF-1, SIRT1, ex vivo copper-catalyzed LDL peroxidizability, TOR, etc etc). Real-world lifespan results trump mechanistic speculation every single time.




1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users