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Do "Naturally Thin" People Benefit Less from CR? Good Non-technical CR Science Overview

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Arg.... Forum ate my post. Take 2.

 

 

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Dean, I have the same results as you, also on the 5th SNP, rs3751812!

 

By the way, there's a much easier way to check status on any SNP than logging into 23andMe. Use SNPTips with FireFox.

 

Yes, we learn a lot about the thin phenotype, but I think the real question is the effect on the possibility of benefitting from CR. CR might be easier for you and me, one might guess. I'd say almost the opposite: being thin is easier, but that's not the goal. Someone with the opposite genetic tendency might go from a BMI of 30 to a BMI of 22 or 21 on CR, benefit tremendously, not look scrawny -- maybe not have really low testosterone, etc. -- whereas we, on CR, go from a BMI of 22 or 23 to 18 or less, and maybe don't get as many CR benefits, and get a lot of the downsides. Maybe. Leanness per se confers some health benefits, according to some studies. But being in "survival mode", as you rightly have called it, might be the real goal. And we might not be able to be in extreme survival mode without being dangerously fat-less.

 

Here's where a citizen science project might be very useful!

 

Zeta

 

 

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By the way, there's a much easier way to check status on any SNP than logging into 23andMe. Use SNPTips with FireFox.

 

Thanks for the tip. I'm not a Firefox user, but maybe I'll have to give it a try.

 

 

Yes, we learn a lot about the thin phenotype, but I think the real question is the effect on the possibility of benefitting from CR. CR might be easier for you and me, one might guess. I'd say almost the opposite: being thin is easier, but that's not the goal. Someone with the opposite genetic tendency might go from a BMI of 30 to a BMI of 22 or 21 on CR, benefit tremendously, not look scrawny -- maybe not have really low testosterone, etc. -- whereas we, on CR, go from a BMI of 22 or 23 to 18 or less, and maybe don't get as many CR benefits, and get a lot of the downsides. Maybe. Leanness per se confers some health benefits, according to some studies. But being in "survival mode", as you rightly have called it, might be the real goal. And we might not be able to be in extreme survival mode without being dangerously fat-less.

 

I agree that its unclear whether having a 'naturally thin' phenotype is a good, bad or indifferent thing when it comes to either the ease or efficacy of practicing CR, and what (if anything) the FTO gene has to do with either of these.

 

 

Here's where a citizen science project might be very useful!

 

I agree. I really think the CR Society should consider starting up some kind of citizen science effort to learn more about the impact of CR in humans. I think there is a lot we could learn, particularly from long-term CR practitioners willing to share (privately if preferred) the details of their practice of CR, health metrics, biomarkers and genetics.

 

The CR survey I posted about here, and encourage everyone to take, has a question that includes how interested people are in citizen science projects. Hopefully we'll see support for the idea on that question, and in the comments. 

 
Now that the 2015 SENS Conference is over, perhaps Michael can share his perspective on the idea of CR citizen science. I'd be happy to help organize and administer such an effort if there is enough interest and support.

 

--Dean

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Regarding:  "I agree that its unclear whether having a 'naturally thin' phenotype is a good, bad or indifferent thing when it comes to either the ease or efficacy of practicing CR, and what (if anything) the FTO gene has to do with either of these."

 

I don't want to be unnecessarily repetitive (says he, repeating himself) but, as I have noted previously, IMO being naturally thin is appreciably bad news.  I first tumbled over this thought a decade or two ago, when I noticed that among my educational institution contemporaries it stuck out like a sore thumb that those who had been at the thin end of the spectrum around age 18 had been dropping like flies, while the kid I knew who was simply huge at age 16 was still alive and organizing golf tournaments!  This included, incidentally, individuals who, although thin, had been quite endurance-athletically-competent in their late teens and early 20s..  So they were not all shrinking violets.

 

Eventually, a contemporary I had competed with died early and it prompted me to do something to try to get past the 'anecdotal' stage of this debate.  So I wrote to the WNPRC and, in short, predicted that if they were to examine their monkey data they would find the CR monkeys that had been the slimmest at the beginning of the experiment (when being tested ad lib initially) would have since experienced a higher mortality rate than the initially heavier CR monkeys.

 

I had expected perhaps 10% higher mortality or, with luck, maybe even 25%.  It turned out that my prediction was correct.  But the difference was far greater than I had even hoped for.  At the time of my enquiry, mortality in the naturally slim lowest tertile was 2.5 TIMES higher than for the two top tertiles.  They also noted that, because they didn't have a large enough number of subjects, the difference, large as it was, did not reach 95% statistical significance.

 

Nevertheless, from my point of view, having predicted what they would find, with absolutely no knowledge of what their data would show, I am confident that with a huge number of subjects the results would not be much different.

 

Seems to me being unusually slim in early adulthood is likely a sub-clinical symptom of something it would be better not to have.  This makes me feel better that my huge appetite has prevented me from getting down to my long-targeted BMI of 20.0.

 

It would be helpful to know what these slim individuals died of, as that would presumably provide a hint about the nature of the problem.  But that is neither practical nor tactful.

 

Rodney.

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Dean's last post of course recalls a lot of information, but I think not directly relevant to what I'll call "Rodney's Hypothesis".

I think that the question underlying Rodney's Hyothesis is the question of metabolic efficiency.

 

Rodney notes (as probably we all have seen) that some people can eat huge amounts of food, possibly including high caloric nutrient poor food, and yet remain thin.  IMO, these people have inefficient metabolisms -- if they weren't living in a society where an abundance of food is readily available, they might not survive.

 

The opposite extreme:  Some people might eat very modestly, even eating healthy, nutrient dense, low calorie food, but find it difficult to avoid weight gain.  These people have efficient metabolisms -- if they were living in an environment where food was scarce, they would be more likely to thrive than people with inefficient metabolisms.

 

Clearly, in a nutrient-poor environment, evolution would favor the latter.

 

Some of what isn't clear is: 

 

(1) In our society of food abundance, if we have two CRONNies (yes, Brian -- I'm one of the people who uses that term -- what's wrong with it :mellow:?), both practising significant calorie restriction with adequate nutrition, is there a longevity advantage to either metabolic type?

 

(2) In our society, if we have two who are ad-lib, or only mildly calorie restricted, is there a longevity advantage to either type?

 

(3) What controls metabolic efficiency?  Obviously, it's at least partly genetic; probably also partly epigenetic.  It's even possible (but I doubt it) that various forms of pollution, or the lack thereof, might be a factor.

 

One thing that I strongly suspect:  there isn't a fast answer to (3).

 

  -- Saul

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I found this new article posted to the CR Society Facebook group (which turns out is pretty active, btw - more on that in another thread). It gives a pretty good overview of the scientific evidence in rodents and primates for (and against) CR. 

 

In addition to the WUSTL and NIA primate studies (which as just above everyone knows, showed modest health benefits and mostly mixed/null results for longevity), the article references [1], a study of a bunch of genetically different strains of mice subjected to 40% food restriction (not just calorie restriction) from weaning, a paradigm that has generally been shown to be effective at extending lifespan in standard mice strains. The study has a cool (although kinda discouraging) plot of lifespan effects across the different strains (click to enlarge):

 

post-7043-0-55875200-1441918021_thumb.jpg

 

It shows that in both male and female mice, longevity was reduced at least as often as it was extended depending on the mice strain, and to a larger degree as well. When this study was previously discussed on the CR email list, Michael Rae posted the following: 

 

I wish the problem [of CR shortening lifespan in many of these strains of mice]

could be chalked down to this [i.e. food restriction vs. calories-only restriction],

but unfortunately this was juvenile-onset CR. While adult-onset CR has never been

found to work in mice except when nutrients and protein are held at the same absolute
level as the AL animals (this requirement doesn't seem to be present in
rats, at least in Brian Merry's lab and a couple others), it's [i.e. food restriction] always
works just fine when started in weanlings. And while we don't know much
yet about these new strains, they're new, complex hybrids, not weird lab
fuckups.

This very surprising result does have to be taken seriously. If it 
weren't for the primate data, the Okinawan anecdote, our health risk 
factors, the short-term health and QOL benefits, and the fact that these 
were very small cohort groups (but replicated at the 2 labs 
semi-independently), I'd already be at Pizza Hut [my emphasis added - DP]

 

Well, you can pretty much scratch the "primate data" from the above list of factors in favor of CR...

 

Interestingly, in light of the discussion on the Genetics of Obesity thread about whether a tendency towards obesity is a good or bad thing, a follow up analysis by the same authors [2] found that among these mice strains, those that were able to preserve the most fat (due to genetic variations) when subjected to food restriction benefited the most. Those mice that couldn't maintain fat on food restriction, died early(ier). They conclude "[genetic] factors associated with maintaining adiposity are important for survival and life extension under DR."

 

These mice results, along with the (at best) underwhelming results from the primate CR studies, would indeed seem to cast doubt on the likely longevity benefits of CR in people, especially skinny-ass CR practitioners. But as Michael Rae points out, we do seem healthier and have better biomarkers of health, so (to paraphrase the immortal words of Bill Murray) we've got that goin' for us, which is nice...

 

--Dean

 

--------------------------------

[1] Aging Cell. 2010 Feb;9(1):92-5. doi: 10.1111/j.1474-9726.2009.00533.x. Epub 2009

Oct 30.

Genetic variation in the murine lifespan response to dietary restriction: from
life extension to life shortening.

Liao CY(1), Rikke BA, Johnson TE, Diaz V, Nelson JF.

Author information:
(1)Department of Physiology, University of Texas Health Science Center at San
Antonio, San Antonio, TX 78229, USA.

Comment in
Aging Cell. 2010 Jun;9(3):448-9; discussion 450-2.

Chronic dietary restriction (DR) is considered among the most robust
life-extending interventions, but several reports indicate that DR does not
always extend and may even shorten lifespan in some genotypes. An unbiased
genetic screen of the lifespan response to DR has been lacking. Here, we measured
the effect of one commonly used level of DR (40% reduction in food intake) on
mean lifespan of virgin males and females in 41 recombinant inbred strains of
mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL)
feeding and 6- to 10-fold under DR, in males and females respectively. Notably,
DR shortened lifespan in more strains than those in which it lengthened life.
Food intake and female fertility varied markedly among strains under AL feeding,
but neither predicted DR survival: therefore, strains in which DR shortened
lifespan did not have low food intake or poor reproductive potential. Finally,
strain-specific lifespans under DR and AL feeding were not correlated, indicating
that the genetic determinants of lifespan under these two conditions differ.
These results demonstrate that the lifespan response to a single level of DR
exhibits wide variation amenable to genetic analysis. They also show that DR can
shorten lifespan in inbred mice. Although strains with shortened lifespan under
40% DR may not respond negatively under less stringent DR, the results raise the
possibility that life extension by DR may not be universal.

PMCID: PMC3476836
PMID: 19878144

 

----------------------

[2] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub

2011 Apr 25.

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

Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.

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.

PMCID: PMC3685291
PMID: 21388497

Edited by Dean Pomerleau

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All:

 

In addition to the WUSTL and NIA primate studies (which as just above everyone knows, showed modest health benefits and mostly mixed/null results for longevity)

 

Careful in your phrasing, here. As I know you (Dean) know but contrary to possible misinterpretation: the results on longevity were not each/both "mixed/null" in some sense.  Rather, they were mixed (discordant) between the two studies: the data on lifespan very positive in WUSTL, but evidently null at NIA — although one might say that the NIA data were at least slightly mixed, as there were some positive-looking trends, and the final analysis hasn't been completed as there are still animals alive today.

 

the article references [1], a study of a bunch of genetically different strains of mice subjected to 40% food restriction (not just calorie restriction) from weaning ... It shows that in both male and female mice, longevity was reduced at least as often as it was extended depending on the mice strain, and to a larger degree as well. When this study was previously discussed on the CR email list, Michael Rae posted the following: 

 

I wish the problem [of CR shortening lifespan in many of these strains of mice] could be chalked down to this [i.e. food restriction vs. calories-only restriction], but unfortunately this was juvenile-onset CR. While adult-onset CR has never been found to work in mice except when nutrients and protein are held at the same absolute level as the AL animals (this requirement doesn't seem to be present in rats, at least in Brian Merry's lab and a couple others), it's [i.e. food restriction] always works just fine when started in weanlings. And while we don't know much yet about these new strains, they're new, complex hybrids, not weird lab fuckups.

 

This very surprising result does have to be taken seriously. If it weren't for the primate data, the Okinawan anecdote, our health risk factors, the short-term health and QOL benefits, and the fact that these were very small cohort groups (but replicated at the 2 labs semi-independently), I'd already be at Pizza Hut [my emphasis added - DP]

 

Well, you can pretty much scratch the "primate data" from the above list of factors in favor of CR...

 

Well, you can't exactly scratch them, as they both show significant health benefits and certainly neither shows an overall detriment — but they certainly can't be used to support a classical anti-aging effect of CR as seen in the rodent studies.

 

More about (1) in my own (massive, technical) analysis of the nonhuman primate Calorie restriction data:

 

the generalizability of the high level and opposing directions of response to CR in this study(40) is rendered unlikely by the inclusion of the DBA/2 strain as one of 8 inbred mouse strains contributing to the recombinant crosses used in this study. DBA/2 is an extremely fragile, short-lived, and disease-prone strain, [...] which seems from other research to be uniquely inflexible in metabolically adapting to CR,([refs]), which was seeded across the spectrum of these strains, rendering parlous any extrapolation of the results of this study to the distribution of genetically-based responsiveness to CR in genetically-heterogeneous populations such as humans, or even Indian- vs. Chinese-sourced rhesus macaques.

Interestingly, in light of the discussion on the Genetics of Obesity thread about whether a tendency towards obesity is a good or bad thing, a follow up analysis by the same authors [2] found that among these mice strains, those that were able to preserve the most fat (due to genetic variations) when subjected to food restriction benefited the most. Those mice that couldn't maintain fat on food restriction, died early(ier). They conclude "[genetic] factors associated with maintaining adiposity are important for survival and life extension under DR."

 

These mice results, along with the (at best) underwhelming results from the primate CR studies, would indeed seem to cast doubt on the likely longevity benefits of CR in people, especially skinny-ass CR practitioners.

From the same analysis quoted above,

 

successful adaptation to CR was associated with greater ability to maintain fat mass under the diet,([(2) below; see also their later (6)], which is consistent with much a more modest effect of adipose maintenance observed in previous studies in individual animals within CR cohorts.[(3-5) below]

 

The "skinny-assed" bit is the thing that concerns me, personally, the most about (1).

 

But as Michael Rae points out, we do seem healthier and have better biomarkers of health, so (to paraphrase the immortal words of Bill Murray) we've got that goin' for us, which is nice...

I confess to have been unfamiliar with this versatile little chestnut; thanks ;) . And nice use of "immortal" ;) . FWIW, even atheist ol' me would rather have a blessing from the Dalai Lama than a caddying tip — unless it was an awfully big one ...

 

References

--------------------------------

[1] Aging Cell. 2010 Feb;9(1):92-5. doi: 10.1111/j.1474-9726.2009.00533.x. Epub 2009

Oct 30.

Genetic variation in the murine lifespan response to dietary restriction: from

life extension to life shortening.

Liao CY(1), Rikke BA, Johnson TE, Diaz V, Nelson JF.

PMCID: PMC3476836

PMID: 19878144

 

----------------------

[2] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub

2011 Apr 25.

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

restriction.

Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.

PMCID: PMC3685291

PMID: 21388497

 

3. Bertrand HA, Lynd FT, Masoro EJ, Yu BP. Changes in adipose mass and cellularity through the adult life of rats fed ad libitum or a life-prolonging restricted diet. J Gerontol. 1980 Nov;35(6):827-35. PMID: 7440923; UI: 81070531

 

4. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986 Apr;116(4):641-54. PubMed PMID: 3958810.

 

5. Personal communication, SR Spindler.

 

6: Rikke BA, Liao CY, McQueen MB, Nelson JF, Johnson TE. Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension. Exp Gerontol. 2010 Sep;45(9):691-701. Epub 2010 May 7. PubMed PMID: 20452416; PubMed Central PMCID: PMC2926251.

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Thanks Michael,

 

Michael Rae wrote: 

the generalizability of the high level and opposing directions of response to CR in this study([1]) is rendered unlikely by the inclusion of the DBA/2 strain as one of 8 inbred mouse strains contributing to the recombinant crosses used in this study. DBA/2 is an extremely fragile, short-lived, and disease-prone strain, [...] which seems from other research to be uniquely inflexible in metabolically adapting to CR,([refs]), which was seeded across the spectrum of these strains, rendering parlous any extrapolation of the results of this study to the distribution of genetically-based responsiveness to CR in genetically-heterogeneous populations such as humans, or even Indian- vs. Chinese-sourced rhesus macaques.

 

The fact that the variety of mice in these studies [1][2] has some of the genes from a fragile strain is important information. Thanks for pointing it out.

 

But I don't understand how this fact prevents extrapolation to genetically-heterogeneous populations like humans. Isn't it possible that humans are analogous to these mixed strain mice, with some good genes and some bad genes with regard to our ability to benefit from (or withstand) CR? In fact, couldn't the inability of some of us to retain body fat when subjected to calorie restriction be one such maladaptive, genetically-determined "fragility" trait that undermines our ability to benefit from (or even survive) serious CR? It seems the same argument could be made for excess muscle loss or bone loss under CR as well.

 

In short, because we humans are genetically heterogeneous, it seems to me very likely that some people will naturally benefit from a given level of CR more than other, and it's not unreasonable to expect that some of us might even suffer lifespan shortening if subjected to particularly severe CR, just like these genetically-varying mice. Do you dismiss this possibility? Or do you accept this idea but nevertheless have some other reason for discounting the relevance and generalizability of this multi-strain mice study?

 

 

 

FWIW, even atheist ol' me would rather have a blessing from the Dalai Lama than a caddying tip — unless it was an awfully big one ...

 

I feel exactly the same way. I'm an atheist but would cherish a blessing from (or a golf game with!) the Dalai Lama. He's a role-model for compassionate engagement to theist and atheists alike, not to mention a really nice guy to be around based on what I've heard, unlike accounts of other extremely compassionate people, e.g. Gandhi, Nelson Mandela, Mother Teresa who had a reputation for being hard to get along with in person. And I would argue (as others have) that the Dalai Lama should be considered (and would consider himself) an atheist as well, at least when defined as a disbeliever in the Abrahamic conception of God...

 

[bTW: apparently the real Dalai Lama has never heard of the Movie Caddyshack, has never played golf, and wasn't very amused when a Fox News reporter asked him such a frivolous question.]

 

Thanks,

 

--Dean

 

References

--------------------------------
[1] Aging Cell. 2010 Feb;9(1):92-5. doi: 10.1111/j.1474-9726.2009.00533.x. Epub 2009
Oct 30.
Genetic variation in the murine lifespan response to dietary restriction: from
life extension to life shortening.
Liao CY(1), Rikke BA, Johnson TE, Diaz V, Nelson JF.
PMCID: PMC3476836
PMID: 19878144

 

----------------------

[2] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub
2011 Apr 25.
Fat maintenance is a predictor of the murine lifespan response to dietary
restriction.
Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.
PMCID: PMC3685291
PMID: 21388497

Edited by Dean Pomerleau

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Dean, and all:
 

Michael Rae wrote:

the generalizability of the high level and opposing directions of response to CR in this study([1]) is rendered unlikely by the inclusion of the DBA/2 strain as one of 8 inbred mouse strains contributing to the recombinant crosses used in this study. DBA/2 is an extremely fragile, short-lived, and disease-prone strain, [...] which seems from other research to be uniquely inflexible in metabolically adapting to CR,([refs]), which was seeded across the spectrum of these strains, rendering parlous any extrapolation of the results of this study to the distribution of genetically-based responsiveness to CR in genetically-heterogeneous populations such as humans, or even Indian- vs. Chinese-sourced rhesus macaques.


The fact that the variety of mice in these studies [1][2] has some of the genes from a fragile strain is important information. Thanks for pointing it out.

But I don't understand how this fact prevents extrapolation to genetically-heterogeneous populations like humans. Isn't it possible that humans are analogous to these mixed strain mice, with some good genes and some bad genes with regard to our ability to benefit from (or withstand) CR?

 


To be clear, I have little doubt that there is genetic variability in this. However, few of us have ancestors that are as screwed up as the DBA/2 mice, which presumably wouldn't survive in the wild; they're an extreme genotype, and their inclusion as one of the 8 strains in the mix is inevitably going to exaggerate on the downside variability in response. Consider that essentially every other inbred strain of laboratory mouse or rat, several outbred stocks, Richard Miller's robust heterogeneous mice, and (despite the abstract) even wild-derived mice (3) respond to CR with an anti-aging response — then out of the blue, a subset of the mixes of these mice, with DBA/2 ancestry, get killed by it, or at least don't benefit. And then, remember that humans are very substantially more genetically mixed in our ancestry than even an 8-strain mix; that our ancestors were selected in the wild to survive occasional bouts of famine, as well as many other stressors, whereas the DBA/2 survives at the whim of the investigator; and the phenomenon of "hybrid vigor."
 

In fact, couldn't the inability of some of us to retain body fat when subjected to calorie restriction be one such maladaptive, genetically-determined "fragility" trait that undermines our ability to benefit from (or even survive) serious CR? It seems the same argument could be made for excess muscle loss or bone loss under CR as well.

 
As I indicated, the fact that several previous studies have found that "successful adaptation to CR was associated with greater ability to maintain fat mass under the diet ... [to a] more modest [degree] ... in individual animals within CR cohorts" is the thing that concerns me, personally, the most about  (2) above.
 
(By the way, one of the nice features of the Forums vs. the List is that one can always see the context of previous posts, so I don't think we need to keep re-posting the same references in the same thread; at minimum, I won't be bitching to those who neglect to do so, so long as they indicate which study they're talking about in subsequent posts therein).

 

Reference

3: Harper JM, Leathers CW, Austad SN. Does caloric restriction extend life in wild mice? Aging Cell. 2006 Dec;5(6):441-9. Epub 2006 Oct 27. PubMed PMID: 17054664; PubMed Central PMCID: PMC2923404.

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These mice results, along with the (at best) underwhelming results from the primate CR studies, would indeed seem to cast doubt on the likely longevity benefits of CR in people, especially skinny-ass CR practitioners. But as Michael Rae points out, we do seem healthier and have better biomarkers of health, so (to paraphrase the 

 of Bill Murray) we've got that goin' for us, which is nice...

 

I wouldn't put stock in subjective feeling of being healthier. Humans have difficulty being unbiased when it concerns ourselves (recall a discussion thread some years ago in the CR email list where a lot of practitioners felt (or told they were remarked upon by others that) they were one or multiple decades younger than their biological age). Given that most of the folks haven't been doing life long CR, and given the not too great results in NIA monkeys, this appears highly implausible on face value.

 

Now, the biomarkers indeed are a good evidence, but most of us are much more health conscious than the general population (e.g. obesity avoidance, healthy food, exercise, stress management, yoga etc). So it's difficult to guess how much of this benefit is due to CR alone.

 

Regarding fat maintenance during CR:

 

I became aware of this when Rodney first remarked about it, and since then this has turned out to be true in other studies (for example, check out figure 1B in wild mice study [1] posted by Michael. But note that this deals with maintenance of body mass, not just fat mass). This was also the case in one of the old time classical studies (by the likes of Weindruch or some such experimenter, year < 2000), posted by Al Pater on the mailing list within the past year, but I'll be damned if I can find it among the huge pile of emails.

 

My empirical take on this, FWIW is this:

Weight measure = BMI (if relative "fattiness" is more important during CR), or weight (if total weight is more important)

Let's take BMI for illustration.

 

Assuming 95% of healthy population lies between BMI x and y (let x=18.5, y=24.5. In reality these need to be determined from data), and assuming people with the lower BMI cutoff still stand to benefit by a little CR (let's say 5% = 0.05), then this gives lower BMI cutoff, L = 18.5 * (1-0.05) = 17.575.

 

Let your healthy early adult BMI = B

=> Individual optimal BMI, B' = L^x * B^(1-x), where 0 < x < 1 depends upon what CR%, c you consider safe for humans on average               ... (1)

 

This equation means higher BMI should lose more weight, consistent with the discussion above.

(I suggest c = 0.15 = ~15% based on NIA monkeys' 30% CR. Humans live longer (hence less likely for CR to be as effective), have access to better medical facilities and supplements (thus getting some of the life extension & health advantages through this means), start CR late (thus the body is less adaptable to CR stress), don't live in highly controlled, accident free, pathogen free environment (hence CR more risky)).

 

Assuming average CR% for human population following equation (1) = CR% of the human following equation (1) with B = (x+y)/2 = 21.5 (note that this depends upon BMI distribution. Taking arithmetic mean to keep things simple. Assuming normal distribution with [mu-2*sigma, mu+2*sigma] = [18.5, 24.5] gives similar x (0.794))

=> B'                       = L^x          * 21.5^(1-x)

=> B     * (1-c)         = 17.575^x * 21.5^(1-x)

=>21.5 * (1-0.15)    = 17.575^x * 21.5^(1-x)

=> x   =   ~0.8

 

There you have it folks, a simple answer to "how much CR% should I follow?". Highly crude, but better than nothing.

 

One last point: During CR, we want to keep as much muscle mass as possible, as much bone mass as possible, as much organ mass as possible (brain, heart, etc), and finally, as much fat mass as possible (fat is also the least metabolically expensive tissue. So you can keep a higher weight with same degree of CR). So instead of trying to game the system to keep more of this tissue of less of that tissue (which has no evidence in any of the experiments, as far as I am aware), how about we follow our usual routine during weight loss and let the body decide what it wants to keep in what proportions. By doing adult CR, we are already skewing this in favor of certain tissues (for example, your bones won't (typically) grow shorter after CR).

Edited by Shwet Shyamal

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Shwet,

 

 

My empirical take on this, FWIW is this:

 

Assuming 95% of healthy population lies between BMI x and y (let x=18.5, y=24.5. In reality these need to be determined from data), and assuming people with the lower BMI cutoff still stand to benefit by a little CR (let's say 5% = 0.05), then this gives lower BMI cutoff, L = 18.5 * (1-0.05) = 17.575.

 

Let your healthy early adult BMI = B

=> Individual optimal BMI, B' = L^x * B^(1-x), where 0 < x < 1 depends upon what CR%, c you consider safe for humans on average               ... (1)

 

...

=> x   =   ~0.8

 

There you have it folks, a simple answer to "how much CR% should I follow?". Highly crude, but better than nothing.

 

You lost me when you reference 'c' where 'c' doesn't show up in the equation you've defined so far. Plus I'm not sure where your equation (1) comes from. Can you share an intuition for what it means, and why it has the form that it does?

 

In the end you say "x = ~0.8". I presume that represents 20% calorie restriction, but relative to what?

 

 

 

One last point: During CR, we want to keep as much muscle mass as possible, as much bone mass as possible, as much organ mass as possible (brain, heart, etc), and finally, as much fat mass as possible (fat is also the least metabolically expensive tissue. So you can keep a higher weight with same degree of CR). So instead of trying to game the system to keep more of this tissue of less of that tissue (which has no evidence in any of the experiments, as far as I am aware), how about we follow our usual routine during weight loss and let the body decide what it wants to keep in what proportions (my emphasis - DP). By doing adult CR, we are already skewing this in favor of certain tissues (for example, your bones won't (typically) grow shorter after CR).

 

The sentence I've bolded above seems rather fatalistic. Isn't there at least some evidence that we can spare some muscle, perhaps bone and hopefully cardiac tissue by engaging in exercise? What if our "usual routine" would be a very sedentary lifestyle?  Shouldn't we change that routine to maximize the chance of not losing important components of our body?

 

Plus, as you said yourself, its very difficult to attribute the benefits we enjoy to CR alone. They could be the result of our healthy lifestyle, including exercise as you point out. But here you seem to be advocating (at least for a couch potato subpopulation of potential CRers) that they follow their "usual routine", which would seem to be putting all their eggs in the CR basket. That would be unwise given the evidence, IMO.

 

Instead we're best to practice moderate CR + exercise (and other healthy lifestyle behaviors, e.g. not smoking, wearing a seat belt, etc.) to maximize our chances of successful aging, even if some of those behaviors require backing off CR to support them (e.g. eating extra to allow calorie expenditure for exercise).

 

--Dean

Edited by Dean Pomerleau

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Hi Dean,

 

Thanks for your comments.

 

 

 

You lost me when you reference 'c' where 'c' doesn't show up in the equation you've defined so far. Plus I'm not sure where your equation (1) comes from. Can you share an intuition for what it means, and why it has the form that it does?

 

c = %CR that humans should do on average (from my earlier post, with emphasis added on c : "Individual optimal BMI, B' = L^x * B^(1-x), where 0 < x < 1 depends upon what CR%, c you consider safe for humans on average").

 

For example, in NIA monkeys, c = 0.3 = 30% (btw, in this case average and individual CR% are same, since all monkeys are subject to same degree of restriction irrespective of their body size or fat)

 

 

In the end you say "x = ~0.8". I presume that represents 20% calorie restriction, but relative to what?

 

No, just put the value of x in equation (1). Let's say my healthy early adult non-CRed BMI = 24.5.

17.575 is the number that we got earlier (L). This is the lowest CRed BMI the thinnest of us should aim for.

 

So by equation (1), my CRed BMI becomes = (17.575^x) * (24.5^(1-x))  = 17.575^0.8 * 24^0.2 =~ 18.78

So I should aim for a BMI of 18.78.

 

The basic idea is to come up with a range of CRed BMI instead of a single value for everybody. Thinner folks should practice less severe CR compared to fatter folks. Their final CRed BMI will still be lower (than fatter folks' final CRed BMI), but the difference won't be as much as before.

 

So going from non-CR to CR, we are doing a BMI conversion of [18.5, 24.5] to [L, 18.78]

(why 18.78? because that's what I got just before when I put in my pre CR BMI value of 24.5)

 

Recall that indeed we got by taking the minimum non-CR BMI = 18.5, and applying our minimum safe CR% (=5%) on it.

 

The reason behind such a formula is to take some kind of average, between minimum safe BMI, and your adult BMI. Higher your adult BMI, higher will be this average (which is your final goal). Now, simple average comes to mind, but the thing is that simple average doesn't "compress" the final range enough. It gives equal weightage to both numbers. And if one value is extremely large (your adult BMI, for example), the average gets extremely large.

 

So what can we do? Geometric mean comes to mind. Geometric mean of two number A and B = A^0.5 * B^0.5,

which is the same as A^x *B^(1-x) with x = 0.5

by using various values of x, you will get various final ranges. You can see that higher the value of x, close the value will be to A. So x is some kind of weight given to lowest BMI, relative to your adult BMI. When x = 0.5, both numbers are given equal weight.

 

Finally, if we decide that the population average CR should be, say 15%, then that fixes a unique value of x. Conversely, if you decide on a value of x, the population average CR% will get fixated to a unique value.

 

 

The sentence I've bolded above seems rather fatalistic. Isn't there at least some evidence that we can spare some muscle, perhaps bone and hopefully cardiac tissue by engaging in exercise? What if our "usual routine" would be a very sedentary lifestyle?  Shouldn't we change that routine to maximize the chance of not losing important components of our body?

 

I meant that there shouldn't be much difference between our post CR routine and the routine during transition period (i.e. weight loss). I guess if one doesn't want to exercise post CR, he could still do some of it during weight loss phase. But going overboard during this transition phase only just to keep as much muscle as possible is probably not a great idea. Like you said, moderation is the key  :)

Edited by Shwet Shyamal

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Shwet,

 

Thanks for the clarification. I now understand your motivation, math and justification much better.

 

I'm not sure how actionable your formula is however. Take my case for example. Upon graduation from high school I weighed 128 lbs (BMI = 19.2). The follow year I gained 40 lbs of mostly muscle via weight lifting and swim team in college, so my BMI went to 25.2. I was healthy at both weights so which would you consider my "healthy early adult BMI", since it determines B, which in turn determines my optimal BMI to target, B'.

 

In the first case (healthy early adult BMI = 19.2), using 0.8 as the weighting factor as you suggest, according to your equation:

 

Let your healthy early adult BMI = B

=> Individual optimal BMI, B' = L^x * B^(1-x), where 0 < x < 1 depends upon what CR%, c you consider safe for humans on average               ... (1)

 

my optimal BMI would be:

 

B' = 17.5^0.8 * 19.2^(0.2) = 17.8  (= 119 lbs at my height  of 5' 8.5") 

 

In the second case (healthy early adult BMI = 25.2), according to your equation my optimal BMI would be:

 

B' = 17.5^0.8 * 25.2^(0.2) = 18.8 (= 126 lbs at my height)

 

My current weight (117lbs) is a bit below the first alternative, and substantially below the second. It's hard for me to see a sound basis for adjudicating between them.

 

--Dean

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Al just posted a new study that is relevant here:

 

Caloric restriction in lean and obese strains of laboratory rat: Effects on body composition, metabolism, growth, and overall health.
Aydin C, Jarema K, Phillips P, Gordon CJ.
Exp Physiol. 2015 Aug 18. doi: 10.1113/EP085469. [Epub ahead of print]
PMID:26283239

Abstract

Reduced body fat is associated with improved longevity with caloric restriction (CR) in rodents. Little is known regarding effects of CR in genetically lean versus obese strains. The Long-Evans (LE) and Brown Norway (BN) rats make an ideal comparison for a CR study because %body fat of young adult LE's is double that of BN rats. Male LE and BN rats were either fed ad libitum (AL) or were calorically restricted to 80 or 90% of their AL weigh.Percent fat, lean, and fluid mass were measured non-invasively at 2-4 week intervals. Metabolic rate (MR) and respiratory quotient (RQ) were measured after 3, 6, 9, and 12 months of CR. Overall health was scored monthly. Percent fat of the LE strain decreased with CR, whereas %fat of the BN strain remained above the AL group for several months. Percent lean mass increased above the AL for both strains subjected to CR. Percent fluid was unaffected by CR. Average MR over 22 hr of the BN rats subjected to CR was reduced, whereas that of LE rats was increased slightly above the AL's. RQ of BN rats was decreased with CR. Overall health of the CR LE strain was significantly improved over that of the AL group, whereas health of the CR BN rats was impaired compared to the AL group. Overall, the lean BN and obese LE strains differ markedly in fat utilization and metabolic response to prolonged CR. There appears to be little benefit of CR in the lean strain. [Emphases mine.]

 

I haven't read the paper yet, but I intend to, since it seems so important.

 

Zeta

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With what I would normally admit to be the very substantial caveat that I have not read the full paper, I think we can more or less dismiss this unless there's something really unusual and of clear translational relevance in the methodology or results. The BN rat has been very extensively and successfully used in CR research: in fact, the fact that it is resistant to obesity (and thus avoids the confounding effects of obesity-avoidance with no special effort) is one of the reasons it's so attractive, and the eminent CR researcher Brian Merry has used this strain almost entirely (and, again, successfully) for decades now. Here is their survival curve in the massive and rigorous Biomarkers of Aging Study from the NIA, which "generated data from over 60,000 individually housed animals of the seven different genotypes and both sexes":
 

gallery_727_15_19468.jpg

 
(If that doesn't come through after clicking on it, try here). At the tail end of that curve on the right, you see a record-holder: "the oldest female rat, BN, lived to 1,686 days (all these animals were from the CR cohorts."

 

Reference

1: Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501. PubMed PMID: 10619312.

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Zeta posted [1], a study of CR in two different strains of rats, obesity prone Long-Evans (LE) rats and lean Brown Norway (BN) rats. 

 

It purports to show that calorie restriction was beneficial for the obesity-prone LE rats, but detrimental for the obesity-resistant, naturally-thin BN rats.

 

Overall, this study was disappointing, not for the obvious reason that, if the authors' conclusions are true, its implications would suck for naturally skinny folks like me. Instead, it was disappointing because it wasn't a very good study (to put it mildly).

 

First of all, there were only a total of 24 rats in each strain, divided into three groups - AL, 10%-CR and 20%-CR, for a total of six groups of 8 rats each between the two strains. This is tiny compared with the 60,000 rats in the research program Michael cites [2] (although divided over 7 strains rather than 2), in which (contra this study) CR was seen to be beneficial, even for skinny BN rats.

 

Besides the small population size in this study, what else might explain the discrepancy? 

 

Well, in Michael's study [2] the authors actually used longevity as a metric. Here, the primary endpoint was something the authors called the healthy appearance score, basically a subjective assessment based on four factors - appearance, posture, mobility, and muscle tone, all assessed by manually observing and/or manipulating the rats.

 

Their main finding was that the healthy appearance score of obesity-prone LE rats was better in the CR group than the AL control group  - i.e. CR benefited the healthy appearance in the LE strain. But in the naturally-thin BN strain, the CRed rats looked and acted less healthy than the AL controls, with the more severe CRed rats looking / doing worse than the mildly CRed rats. Here is their graphs of the score of the three different groups for both strains over time, with the naturally-thin BN rats on the left and obesity-prone LE rats on the right (note: lower is better):

 

post-7043-0-48946500-1443035822_thumb.jpg

 

A few things to observe from these two graphs. First, after the first few months, all of the skinny BN rats had better (lower) healthy appearance scores than the obesity-prone LE rats, throughout the remainder of the study. Furthermore, while the score for all three groups (AL, 10%CR, 20%CR) of the obesity-prone LE rats got worse over the course of the study, the scores for all three BN groups stayed virtually constant.  The authors conclusion that CR was beneficial in the obesity-prone LE rats is based on the fact that the CR groups didn't get worse as rapidly as the AL group!

 

The fact that none of the three groups of lean BN rats got worse after four months of age, and stayed at a relatively healthy level in all three groups (albeit with the AL group slightly better than the two CR groups), says something (bad) about their methodology. The explanation isn't hard to see. At the end of the study, the rats were killed at 16 months of age. This is about 480 days, which (from Michael graph above), is about half the natural lifespan of BN mice in the lab! Again looking at Michael's graph of BN rats on CR vs. AL, at 16 months, virtually all of both groups were still alive, and presumably still quite healthy. 

 

So these bozos, I mean researchers, were measuring the naturally-thin BN rats up through the human-equivalent of about 40 years of age, seeing that the CRed rats looked slightly worse than the AL rats, although both groups looked pretty healthy, and weren't getting worse. From this they concluded:

 

...health of the CR BN rats was impaired compared to the AL group. ... There appears to be little benefit of CR in the lean strain.

 

That seems logical...

 

Overall, this study was pretty worthless, not to mention misleading in its data interpretation, for the reasons listed above. 

 

--Dean

 

------------

[1] Caloric restriction in lean and obese strains of laboratory rat: Effects on body composition, metabolism, growth, and overall health.

Aydin C, Jarema K, Phillips P, Gordon CJ.
Exp Physiol. 2015 Aug 18. doi: 10.1113/EP085469. [Epub ahead of print]
PMID:26283239

Abstract

Reduced body fat is associated with improved longevity with caloric restriction (CR) in rodents. Little is known regarding effects of CR in genetically lean versus obese strains. The Long-Evans (LE) and Brown Norway (BN) rats make an ideal comparison for a CR study because %body fat of young adult LE's is double that of BN rats. Male LE and BN rats were either fed ad libitum (AL) or were calorically restricted to 80 or 90% of their AL weigh.Percent fat, lean, and fluid mass were measured non-invasively at 2-4 week intervals. Metabolic rate (MR) and respiratory quotient (RQ) were measured after 3, 6, 9, and 12 months of CR. Overall health was scored monthly. Percent fat of the LE strain decreased with CR, whereas %fat of the BN strain remained above the AL group for several months. Percent lean mass increased above the AL for both strains subjected to CR. Percent fluid was unaffected by CR. Average MR over 22 hr of the BN rats subjected to CR was reduced, whereas that of LE rats was increased slightly above the AL's. RQ of BN rats was decreased with CR. Overall health of the CR LE strain was significantly improved over that of the AL group, whereas health of the CR BN rats was impaired compared to the AL group. Overall, the lean BN and obese LE strains differ markedly in fat utilization and metabolic response to prolonged CR. There appears to be little benefit of CR in the lean strain. [Emphases mine.]

 

-----------

[2] Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501. PubMed PMID: 10619312.

Edited by Dean Pomerleau

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Al Pater kindly provided me with the full text of this new study [1], which appears from the abstract to be relevant to the question of "how thin is too thin?", particularly in the elderly.

 

It was a study of nearly 5000 elderly Japanese men and women, who were followed for an average of about 14 years, with their height, weight, and other demographical & health information self-reported at multiple time points during the follow-up between 1987 and 2006. The Japanese have weight distribution skewed much more towards the normal and underweight categories than in the US, where most people are overweight or obese, even in the elderly. In 2012, the researchers looked at the mortality statistics for these subjects, and tried to correlate risk of dying with the subjects' weight trajectory during the study. 

 

Using some fancy statistical clustering technique, they identified four weight trajectory profiles that were common in the group, and best able to model the weight trajectory data. The four categories they classified subjects into were:

  • low-normal weight, decreasing; (24% of subjects)
  • mid-normal weight, decreasing; (45% of subjects)
  • high-normal weight,decreasing; (27% of subjects)
  • overweight, stable                   ( 5% of subjects)

Here is the figure showing the model BMI trajectory for each of these categories:

 

post-7043-0-76032400-1443466108_thumb.jpg

 

As you can see, the trajectory most relevant to "serious" CRers is probably the bottom one in the graph "low-normal weight, decreasing". It starts at a BMI of just under 19, and drops by about 0.05 kg/m^2 per year, which for a 5'9" person corresponds to losing about 1/3 lb per year on average.

 

Here is the table with the relevant results:

 

post-7043-0-72256500-1443467039_thumb.jpg

 

Compared with the "mid-normal weight, decreasing" group, which they used as a reference, the "low-normal weight, decreasing" group was 38% more likely to die during the follow-up in an unadjusted model. The "overweight, stable" group did the best. They were 39% less likely to die during the follow-up period than the "mid-normal weight, decreasing" group.

 

So that would seem to suggest being thin and getting thinner during one's elderly years, is quite bad for longevity, compared with being heavy and staying heavy.

 

But notice the results of "model 2b" in the above table. It focused on "current non-smokers", and then adjusted for the following:

 

age; sex; marital status; currently working; education; annual household income; weight (kg); number of drinking days per month; frequency of exercise; history of cardiovascular disease, stroke, lung disease, liver disease, and kidney disease; self-rated health and functional status at baseline; and entry wave.

 

After these adjustments, the two groups in question ("low-normal weight, decreasing" and "overweight, stable") were now statistically indistinguishable from the "mid-normal weight, decreasing" group in terms of their likelihood of dying. And note this eliminated only current smokers, not people who smoked in the past, so the picture might have been even more favorable for the thin people if they'd done the analysis on the subpopulation of "never smokers".

 

Indeed, looking at the baseline characteristics of the different groups shows why adjusting for all these factors might eliminate the longevity disadvantage of the "thin and getting thinner" group. These "thin and getting thinner" folks were more likely than the "heavy and staying heavy" folks at baseline to be:

  • older (by 3+ years)
  • not married
  • not working
  • heavier smokers (nearly 2x cigarettes per month!)
  • heavier drinkers

With all these adverse demographics and bad habits, it's no wonder the "thin and getting thinner" folks were more likely to die.

 

So overall, not a very relevant or informative study of CR practitioners. 

 

For a good discussion of the relationship between BMI, disease and longevity, see this post from Michael Rae, which, among many other interesting things, points out that studies have found people tend to lose weight over a 9 year period prior to death from a chronic illness, and that very few studies, (including this new one) take this long disease-induced weight drop into account in their analysis.

 

--Dean

 

-------------

[1] Am J Epidemiol. 2015 Oct 1;182(7):597-605. doi: 10.1093/aje/kwv107. Epub 2015 Sep 12.

 

Trajectories of Body Mass Index and Their Associations With Mortality Among Older Japanese: Do They Differ From Those of Western Populations?

 

Murayama H, Liang J, Bennett JM, Shaw BA, Botoseneanu A, Kobayashi E, Fukaya T, Shinkai S.

Abstract

Few studies have focused on the relationship between the trajectories of long-term changes in body mass index (BMI; weight (kg)/height (m)2) and all-cause mortality in old age, particularly in non-Western populations. We evaluated this association by applying group-based mixture models to data derived from the National Survey of the Japanese Elderly, which included 4,869 adults aged 60 or more years, with up to 7 repeated observations between 1987 and 2006. Four distinct BMI trajectories were identified: “low-normal weight, decreasing” (baseline BMI = 18.7; 23.8% of sample); “mid-normal weight, decreasing” (baseline BMI = 21.9; 44.6% of sample); “high-normal weight, decreasing” (baseline BMI = 24.8; 26.5% of sample); and “overweight, stable” (baseline BMI = 28.7; 5.2% of sample). Survival analysis with an average follow-up of 13.8 years showed that trajectories of higher BMI were associated with lower mortality. In particular, relative to those with a mid-normal weight, decreasing BMI trajectory, those with an overweight, stable BMI trajectory had the lowest mortality, and those with a low-normal, decreasing BMI trajectory had the highest mortality. In sharp contrast with prior observations from Western populations, BMI changes lie primarily within the normal-weight range, and virtually no older Japanese are obese. The association between BMI trajectories and mortality varies according to the distribution of BMI within the population.

 

PMID: 26363514

Edited by Dean Pomerleau

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Dean,
 
First, I agree with the criticisms you made of the paper I posted.
 
Now, on to this new, very cool (thanks, Al!), if not entirely relevant, study:
 

As you can see, the trajectory most relevant to "serious" CRers is probably the bottom one in the graph "low-normal weight, decreasing".

 

-- Most relevant of the four groups, yes, but not necessarily very relevant, since -- I believe -- there are long-term CR practitioners who lose no or very little weight as they age, though sarcopenia probably affects everyone at least a bit, eventually. And then there are the reasons for its non-relevance you cite:

 

But notice the results of "model 2b" in the above table. It focused on "current non-smokers", and then adjusted for the following:

 

age; sex; marital status; currently working; education; annual household income; weight (kg); number of drinking days per month; frequency of exercise; history of cardiovascular disease, stroke, lung disease, liver disease, and kidney disease; self-rated health and functional status at baseline; and entry wave.

 

So overall, not a very relevant or informative study of CR practitioners. 

 

For a good discussion of the relationship between BMI, disease and longevity, see this post from Michael Rae, which, among many other interesting things, points out that studies have found people tend to lose weight over a 9 year period prior to death from a chronic illness, and that very few studies, (including this new one) take this long disease-induced weight drop into account in their analysis. 

 

An additional problem is the existence of numerous chronic weight-loss inducing illnesses that go undiagnosed -- I mean, those that, in many cases, are never diagnosed. These are mostly gut conditions like IBD and celiac disease. (Why can't researchers simply add a question like: "How often do you poop, and how loose is the poop?")

 

One simply can't control for all conditions that shorten lifespan and cause weight loss.

 

Zeta

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[Note: Michael's post below refers to a post by me (Dean) that has been moved as a result of his (very valid) observation - sorry for the confusion. Please see this thread for the post he's referring to, and I refer to as well in the post after this one. - Dean]

 

Dean, in the last couple of weeks you've posted a ton of stuff, all of which has been of high quality and that I've appreciated learning from. As it happens, one of those very useful posts is in this very thread: your analysis of PMID:26283239, with which I agree entirely. So I apologize that my first actual comment on one of these posts is a complaint ;) .

These are very useful data on a question in the BMI-mortality epidemiology on which conclusioins are too often drawn based on shoddy data — namely, "is being thin in itself bad for you?"

This is an important question for people who are thin and for people who get thinner (or anticipate getting thinner) as a result of CR — but still, as Saul said of a previous post, it's a fundamentally different question from the subject of this thread, raised by PMID: 21388497 op cit and the related reports that I cited in my reply, which is whether something about the kind of metabolism that loses fat mass easily in response to CR reduces the benefits of practicing it.

It's certainly possible that the mechanism for any such effect would be mediated by an inherent riskiness of reaching a too-low BMI (or, likely, a too-low level of lean mass bundled into a low BMI), but at most all studies like the ones in the above post suggest is that if CR is harmful or less effective in naturally-lean people, it wouldn't be mediated by simply leading to a low BMI.

As Zeta says, PMID: 26363514, although heartening, is also not really informative, though not for the exact reasons he says: the real reason it's not very informative is that it doesn't distinguish between intentional and unintentional (eg., cachexia or disaease-associated) weight loss, or between intentional weight loss or even intentional maintenance that is the result of restricted energy intake and weight loss/maintenance resulting from physical activity.

What would at least be close would be studies of intentional weight loss in already-thin, healthy people, which (unsurprisingly) don't really exist, aside from some limited and highly confounded data on anorexics, because already-thin healthy people aren't normally motivated to intentionally lose weight! (Even that wouldn't, strictly, get at the question of whether the subjects were "naturally" thin or not: this would presumably require either specific questioning or, better yet, expensive energy-balance and -challenge tests. Good luck ;) ).

Again, all of these studies above are useful, informative papers on the BMI-mortality question, which is of relevance to we very-thin CR people, so I really do thank you for posting and analyzing them — but they really don't address the subject of this thread, and would be better placed in the thread on BMI and mortality to which you previously alluded.

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Michael,

 

Wow - I got of easy. After posting your picture in the thread on CR Luminaries, I thought I might really be in the dog house.  :)

 

 If I'm interpreting you correctly, the problem with my most recent post on the Adventist is not the analysis, but that it is off-topic for this thread - a point I'll readily concede. It was about the benefits of being thin (naturally or not), rather than the benefits of being naturally thin and then starting to practice CR on top of that, relative to being naturally heavier and practicing CR which is the topic of this thread.

 

If you'd like to shift it to the other thread let me know, since I'll need to update the link I posted to it on the CR Facebook group.

 

--Dean

Edited by Dean Pomerleau

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Per Michael Rae's suggestion, and my new moderator superpowers (mu ha ha! - that's supposed to be a diabolical laugh  :)xyz ), I've moved my last several posts to the thread he (correctly) suggested would be a more appropriate place for them, the thread on BMI and mortality. Please follow up there.

 

Note: I've left the last two posts that focus mostly on administrivia, since in addition, they (esp. Michael's) contain useful information that would be lost otherwise.

 

--Dean

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Interestingly, in light of the discussion on the Genetics of Obesity thread about whether a tendency towards obesity is a good or bad thing, a follow up analysis by the same authors [2] found that among these mice strains, those that were able to preserve the most fat (due to genetic variations) when subjected to food restriction benefited the most. Those mice that couldn't maintain fat on food restriction, died early(ier). They conclude "[genetic] factors associated with maintaining adiposity are important for survival and life extension under DR."

 

If part or all of the benefits of CR seen in rodents are explained by an underlying evolutionary adaption to surviving famine, then a preferential retention of body fat could be an obvious sign that a particular rodent/strain strongly expresses this adaption. Preferential retention of body fat could be suggestive of the organism attempting to store away energy supplies for the future, with the "plan" of sitting out the famine period in a pro-survival("anti-aging") state whilst living off the stored "rations."

 

There is of course evidence to suggest however, in humans, that too much body fat, particularly visceral fat, may be detrimental, possibly because it is pro-inflammatory.

 

Taken together, I wonder if in humans the much popularly maligned "skinny-fat" body morphology could actually reflect something akin to the successful CR'ed rodents. The skinny-fat combination might ideally reflect a state of lowered caloric intake (skinny) which implies famine, coupled with the pro-survival/anti-aging adaption (fat), along with keeping absolute body fat amounts low enough to avoid the health problems observed in the conventionally overweight/obese.

 

It also makes me wonder if womens' tendency toward proportionally higher body fat, as well as live longer, reflects a similar pro-survival evolutionary strategy. Due to the higher and longer-lasting investment requirements for reproduction in females, evolution may have given females similar pro-famine-survival adaptions like preferential fat accumulation and retention.

Edited by Brett Black

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"It also makes me wonder if women's tendency to have higher proportional body fat, as well as live longer, reflects a similar pro-survival evolutionary strategy. Due to the higher and longer-lasting investment requirements for reproduction in females, evolution may have given females similar pro-famine-survival adaptions like preferential fat accumulation and retention."

 

Reminds me of the thought experiment:  Take two populations of cats, each with 100 males and 100 females.  In one group neuter 99 of the males and none of the females; in the other neuter 99% of the females and no males.  How many litters will you end up with?

 

In one group just one.  In the other 100.

 

Broadly speaking the same applies to primitive, and not so primitive, human societies.  Native americans at war with each other killed all the enemy males and kept the females for the obvious reason that their tribe was more likely to flourish that way. 

 

So it would not be surprising to find that nature itself discovered that giving females higher body fat serves a similar purpose for the species.

 

Rodney.

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On 9/2/2015 at 8:00 AM, Zeta said:

... Dean, I have the same results as you, also on the 5th SNP, rs3751812!

 

Hah, I just checked my results for rs3751812 and I am T;T....

In fact, according to Promethease, I should be a rolling ball of lard, based on some of my other FTO genes:

 rs1421085(C;C)
~1.7x increased obesity risk

 rs1121980(T;T)
Moderate increase (2.76x) in risk for obesity

 rs9939609(A;A)
obesity risk and 1.6x risk for T2D

 rs8050136(A;A)
1.4x increased risk for T2D in some populations

 rs17817449(G;G)
~1.7x increased obesity risk

Yet, I've been "naturally skinny" for most of my life. I am 6'1" (187cm) and have hit close to 180lbs (80kg) in my late 30s and early 40s, basically because my job was sedentary, intense and conducive to overeating at long meetings and "good" restaurants. But mostly I have hovered about 150-160lbs (70kg or so), currently at 147lbs. BMI never crossed 23. I do have a few FTO genes which would predispose me to be a bit skinnier, so maybe it's a matter of epigenetics.

Edited by Ron Put

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On 9/2/2015 at 12:00 PM, Zeta said:

Arg.... Forum ate my post. Take 2.

 

 

----------

 

Dean, I have the same results as you, also on the 5th SNP, rs3751812!

 

By the way, there's a much easier way to check status on any SNP than logging into 23andMe. Use SNPTips with FireFox.

 

Yes, we learn a lot about the thin phenotype, but I think the real question is the effect on the possibility of benefitting from CR. CR might be easier for you and me, one might guess. I'd say almost the opposite: being thin is easier, but that's not the goal. Someone with the opposite genetic tendency might go from a BMI of 30 to a BMI of 22 or 21 on CR, benefit tremendously, not look scrawny -- maybe not have really low testosterone, etc. -- whereas we, on CR, go from a BMI of 22 or 23 to 18 or less, and maybe don't get as many CR benefits, and get a lot of the downsides. Maybe. Leanness per se confers some health benefits, according to some studies. But being in "survival mode", as you rightly have called it, might be the real goal. And we might not be able to be in extreme survival mode without being dangerously fat-less.

 

Here's where a citizen science project might be very useful!

 

Zeta

 

 

When I finish my treatment I will eat just to survive if anyone else is willing to participate in this study, this study will be revolutionary we can pass the age of 120.

Edited by Fernando Gabriel

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