Rodney,

Whenever I see someone use the word "surely", I figure the writer isn't very sure about, or doesn't have real evidence to support, what they are about to say. I'm guilty of it sometimes myself.

People's appetites differ for a lot of reasons, many of them without negative health implications. Genetics is one example that can alter metabolic rate and therefore hunger (remember the ob/ob mice who ate more but didn't live shorter lives).

Exercise or exposure to cold (and extra brown fat that cold exposure can create/promote) will increase calorie expenditure without detrimental effects. In fact, perhaps my favorite study of all time (except for the suffering of the animals involved) was the famous "rats with cold feet" study [1] by John Holloszy. Holloszy found that rats who lived their lives standing in a cold puddle of water ate 44% more than normally-housed rats, but nonetheless stayed thin and didn't live any shorter lives than the normally-housed rats. In fact they lived slightly longer and got less cancer.

Our friend Josh Mitteldorf did a whole blog post about the hormetic benefits of cold exposure, and how it casts serious doubt (if not debunks) the popular "rate of living" theory of aging.

--Dean (who composed this post while pedalling shirtless and wearing just bike shorts on his stationary bike in his 59 degF basement to maximize hormesis...   )

--------

[1] J Appl Physiol (1985). 1986 Nov;61(5):1656-60.

Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory".

Holloszy JO, Smith EK.

It has been postulated that increased energy expenditure results in shortened
survival. To test this "rate-of-living theory" we examined the effect of raising
energy expenditure by means of cold exposure on the longevity of rats. Male
6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water
(23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5
days/wk. They were maintained on this program until age 32 mo. The cold exposure
resulted in a 44% increase in food intake (P less than 0.001). Despite their
greater food intake, the cold-exposed rats' body weights were significantly lower
than those of control animals from age 11 to 32 mo. The average age at death of
the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the
controls. The cold exposure appeared to protect against neoplasia, particularly
sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared
with 57% for the controls. The results of this study provide no support for the
concept that increased energy expenditure decreases longevity.

PMID: 3781978 [PubMed - indexed for MEDLINE]

"The most parsimonious interpretation of the NIA monkey data (esp when coupled with the Wisconsin monkey data) is that once obesity is avoided, a healthy diet with (albeit only mild) calorie restriction is no better for primate longevity than the same diet without calorie restriction (or only enough CR to avoid obesity)."

Here are the survival curves for male (M) and female (F) control (CON) and 30% calorie-restricted (CR) monkeys, both for all-cause (left) and age-related (right) morality:




I don't know about you folks, but the corresponding CR and Control curves look pretty-darn indistinguishable to me. Hence the pessimism over the primate study results.

Having read both studies, it appears to me the primary difference between the Wisconsin and NIA studies were that the NIA diet was much healthier and less refined, and the NIA control monkeys were very modestly calorie restricted to prevent obesity and its ill effects, which appeared to plague the Wisconsin controls to a much larger degree. Hence the interpretation that CR doesn't seem to provide much if any longevity benefit in primates relative to controls eating a healthy, obesity-avoiding diet.

While acknowledging it's less than definitive, Michael seems to favor this interpretation of the Monkey CR studies as well, in this (extended) passage from is very thorough analysis of the monkey data, he acknowledges this as a pretty reasonable interpretation of the Wisconsin & NIA primate CR results, saying (my emphasis):


A straightforward reading of the two nonhuman primate CR studies, then, is that in rhesus macaques, the relationship between energy intake, body weight, and lifespan is the commonsensical one, against which the rodent CR phenomenon stands as such a stark contrast: that overweight and excess adiposity are bad for one's health and prospects for long life, but that some normative "healthy" anthropometry is optimal, with diminishing returns at best as energy intake and body weight are progressively reduced beyond that juste milieu. Indeed, skeptics of the human translatability of CR have long argued that the weight loss that is associated with CR appears to only be salutary to health within a relatively narrow range. They argue instead that further limiting energy intake and adiposity will lead to progressively less marginal benefit, especially in light of the uniquely metabolically deranging effects of visceral adipose tissue, which is preferentially lost early in the process weight loss, whether achieved by diet or exercise.(ref) Such skeptics also point to the importance of maintaining lean mass — both muscle and bone — for preserving health during aging, and to the large number of epidemiological findings (eg. (ref,ref)) suggesting a J-shaped or U-shaped relationship between body mass index (BMI) and mortality, although the relevance of these findings to the Calorie restriction phenomenon is dubious.*

In this interpretation, the slight restriction imposed on NIA control animals, leading to an energy intake and body weight that was intermediate between those of WNPRC's ad libitum and restricted groups, was sufficient to achieve or closely approach the point of diminishing health and longevity gains, and a further restriction from this point in the CR group therefore yielded no further extension of lifespan.

This explanation of the discrepancy in the effects of CR as compared to internal control animals in the WNPRC (2) and NIA (3) studies has much to offer. It is conceptually straightforward; it is consistent the major findings of the two studies, and with an important body of research in humans; it fits with some models of the postulated evolutionary basis for the slow-aging phenotype of CR; and is not exclusive of some of the other explanations we have explored. And, as we shall see in the next section, it can also provide a consistent explanation for several differences in health and metabolic outcomes between the two studies, and accommodate a broader body of research on diet and metabolism in nonhuman primates.


So Michael seems to concur that a good (perhaps the best) explanation of the disappointing CR primate results is that after calories are restricted enough to avoid obesity, there aren't many additional benefits to be had - "against which the rodent CR phenomenon stands as such a stark contrast."


Evidence from CR in Rodents

But is Michael even correct in his contrasting the failure of CR in primates with the success of CR in rodents?

In particular, is the "CR phenomena" in rodents really as robust and linear with degree of calorie restriction as nearly everyone (including Michael) have always contented? We're all familiar by now which this famous graph from Weindruch's study [5], apparently showing consistent increase in longevity with degree of CR in mice, right up to 65% CR, which must be pretty close to the point of starvation:
 

Looks very promising right?

But it turns out there are quite a few rodent CR studies that show only marginal benefits of CR beyond obesity avoidance. For example, in this post, I discuss ]study [6] from last year, which found that in F344 rats "10% CR increased life span to almost the same extent as 40% CR." There was some extra benefit of severe CR in the last few rats to die (maximum lifespan), but that was offset by early mortality in the severe CR group.

Overall the mean and median lifespans of the 10% CR and 40% CR rats were indistinguishable. And note these rats were CRed all their lives, from 6 weeks of age - which if anything should have maximized the benefits of severe CR and minimized the early mortality effect (which wasn't seen until middle age in the 40% CR group). Early onset CR is something none of us have the luxury of. The authors of [6] conclude:
 

These data in combination with the data from Duffy et al.,[ref] which reported that feeding rats 10% and 25% DR was as effective as 40% DR in reducing the early mortality of male Sprague–Dawley rats, demonstrate that the lifespan of certain strains of rats and mice does not increase linearly up to 40% DR. Most of the extension of lifespan appears to be achieved by levels of DR much lower than 40% DR.

And [6] isn't the only rodent study to show that mild CR is nearly as good as severe CR. In this post, I discuss [7], which studied lifelong CR in another commonly employed rat strain (Sprague Dawley rats). They found:

 

The average lifespan of AL rats was 115 <sic> months [they mean weeks].

At 104 weeks on study (110 weeks of age), the survival rate for the AL and

10%, 25%, and 40% DR groups was 63.4, 87.5, 87.5, and 97.5%, respectively.

The largest increase in survival (24.1%) occurred between AL and 10% DR,

indicating that very low levels of DR have a significant effect on survival.

This further supports the idea articulated above, that most of the benefits of CR, at least for the average individual, can be had via modest, 10% CR to basically avoid obesity. Unfortunately all the rats in this study were sacrificed early to study their organs, rather than allowing them to live out their natural lives, so there isn't data on total lifespan, just survival to 104 weeks.


One potentially troubling explanation for this discrepancy between successful mouse CR studies like Weindruch et al [5] and these less-successful rat studies is the highly in-bred nature of laboratory mice used in virtually all CR experiments. For example, Austed et al [8] studied early-onset 40% CR in male grand-offspring of wild-caught mice and found:
 

Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups...

In fact they observed higher mortality in CR wild-type mice throughout most of their life, with a few wild-type CR mice hanging on longer than any of the AL-fed mice at the end of life. Here is the AL vs. CR survival graphs for these wild-type mice:
 

Importantly, the wild-type mice in [8] were literally fed as much food as they wanted, without any restriction. As a result, they were pretty overweight, topping out at around 32g in mid-life, which was nearly than twice the wild-type CR mice. But at 32g, this is still quite a bit less than the peak weight of really obese (and short lived) in-breed ad-lib fed mice, which often top out in the neighborhood of 40g in CR experiments.

So we see that in a less genetically inbred, obesity-prone strain of mice, severe CR may in fact be detrimental for longevity except for a few very lucky individuals - a small advantage that may have disappeared altogether had the control mice been mildly restricted rather than given unlimited access to food.

So in heavily inbred mice, the control mice get really obese and so CR which prevents obscene amounts of weight gain has benefits. But in naturally thinner wild-type mice, CR provided no average lifespan benefits relative to ad-lib fed controls.

Sohal et al have taken these clues about the importance of obesity avoidance in rodent longevity to heart, and done a really interesting study [9] that shows in both inbred mice and rats, that CR benefits are directly proportional to degree of obesity it prevents. In other words, as can be seen from these graphs, strains of rodents that get really fat when fed ad lib benefit a lot from CR, while strains that naturally don't get so fat benefit much less:
 

In short, Sohal et al argue that that what matters for lifespan benefits of CR is the amount of obesity burden avoided. In other words, in Sohal's model, obesity is like smoking. It not so much that CR (or not smoking) is actively good for your longevity. Instead, getting (and staying) obese is actively bad for you, just like picking up the habit of smoking is actively bad for you. And the more years you are obese, the worse it is for your longevity, just like the more "pack-years" you smoke, the worse it is for your longevity. The last sentence in Sohal's paper pretty much sums it up:
 

In a nutshell, CR increases life span when it counteracts a significant energy imbalance.

As a corollary, what Sohal is suggesting is that even in rodents, if there is no energy imbalance there will be little if any lifespan increase from CR. Put differently, avoiding obesity and maintaining an "energy balance" will get you most if not all of the benefits of CR.

Speaking of varying benefits of CR across mouse strains, I know Michael is pretty critical of this Nelson study [10], which looked at 41 different inbred strains of mice subjected to CR, and found a tremendous range of benefits and harm depending on strain and sex, as illustrated by this figure. Bars below the 0 line represent CR shortening lifespan relative to ad lib controls in a particular strain:




Regardless of Michael's criticism of the particular strains used in [10], which he mentioned at the recent Conference and which I discuss here, we shouldn't simply ignore these results. Instead, as good Bayesians, we should incorporate this negative result into our model representing the probability that CR will work in humans...

And it's not that we lack any good explanations for the potential life-shortening effects of serious CR. On the contrary, we've got an entire thread devoted to how CR weakens the immune response and makes animals much more likely to die from an illness once they get sick - a point brought home by the presentation by Dr. Janko Nikolich-Žugich at the Conference and discussed in this thread. This is one of the major reasons why I think there is general agreement that people should back off serious CR when they reach elderly years, to allow their (hopefully) preserved immune system to "recharge" and get ready for the slings and arrows of illnesses and injury that inevitably (at least for now) accompany old age.

Finally, like the successful Wisconsin primate study, (virtually?) all CR rodent studies feed both the CR and the control group pretty crappy, refined, unnatural diets of Purina rodent chow. It's no wonder eating less of a bad diet might give CR rodents a modest longevity advantage, just like was seen in the Wisconsin arm of the CR primate studies.

Does anyone know of rodent studies where they fed the CR and AL animals a more healthy, natural diet? Lacking evidence from a healthy-diet rodent CR study, it seems to me that the discrepancy between the Wisconsin and NIA primate CR results (which appears likely to have hinged at least in part on diet quality) calls into question the relevance of any of the positive results of CR in rodents.

In fact, it seems to me the only really credible rodent evidence would be a study of nearly wild-type mice (i.e. not heavily inbred), like the mice Austad used in [8], feeding them a healthy, natural diet either in modestly CRed amounts (i.e. 10% CR) vs. serious CR (40%). If the serious CR mice in such a study lived substantially longer, I'd interpret that as significant evidence in favor of CR efficacy. Short of that, I'd say none of the rodent data tells us very much.

Given what we do know, the available evidence (e.g. lack of mean/median lifespan benefits with wild-type mice fed a crappy diet completely ad lib [8]), suggests to me that the seriously CRed mice wouldn't have any advantage in the ideal experiment I describe.




Evidence from CR in Dogs


Before discussing evidence from humans, there is one more mammal species where CR has been experimentally investigated - namely dogs.

Here is the post where I discuss [4], a study of 25% CR in Labrador retrievers. Since I discussed it in detail in that post, I won't go into weeds about it here, but my summary of that study is:
 

The control dogs in this study were fed too much, given their caged lifestyle, so they grew fat. The CR dogs were fed an amount commensurate with (or a bit higher) than is recommended by canine nutrition experts, remained slim (in the lower part of the recommended weight range for Labradors) and lived 17% longer than controls, enjoying nearly as much CR longevity benefit as can be hoped for in [relatively long-lived] mammals.

In other words, it looks like in dogs, as well as monkeys and rodents, that simply avoiding obesity is where most if not all of the benefits of CR are to be had.

Evidence from Humans

So what about the species that really counts - humans? What can we learn from studies of people about the relative advantage of serious CR vs. simply avoiding obesity while eating a healthy diet?

Fresh in my mind is a discussion I had with Michael about [11], the recent, widely-discussed study (critiqued by me here - which includes my "fragile test tube" analogy) that appears to show that over the last 30-40 years, the healthiest BMI has shifted dramatically higher among healthy never-smokers, from an optimal BMI around 18 in folks in a cohort started in 1976-78 to a BMI around 26 in folks in a cohort started in 2003-2013.

I was surprised at what Michael said was the most likely explanation - which I hope he'll forgive and correct me if I get it not quite right.

What I understood Michael to be saying was that the reason the lowest mortality BMI has increased so much in the last 30-40 years is that, as the authors of [11] suggest, medical advances (e.g. statins, metformin, stents, etc.) have dramatically reduced the deleterious effects of being obese and overweight.

In short, being very thin doesn't pay as much as it used to in terms of longevity dividends. Very thin folks are still saddled with the burden of increased fragility (e.g. likelihood of dying if/when they get sick), while more robust chubby folks aren't penalized as much as they used to be for being overweight/obese as a result of the hundreds of billions of dollars that have been spent over the last few decades to develop treatments to prevent and manage the deleterious effects of obesity and obesity-related diseases like CVD and diabetes.

The reason I was a bit surprised by Michael's explanation for the cause of the increase in the healthiest BMI is that it would seem to undermine to some degree the motivation for practicing CR. By analogy, once vaccines, antibiotics and other medicines for combating infectious diseases were invented, one no longer needed to avoid infections like the plague (both literally and figuratively ☺). Similarly, since we can now prevent and/or manage the negative consequences of obesity better, it isn't as critical to stay rail-thin in order to live a long time.

But you should be thinking "but Dean, study [11] was in the general population - people who are lucky to live 75-80 years, with the last few years spent managing and suffering from diseases of excess. I don't want to live like that. I want to live a healthy life for as long as possible, free from any of the debilitating consequences of obesity. Surely serious CR is the best bet we have for accomplishing that - right? Isn't that what the Okinawans have shown us?"

In short, no. As I discussed in my post comparing Okinawans to Adventists, the Adventists, particularly male Adventists, live substantially longer than Okinawans eating their traditional diet, and the longest-lived Adventists had a "medium" BMI (22.5-25). In fact, according to [12], having a medium BMI added approximately 1.5-2.5 years to an Adventists' lifespan relative to a lower or higher BMI.

So in the the longest-lived population in the world, the clean-living, healthy-eating Adventists from Loma Linda California where (like us) they enjoy the benefits of modern healthcare, and where the men live to a ripe old average age of 87, the best weight to be is not rail thin, and therefore not seriously calorie restricted.

In short, based on the available evidence from primates, rodents, dogs and people, it appears to me that serious CR is unlikely to significantly benefit human longevity relative to a healthy diet eaten in moderation and coupled with an active lifestyle sufficient to avoid obesity and keep a person in the BMI "sweet spot" of ~20-24, or perhaps even 22-25.

--Dean

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[1] Neurobiol Aging. 2005 Jul;26(7):1117-27. Epub 2004 Dec 10.

Age-related decline in caloric intake and motivation for food in rhesus monkeys.

Mattison JA(1), Black A, Huck J, Moscrip T, Handy A, Tilmont E, Roth GS, Lane MA,
Ingram DK.

Author information:
(1)Laboratory of Cardiovascular Science, Gerontology Research Center, National
Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive,
Baltimore, MD 21224, USA.

Full text: http://gen.lib.rus.e...3&downloadname=

Human studies have documented age-related declines in caloric intake that are
pronounced at advanced ages. We examined caloric intake from a longitudinal study
of aging in 60 male and 60 female rhesus monkeys (Macaca mulatta) collected for
up to 10 years. Monkeys were provided a standardized, nutritionally fortified
diet during two daily meals, and intake was measured quarterly. About half of the
monkeys were on a regimen of caloric restriction (CR) representing about a 30%
reduction in caloric intake compared to controls (CON) of comparable age and body
weight. CR was applied to determine if this nutritional intervention retards the
rate of aging in monkeys similar to observations in other mammalian studies.
Following reproductive maturity at 6 years of age, there was a consistent
age-related decline in caloric intake in these monkeys. Although males had higher
intake than females, and CON had higher intake compared to CR, the sex and diet
differences converged at older ages (>20 years); thus, older CR monkeys were no
longer consuming 30% less than the CON. When adjusted for body weight, an
age-related decline in caloric intake was still evident; however, females had
higher intake compared to males while CR monkeys still consumed less food, and
again differences converged at older ages. Motivation for food was assessed in 65
of the monkeys following at least 8 years in their respective diet groups. Using
an apparatus attached to the home cage, following an overnight fast, monkeys were
trained to reach out of their cage to retrieve a biscuit of their diet by pushing
open a clear plastic door on the apparatus. The door was then locked, and thus
the biscuit was irretrievable. The time spent trying to retrieve the biscuit was
recorded as a measure of motivation for food. We observed an age-related decline
in this measure, but found no consistent differences in retrieval time between CR
and CON groups of comparable age and time on diet. The results demonstrate an
age-related decline in food intake and motivation for food in rhesus monkeys
paralleling findings in humans; however, we found no evidence that monkeys on a
long-term CR regimen were more motivated for food compared to CON. Examining the
relationship of selected blood proteins to food intake following 7-11 years on
the study, we found a negative correlation between globulin and intake among
males and females after accounting for differences in age. In addition, a
positive correlation was observed between leptin and intake in males.

PMID: 15748792

---------
[2] Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4. PubMed PMID: 19590001; PubMed Central PMCID: PMC2812811.
-----------
[3] Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R.Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012 Sep 13;489(7415):318-21. doi: 10.1038/nature11432. [Epub ahead of print] PubMed PMID: 22932268.

-----------

[4] J Am Vet Med Assoc. 2005 Jan 15;226(2):225-31.
Influence of lifetime food restriction on causes, time, and predictors of death
in dogs.

Lawler DF(1), Evans RH, Larson BT, Spitznagel EL, Ellersieck MR, Kealy RD.

Author information:
(1)Néstle Purina PetCare Research, 835 S 8th St, St Louis, MO 63164, USA.

Free full text: https://www.avma.org...a_226_2_225.pdf

OBJECTIVE: To describe effects of lifetime food restriction on causes of death
and the association between body-mass characteristics and time of death in dogs.
DESIGN: Paired-feeding study.
ANIMALS: 48 dogs from 7 litters.
PROCEDURES: Dogs were paired, and 1 dog in each pair was fed 25% less food than
its pair mate from 8 weeks of age until death. Numerous morphometric and
physiologic measures were obtained at various intervals throughout life.
Associations of feeding group to time and causes of death were evaluated, along
with important associated factors such as body composition components and
insulin-glucose responses.
RESULTS: Median life span was significantly longer for the group that was fed 25%
less food, whereas causes of death were generally similar between the 2 feeding
groups. High body-fat mass and declining lean mass significantly predicted death
1 year prior to death, and lean body composition was associated with metabolic
responses that appeared to be integrally involved in health and longevity.
CONCLUSIONS AND CLINICAL RELEVANCE: Results were similar to results of diet
restriction studies in rodents and primates, reflecting delayed death from
species- and strain-specific intrinsic causes. Clinicians should be aware that
unplanned body mass changes during mid- and later life of dogs may indicate the
need for thorough clinical evaluation.

PMID: 15706972

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

[5] Weindruch R, et al. (1986). "The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake." Journal of Nutrition, April, 116(4), pages 641-54.



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[1] Aging (Milano). 2001 Aug;13(4):263-72.

The effects of different levels of dietary restriction on aging and survival in
the Sprague-Dawley rat: implications for chronic studies.

Duffy PH(1), Seng JE, Lewis SM, Mayhugh MA, Aidoo A, Hattan DG, Casciano DA,
Feuers RJ.

Author information:
(1)Division of Genetic and Reproductive Toxicology, National Center for
Toxicological Research, FDA, Jefferson, AR 72079, USA. pduffy@nctr.fda.gov

Comment in
Aging (Milano). 2001 Aug;13(4):261-2.
Aging Clin Exp Res. 2002 Apr;14(2):152-4.

A study was undertaken to determine the effects of incremental levels of dietary
restriction (DR) in rats. Survival, growth, reproductive, and dietary intake (DI)
variables were monitored in a chronic study in which male Sprague Dawley (SD)
rats (NCTR colony) were fed their ration ad libitum (AL), or DR. The main
objectives were to determine if low levels of DR could be used to increase the
survival rate of SD rats in the chronic bioassay, and to identify the survival
characteristics of a long-lived SD rat strain (NCTR colony). The average life
span of AL rats was 115 months. At 104 weeks on study (110 weeks of age), the
survival rate for the AL and 10%, 25%, and 40% DR groups was 63.4, 87.5, 87.5,
and 97.5%, respectively. The largest increase in survival (24.1%) occurred
between AL and 10% DR, indicating that very low levels of DR have a significant
effect on survival. Whole-body, liver, prostate, and epididymis weights and body
length were decreased by DR, whereas brain weight, testicular weight, and skull
length were not altered by DR. Rats from the NCTR colony were found to be ideal
for chronic studies because they are much longer-lived than other SD stocks.
Although the 104-week survival rate for these SD, non-obese AL rats exceeds the
FDA's "Redbook" survival guideline (> 50%) for chronic bioassays, the use of DR
is advocated because it reduces individual variability in body weight.

PMID: 11695495

---------
[9] Free Radic Biol Med. 2014 Aug;73:366-82. doi:
10.1016/j.freeradbiomed.2014.05.015. Epub 2014 Jun 2.

Caloric restriction and the aging process: a critique.

Sohal RS(1), Forster MJ(2).

Free full text: http://www.ncbi.nlm....les/PMC4111977/

The main objective of this review is to provide an appraisal of the current
status of the relationship between energy intake and the life span of animals.
The concept that a reduction in food intake, or caloric restriction (CR), retards
the aging process, delays the age-associated decline in physiological fitness,
and extends the life span of organisms of diverse phylogenetic groups is one of
the leading paradigms in gerontology. However, emerging evidence disputes some of
the primary tenets of this conception. One disparity is that the CR-related
increase in longevity is not universal and may not even be shared among different
strains of the same species. A further misgiving is that the control animals, fed
ad libitum (AL), become overweight and prone to early onset of diseases and
death, and thus may not be the ideal control animals for studies concerned with
comparisons of longevity. Reexamination of body weight and longevity data from a
study involving over 60,000 mice and rats, conducted by a National Institute on
Aging-sponsored project, suggests that CR-related increase in life span of
specific genotypes is directly related to the gain in body weight under the AL
feeding regimen. Additionally, CR in mammals and "dietary restriction" in
organisms such as Drosophila are dissimilar phenomena, albeit they are often
presented to be the very same. The latter involves a reduction in yeast rather
than caloric intake, which is inconsistent with the notion of a common, conserved
mechanism of CR action in different species. Although specific mechanisms by
which CR affects longevity are not well understood, existing evidence supports
the view that CR increases the life span of those particular genotypes that
develop energy imbalance owing to AL feeding. In such groups, CR lowers body
temperature, rate of metabolism, and oxidant production and retards the
age-related pro-oxidizing shift in the redox state.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PMCID: PMC4111977
PMID: 24941891
---------
[10] 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

-------
[11] JAMA. 2016 May 10;315(18):1989-1996. doi: 10.1001/jama.2016.4666.
Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013.

Afzal S(1), Tybjærg-Hansen A(1), Jensen GB(2), Nordestgaard BG(1).

Full text: http://sci-hub.cc/10.../jama.2016.4666

Importance: Research has shown a U-shaped pattern in the association of body mass
index (BMI) with mortality. Although average BMI has increased over time in most
countries, the prevalence of cardiovascular risk factors may also be decreasing
among obese individuals over time. Thus, the BMI associated with lowest all-cause
mortality may have changed.
Objective: To determine whether the BMI value that is associated with the lowest
all-cause mortality has increased in the general population over a period of 3
decades.
Design, Setting, and Participants: Three cohorts from the same general population
enrolled at different times: the Copenhagen City Heart Study in 1976-1978
(n = 13 704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study
in 2003-2013 (n = 97 362). All participants were followed up from inclusion in
the studies to November 2014, emigration, or death, whichever came first.
Exposures: For observational studies, BMI was modeled using splines and in
categories defined by the World Health Organization. Body mass index was
calculated as weight in kilograms divided by height in meters squared.
Main Outcomes and Measures: Main outcome was all-cause mortality and secondary
outcomes were cause-specific mortality.
Results: The number of deaths during follow-up was 10 624 in the 1976-1978 cohort
(78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95% CI,
20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95% CI,
9-30]), and 5580 in the 2003-2013 cohort (6%; MR, 4/1000 person-years [95% CI,
1-10]). Except for cancer mortality, the association of BMI with all-cause,
cardiovascular, and other mortality was curvilinear (U-shaped). The BMI value
that was associated with the lowest all-cause mortality was 23.7 (95% CI,
23.4-24.3) in the 1976-1978 cohort, 24.6 (95% CI, 24.0-26.3) in the 1991-1994
cohort, and 27.0 (95% CI, 26.5-27.6) in the 2003-2013 cohort. The corresponding
BMI estimates for cardiovascular mortality were 23.2 (95% CI, 22.6-23.7), 24.0
(95% CI, 23.4-25.0), and 26.4 (95% CI, 24.1-27.4), respectively, and for other
mortality, 24.1 (95% CI, 23.5-25.9), 26.8 (95% CI, 26.1-27.9), and 27.8 (95% CI,
27.1-29.6), respectively. The multivariable-adjusted hazard ratios for all-cause
mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95% CI,
1.23-1.39; MR, 46/1000 person-years [95% CI, 32-66] vs 28/1000 person-years [95%
CI, 18-45]) in the 1976-1978 cohort, 1.13 (95% CI, 1.04-1.22; MR, 28/1000
person-years [95% CI, 17-47] vs 15/1000 person-years [95% CI, 7-31]) in the
1991-1994 cohort, and 0.99 (95% CI, 0.92-1.07; MR, 5/1000 person-years [95% CI,
2-12] vs 4/1000 person-years [95% CI, 1-11]) in the 2003-2013 cohort.
Conclusions and Relevance: Among 3 Danish cohorts, the BMI associated with the
lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978
through 2003-2013. Further investigation is needed to understand the reason for
this change and its implications.

PMID: 27163987


---------
[12] Arch Intern Med. 2001 Jul 9;161(13):1645-52.
Ten years of life: Is it a matter of choice?

Fraser GE(1), Shavlik DJ.

BACKGROUND: Relative risk estimates suggest that effective implementation of
behaviors commonly advocated in preventive medicine should increase life
expectancy, although there is little direct evidence.
OBJECTIVE: To test the hypothesis that choices regarding diet, exercise, and
smoking influence life expectancy.
METHODS: A total of 34 192 California Seventh-Day Adventists (75% of those
eligible) were enrolled in a cohort and followed up from 1976 to 1988. A mailed
questionnaire provided dietary and other exposure information at study baseline.
Mortality for all subjects was ascertained by matching to state death tapes and
the National Death Index.
RESULTS: California Adventists have higher life expectancies at the age of 30
years than other white Californians by 7.28 years (95% confidence interval,
6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88
years) in women, giving them perhaps the highest life expectancy of any formally
described population. Commonly observed combinations of diet, exercise, body mass
index, past smoking habits, and hormone replacement therapy (in women) can
account for differences of up to 10 years of life expectancy among Adventists. A
comparison of life expectancy when these factors take high-risk compared with
low-risk values shows independent effects that vary between 1.06 and 2.74 years
for different variables. The effect of each variable is assessed with all others
at either medium- or high-risk levels.
CONCLUSIONS: Choices regarding diet, exercise, cigarette smoking, body weight,
and hormone replacement therapy, in combination, appear to change life expectancy
by many years. The longevity experience of Adventists probably demonstrates the
beneficial effects of more optimal behaviors.

PMID: 11434797

Some highlights of the study include:

• A study involving 39 Labrador's, 11 (28%) of which reached at least 15.6 years of age or greater (which the researchers refer to as 'exceptional')
• Of note the typical Lifespan of a Labrador is 12 years of age
• These 'exceptional' long-lived dogs accumulated fat slower, though still had similar declines in lean tissue (they measured this with DEXA scans)
• There are mixed results about the impact of neutering on health/longevity in general
• Long-lived dogs have a delayed onset of disease (this sounds just like long-lived humans and the compression of morbidity usually experienced)
• The living conditions for the dogs in this study were fairly well controlled for and sounded pretty good for animals in captivity
• The dogs were fed twice a day and using a fairly normal commercial chow (which is to say that it wasn't particularly healthy IMO)
• Female dogs were 10x as likely to reach the 'exceptional' age (again, this sounds similar to humans)
• Interestingly, 90% of the dogs in this study met or surpassed average life expectancy for the breed
  • Perhaps this suggests that even basic medical care goes a very long way in supporting longevity... at least if you are a cute and cuddly Labrador in captivity getting regular check ups and being closely monitored. 
• To quote directly - "Somewhat paradoxically, the dogs in the Long lifespan group of the current study lost weight between the ages of 9 and 13 years whilst the Exceptional lifespan dogs maintained or slightly gained weight during this time period." This makes me thing of centenarians who need enough mass to protect against frailty without being obese. 
• There were still 5 Labradors alive at the end of the study that were all 16-17 years old! 
  • The researchers state - "There are many factors that may have contributed to the ability of these dogs to exceed a typical lifespan and reach exceptional longevity. These include genetics, husbandry, preventative healthcare, socialisation, housing and environmental enrichment."
• Cancer was the most likely to kill all ages of dogs and was most prevalent in the 'expected' survival group
  • " In the current study, cancer was the cause of euthanasia in 54 % of the dogs that lived to an Expected age, 27 % in the Long group and 33 % in the Exceptional group."

The Kaplan-Meier survival plot can be seen below. 

And because who can resist a cute Lab, here's my own who I hope to have live a long and healthy life! He is about 16 months in this photo from a while back. 

Even for a non-dog owner the paper could be an enjoyable read!

Here is the link. I've made it a "gift" article link so you should be able to read it even without a NYT subscription:

Could Eating Less Help You Live Longer? https://www.nytimes.com/2024/04/24/well/eat/calorie-restriction-fasting-longevity.html?unlocked_article_code=1.m00.2QK3.WribpYAu7QOf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432853/

Brian

https://archive.ph/kTdzH

he seems super-involved

For animals CR's def'd wrt adlib cals but that's a noisy approx to a ref intake for its genes. We shouldn't view gene twins as at diff CR lvl if 1 ate more b4. CR thresh should be a function of tot Cals (& maybe hght) or weight or BMI achieved.

Where should the line be?
On Cals, BMI, or other func?

Should a big % of BMI< 22/22.5 be considered in (at least mild) CR?

2500 Cal/d for men (2000 women) cited as norm. Not sure origin but quoted in papers, eg https://"For the average male to maintain his body weight, he should eat 2500 calories per day" So could take anything below this as CR. Eg male 2000 = 20%CR.

CALERIE study 2467cal baseline tx group achieved ~2175 2yr avg & was called ~12%CR. It was 1987 ie 20%CR 1st 6mo then 2233 ie 9% for 1.5y. Tx grp achieved BMI 22.3 @ 12mo, 22.6 @ 2yr so 9%CR stabilized at BMI ~22.5. But cohort 70% female so these numbers diff v above 2500/2000 ref.

1900s Okinawans estimated to eat 1785 cal. BMI 21. Biosphere 2 male BMI 24.6 -> 20.4 female 21.4 -> 19.0 Some papers say 1750-2100 cal. Others 2200. My notes of Fontana's papers on CRSociety members say 1800 cal 15yrs BMI 24.5 -> 19.5

What other cohorts are relevant?

Should human CR threshold be based on calories or BMI or other?
Where do you think the line should be?

(Clinically drs can test other markers of course, but I'm talking here primarily about an easy to judge test.)

https://www.youtube.com/watch?v=LJ1pIgl542U

children, adolescents, and young adults (under approx 21) should be advised against starting CR. Physical growth may be impaired by calorie restriction, as observed in lab animals. In addition, mental development and physical changes to the brain take place in late adolescence and early adulthood that could be negatively affected by calorie restriction. For this group, the best advice is to follow a normal (non-CR) diet until reaching early twenties.

However, according to this, brain development continues "well into our 20s" (i.e. beyond approx 21). I am wondering if starting CR in one's early or mid 20s would impair brain development. I recall reading that CR can also slow brain deterioration, though, so it might be the case that starting CR in one's early or mid 20s would still be a net positive for brain functioning in the long term.

Any relevant insights would be appreciated.

Aging: https://www.biorxiv.org/content/10.1101/2023.12.28.573547v1.full.pdf

Psychedelics and heart rate: https://comdig.unam.mx/2023/11/10/the-entropic-heart-tracking-the-psychedelic-state-via-heart-rate-dynamics/

====

https://www.brainwavesoftware.ca/#peer

(it also increases stomach size)

__________________________________________________________________________________________________________________________________

I found the above study to be quite interesting. Of all the centenarians included, not a single one of them died of so called old-age and all of them had an identifiable cause of death (as a side note, conducting 42 000+ autopsies is sure a lot - granted only 40 of them were centenarians). Their causes of death tended to be similar to younger folks with cardiovascular disease leading the way at 68% and 78% respectively.

The commentary on their Circumstances of Death and Body Weight was also quite interesting. Sadly, all centenarians in this study were widows. I guess living to such a ripe old age inevitably means you will almost certainly be outliving people you love dearly. The male centenarians included had an average BMI of 21.5, while the female centenarians had an average BMI of 22.8. The authors commentary on their weight is interesting as they state:

What do you think about this topic?

Asymptomatic (or mildly symptomatic) abscesses can  "run in the background" undetected , for years, taxing the immune system subtly, but harmfully affecting tissues and organs. 

Un-careful CR can affect bone and skeletal health in negative ways.

All that said, I am wondering whether CR academia (journals, etc.) have either directly or cursorily looked into the dental health of their CR'd animals? Papers, etc. E.g., how are Wisconsin Rhesuses doing?

Quote

[Associations Between] Low BMI, high mortality

CR diets typically lead to reduced body weight, yet reduced weight can come from other causes and is not in itself necessarily healthy. In some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. Low body weight in the elderly can be caused by pathological conditions associated with aging and predisposing to higher mortality (such as cancer, chronic obstructive pulmonary disorder, or depression) or of the cachexia (wasting syndrome) and sarcopenia (loss of muscle mass, structure, and function). [smoking also lowers current body weight and long-term BMI trajectory, and of course also increases mortality risk -MR]. One of the more famous of such studies linked a body mass index (BMI) lower than 18 in women with increased mortality from noncancer, non−cardiovascular disease causes. The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate. ...

Such epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about caloric intake to begin with, as body weight is influenced by many factors other than energy intake. Moreover, "the quality of the diets consumed by the low-BMI individuals are difficult to assess, and may lack nutrients important to longevity." Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet. As well, "The lower-weight individuals in the studies are not CR because their caloric intake reflects their individual ad libitum set-points, and not a reduction from that set-point.^"

Indeed, simply eliminating people with any history of smoking from an analysis of BMI vs. future risk of death from any cause nearly eliminates the "J-shaped" elevation in mortality amongst people with low body mass indexes:

This was an especially powerful study, too, as it is a meta-analysis of 57 prospective epidemiological studies using individual patient data from over 900,000 subjects. The amazingly huge number of subjects makes it powerful, as is the fact that they used the actual, numerical data for each patient extracted from each study's raw data, than (for instance) pooling studies' "high" and "low" categories as is usually done; as the Cochrane Collaboration acknowledges, although most Cochrane analyses do not take the extra trouble to perform individual patient-data analysis, doing so "can improve the quality of data and the type of analyses that can be done and produce more reliable results (Stewart and Tierney 2002). For this reason they are considered to be a ‘gold standard’ of systematic review." Taking this trouble with the individual data from more than 900,000 people is an enormous scientific labor, and the investigators are to be congratulated.

Another important factor is the degenerative aging process itself. The National Institute on Aging's Baltimore Longitudinal Study of Aging (BLSA), the "most comprehensive and longest running longitudinal examination of human aging in the world," has reported that

Quote

Quote

Approximately 9 years before death, the rate of weight loss increased to an average of 0.39 kg/year (P < 0.001) for all-cause mortality. For cancer deaths, weight loss accelerated significantly 3 years before death, regardless of age group. For cardiovascular deaths, the best-fitting inflection point increased with age, from 5 years for participants aged 60–69 years to 9–10 years before death for those aged 80 years or older. Results suggest that weight loss in older persons may begin earlier than previously believed. The duration of weight loss for noncancer deaths suggests that even distal changes in energy balance may be linked to risk of death.((1); my emphasis)

Predicted weight (in kilograms) by time to death and age at death for male decedents from the Baltimore Longitudinal Study of Aging, Maryland, 1958–2005. Participants who died at A) age 60–69 years (n = 87), B) age 70–79 years (n = 211), C) age 80–89 years (n = 320), D) age ≥90 years (n = 182). Refer to the Statistical Analysis portion of the text for a description of the models.(1)

 

Nearly no epidemiological studies on body weight/BMI have even run for long enough to account for a 9 year trajectory of disease-related weight loss. Most such studies either fail to exclude any early deaths that are likely related to undiagnosed disease onset, or exclude no more than 3 years of such deaths (I have never seen more than 5 years excluded). Aging itself is linked to unintended weight loss, as this graph from the Framingham Heart Study (2) shows:

 ▲ = Females; ◻ = Males

What's more informative is that both men and women who go on to be long-lived have lifelong trajectories of lower body weight than normally-lived people:

(Males)

(Females)

▲ = Long-lived (survived to age 80 for males and age 83 for females); ◻ = medium-lived (i.e., individuals whose age at death was between the ages of 65 and 80 for males and 65 and 83 for females). Also from the Framinham Heart Study (2).

References

1: Alley DE, Metter EJ, Griswold ME, Harris TB, Simonsick EM, Longo DL, Ferrucci L. Changes in weight at the end of life: characterizing weight loss by time to death in a cohort study of older men. Am J Epidemiol. 2010 Sep 1;172(5):558-65. doi: 10.1093/aje/kwq168. Epub 2010 Aug 2. PubMed PMID: 20682520; PubMed Central PMCID: PMC3025636.

2: Yashin AI, Akushevich IV, Arbeev KG, Akushevich L, Ukraintseva SV, Kulminski A. Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study. Age (Dordr). 2006 Dec;28(4):363-374. PubMed PMID: 17895962; PubMed Central PMCID: PMC1994150.

3: Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28;373(9669):1083-96. doi: 10.1016/S0140-6736(09)60318-4. Epub 2009 Mar 18. PubMed PMID: 19299006; PubMed Central PMCID: PMC2662372.

A protein released by blood platelets, PF4, improves cognition in elderly mice.  It declines as we age (in both mice and people).  It may be the reason why young blood improves cognition and reduces frailty in aging mice, when blood vessels are conjoined to younger mice.

Both Calorie restriction and exercise also increase PF4 levels in the blood (of humans).

Read:

https://www.sciencenews.org/article/platelet-pf4-aging-brain-longevity

  --  Saul

The Predimed study is referred to over and over again in so called scientific articles with claims That low fat diet is inferior to a nut or olive oil based diet Wrt cardiovascular risk. The low fat diet reference is 37% fat and a lot of it is saturated! This is pathetic and we can see from this one simpleton example why science is so often scorned, especially wrt personal habits like wearing a mask etc.

These results cannot be attributed to diminished protein intake; MR rats consumed more protein than their CF [control-fed] counterparts when corrected for either body weight (MR: 0.87 g/day vs. CF: 0.58 g/day) or lean body mass (MR: 6.2 g/day vs. CF: 4.9 g/day).

Conventional CR, where carbohydrate and not protein content is sacrificed, is neither protein restriction nor MR. In a preliminary comparison of weight-matched MR and 40% CR rats, CR rats consumed more methionine (CR: 0.16±0.03 g/day vs. MR: 0.02±0.003 g/day) than MR and amounts comparable to CF (0.18 g/day).(7)

There are many, many CR studies (eg, (1-5) in which the percentage of protein in the chow fed to the CR rodents is increased in order to ensure that the absolute intake of protein (and, as a result, Met) is kept exactly the same between the CR and AL groups, and the CR works just fine (better, in fact, in adult-onset organisms). In fact, this is the standard CR protocol of the best labs.

Similarly,(5a) compared one group of animals under 40% total diet CR (including 40% reduction of all macronutrients across the board) with another under 40% CR but with the %protein in the chow boosted up so that they consumed the same absolute amount of protein as the AL animals. The mean and maximum lifespan of the two CR groups was the same. The CR+PR group did fared slightly better on maintaining their renal health with age than the CR-no-PR group (the strain of rat used (F344) is highly prone to nephropathy, which can be ameliorated by PR alone), but only at the very end of life (age 30 months), and only in the form of a modest increase in the number of the lowest grade of lesions.

The non-involvement of PR in CR was also shown in a painstaking meta-analysis of CR studies with varying levels of protein intake.(6)

Protein restriction alone has little or no effect on LS except by introducing "crypto-CR:" studies claiming otherwise either don't track weight and/or Calories rigorously, or are in animals with specific diseases in which a low-pro diet is beneficial, or don't actually measure maximum LS, or uses short-lived controls, the Original Sin of Biogerontology.
 
Now, with that out of the way:
 
What Would it Take to Do This?
What about MetR itself? MetR is one of the very few things rigorously documented to retard the biological aging process in humans. Could you avoid the hassle and huger of CR and still get true anti-aging benefits by restricting your methionine (+cysteine) intake?

Many people would like to believe so. In fact, some (including the ignominious Greger and possibly Mark McCarty) take this idea a step further, suggesting that because plant-based proteins tend to have lower % and/or absolute amounts of Met+Cys compared to animal proteins, one could effect MetR and thus reap anti-aging benefits by simply substituting vegetal for animal proteins.

This Will Not Work. The kind of MetR that retards aging in mice and rats is not a mere "moderation" of Met intake, but a radical and dangerous restriction from normal intake: 80% MetR (ie, about 20% of the rat "RDA" for Met, plus no cysteine in the diet). For instance, in (7) above (an important MetR study that gave some of the first evidence that MetR is not merely a form of "crypto-CR"), "The animals were fed on a purified diet containing either 0.86% methionine (CF) or 0.17% methionine (MR) (Orentreich et al., 1993). The diets were devoid of L-cystine; hence methionine was the sole source of sulfur amino acid."(7) As noted in the quote, MetR animals wound up consuming 0.02±0.003 g Met/day, vs. 0.18 g/day in controls, with no Cys in either group.(7) Similarly, in (8) (another important study, as it was the first to show clearly that MetR works in mice and not just rats):
 

studies of F344 and other rat strains [refs] have shown that maximal lifespan can be extended by diets in which cystine and cysteine are absent and methionine levels are as low as possible. ... [W]e placed a group of CB6F1 female mice on a semi-purified diet containing 0.1% methionine at 6 weeks of age. Control mice were fed a semi-purified diet similar in all respects except that it contained 0.43% methionine by weight. Methionine levels for the experimental group were increased to 0.12% when the mice reached 4 months of age, and again to 0.15% when the mice were 6 months of age, in an effort to reduce the proportion of experimental mice dying as a consequence of rectal prolapse. The experimental diet remained at 0.15% for the duration of the experiment. [both diets contained 0% cystine].(8)

This is a moderately less severe degree of MetR than is standard in the rat studies (starts off at 75% MetR, but loosens up to 66% MetR by age 6 months), but still at all points significantly lower than is achievable by simply consuming vegetal proteins. In his own work on MetR in mice, MetR pioneer Norm Orentreich used a 0.86% Met control diet, but a 0.12% Met diet for MetR — even lower, in absolute terms, than he used in rats, despite the higher-Met control diet.
 
The Numbers
The human Met+Cys RDA is 19 mg/kg•d, or 1330 mg for a 70 kg adult; to achieve the kind of MetR that retards aging in rodents, would require consuming somewhere between 266 (rat studies) to 443 (peak in the mouse study (8)) mg Met per day, with no compensatory Cys — which turns out to be important (see below)).

This cannot be achieved on a natural-food diet. Even a non-CR diet of 2500 Calories of potatoes would contain 1000 mg Met + 800 mg Cys, and it's even worse if you throw in some broccoli (2900 and 2100 mg, respectively). Legumes — as the LORD hath said of counting to 5 with the Holy Hand Grenade of Antioch — are right out.

Now, when I've pointed this out in the past, some people have insisted that this can't possibly be right. Some have argued, for instance, that we shouldn't calculate the degree of restriction from the RDA, but from typical human intakes, derived from either typical American diets or worldwide estimates from the WHO. But this isn't what they do with the rodents: the control chow contains the rodent RDA — no more, no less — and Met is cut back from there in the MetR animals, who additioinally consume zero Cys.

And this more moderate interpretation of the MetR protocol clearly isn't accepted in the scientific community, either. In studies trying to translate the salutary effects of MetR in rodents on metabolism in obese people(11) and in enhancing the effects of chemotherapy,(12-17) Met is radically restricted and Cys excluded entirely, through resort to special chemically-defined medical shakes such as Hominex®-2 and XMet Maxamum®, which were originally designed for people with genetic disorders of vitamin B6-nonresponsive homocystinuria or hypermethioninemia), sometimes supplemented with very low levels of potatoes and vegetables.
 
In (11) (coauthored by MetR pioneer Dr. Norm Orentreich), "Twenty-six obese subjects (six male and 20 female) meeting criteria for metabolic syndrome were randomized to a diet restricted to 2 mg methionine/kg body weight per day [140 mg in a 70 kg adult!] and were provided capsules containing either placebo (n = 12) or 33 mg methionine/kg body weight per day (n = 14)." The same 2 mg/kg•d was used in one of the cancer chemo enhancement studies(16,17), while in the others,(12-15) subjects consumed zero Met+Cys during the brief (1-4 day) window in which they were administered their chemo.
 
No Cheating with Cysteine
As I've noted earlier, the rodent MetR studies involve diets that are not only extremely low in Met, bu contain no Cys at all. This turns out to be quite important. Some people have wondered if you might be able to get the benefits of MetR while minimizing the side-effects by consuming some Cys. Instead, consumption of Cys clearly impairs the metabolic effects of MetR.
 

Although cysteine is the precursor of two sulfur compounds with antioxidant properties, taurine and glutathione (ref), plasma total cysteine (tCys) levels are positively associated with body fat mass (ref), obesity (ref), hypercholesterolemia (ref), and metabolic syndrome (ref) in humans. [see also (27) below]. ...
 
To determine which consequences of methionine-restriction are mediated by decreased cysteine availability, we monitored obesity-related variables in 4 dietary groups for 12 weeks: control-fed (CF), methionine-restricted (MR), MR supplemented with 0.5% l-cysteine (MR+Cys) and CF+Cys rats.
 
MR lowered weight gain and FM/BW% despite higher food intake/weight than CF, and lowered serum cysteine. Hepatic Scd1 expression was decreased, with decreased serum SCD1 activity indices (calculated from serum fatty acid profile), decreased serum insulin, leptin and triglycerides, and higher adiponectin. Cysteine supplementation (MR+Cys) essentially reversed all these phenotypes and raised serum cysteine but not methionine to CF levels.
 
Adding extra cysteine to control diet (CF+Cys) increased serum taurine but did not affect serum cysteine, lipids, proteins, or total weight gain. FM/BW% and serum leptin were modestly decreased. Our results indicate that (24).

In followup work, they showed that many of the gene expression changes in fat, liver, and especially muscle that are induced by MetR are reversed by adding 0.5% Cys.(25) Similarly, "NAC supplementation in MR rats raised tCys and partly or completely reversed MR effects on weight, fat %, Scd1 expression in liver and white adipose tissue, and estimated SCD1 activity. In CF [control-fed] rats, NAC decreased body fat % and lowered SCD1-18 activity index (P<0.001)."(25)
 
On the other hand, "Taurine supplementation of MR rats did not restore weight gain or hepatic Scd1 expression or indices to CF levels, but further decreased adiposity. Taurine supplementation of CF rats did not affect adiposity, but lowered triglyceridemia."(26)
 
Pseudo-Studies of Moderate MetR
Now, hopes were raised a few years back by studies by mitochondrial biologist Gustavo Barja and colleagues, who reported that a much more modest 40% MetR lowered the production of ROS from mitochondria extracted from the kidneys and brains of rats, similar to 40% CR.(9) But of course, while reducing mtROS is likely one important mediator of CR, it's not the whole story, and tweaking one mechanism of aging alone doesn't ultimately impact the overall degenerative aging process (as discussed in more detail here).

The way you most reliably test to see if an intervention is actually impacting the whole-organism degenerative aging process is by seeing if it impacts the one thing that integrates the effects of all aging processes: maximum lifespan, which is limited precisely by the aging process as opposed to selective vulnerability to individual causes of death.

As far as I can see, no proper study of moderate MetR has yet been done. However, what evidence is available does suggest that it doesn't work.

As mentioned above, (5a) compared two CR groups: a CR+PR group in which 40% CR was achieved by cutting all macronutrients across the board, and a CR-no-PR group in which the percentage of protein in the chow was increased even as the amount of food was reduced, so that CR animals consumed 40% fewer Calories but the same absolute amount of protein as the AL animals. The strain of rat used (F344) is highly prone to nephropathy, and as summarized above, the CR+PR group did fare slightly better on maintaining their renal health with age than the CR-no-PR group. However, the mean and maximum lifespan of the two CR groups was the same.(5a)

Of course, cutting the protein meant that the CR+PR group was consuming 40% less Met+Cys than the CR-no-PR group as well, just as in Barja's mtROS study. Yet CR worked just as well without cutting protein or Met, aside from the renal outcome that is unlikely to be driven by mtROS specifically.
 
In a similar study in a different strain of rats, "caloric restricted male rats were fed 18, 30 or 42 percent casein diets that provided two-thirds of the quantity of diet consumed by groups fed 12, 20, or 28 percent casein diets ad libitum, respectively. Hence, caloric restricted groups consumed the same amount of protein as their paired ad libitum fed groups but one-third fewer calories." At one year (youngish adulthood in a rat), the low-protein CR18pro group lived slightly longer than the other two groups — but at two years (seniority), the CR30 and CR40 groups had substantially higher survival (31%, 61%, and 53% survival, respectively).(18) Importantly, in the ad libitum group (in which protein was varied without cutting Calories), the two-year survival was also impaired at 12% protein: 19% survival, vs. 31 and 33% survival on the higher-protein diet.(18) Again, reducing protein intake (and, concomitantly, Met intake) by a moderate amount didn't extend life, and may have shortened it. However, this isn't a very convincing study, because all of these animals were short-lived.

More recently, the matter was put to a more direct test, which seems on its face to give strong evidence that mere methionine moderation yields no life extension benefit. In (10), "three levels of methionine were provided to mice to represent a severe restriction (0.16%) [standard MetR]; approximately 50% reduction (0.43%) compared with standard rodent diets and more achievable in human diets; and an enriched level (1.3%) that remained below toxicity levels." Now, unfortunately, they didn't include a group receiving standard (0.86% Met) chow, but the results initially seem reasonably clear:

--------------0.16% Met -|- 0.43% Met -|- 1.3% Met
Median LS: ---787 days -|- 581 days ---|- 556 days
Maximum^†: 1087days ---|-888 days -|--- 799 days
^†As tenth-decile survivorship

(Pardon the messy attempt at a table). As you can see, the moderate MetR did not enjoy any substantial life extension. However, there are two problems with this study. First, both the moderate-MetR and moderate-Met-overdose groups were somewhat short-lived, and even the MetR group was actually only normally longevous, not demonstrating any actual life extension (and it seems unlikely that moderate MetR would have shortened life; the lack of a normal-Met group makes that difficult to asssess). So the failure of moderate MetR here can't be taken as strong evidence.

Second, their "moderate MetR" group used what others would consider to be a normal level of Met for mice, not a restriction. The group seems to have based their numbers on classical MetR studies in rats, but standard mouse chows today contain more like the 0.43% Met used as moderate MetR in this study — indeed, Rich Miller's strong MetR mouse study above (8) used a 0.43% Met control chow. So it's not clear that this even was "moderate MetR," or indeed MetR at all.

So, the definitive study to test moderate MetR hasn't yet been done. But from what evidence is available, it certainly appears that it Met Moderation will not work as an anti-aging therapy.
 
Moderating Met is Still Good for You
That said, there certainly is some evidence that "moderate MetR" is healthy  — altho' this may simply amount to saying that plant-based sources of protein is good for you, potentially for reasons not related to Met.
 

[in a] "prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42-60 years at baseline" and with "an average follow-up time of 14.0 years," "adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine), the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86) [for an intake of 1.7-2 g Met/d], 1.31 (95% CI: 0.88, 1.96) [2-2.6 g Met/d], and 2.08 (95% CI: 1.31, 3.29) [> 2.6 g Met/d] as compared with the lowest quarter [<1.7 g Met/d]."(19) The major dietary sources of methionine were meat and meat products (31.8%), milk and milk products (31.7%), cereal (17.7%) [meaning, grains: grains are high-Met as a relative proportion of protein, which is why they are used to "complement" the protein in beans] and fish (9.8%)."(19)

 
Not the saturated fat: The significance of the specific finding for methionine may possibly be even greater than that reported, as there was a surprising inverse correlation between methionine intake and saturated fat, which "indicates that although the absolute saturated fat intake increases with increasing methionine intake, its relative proportion of total energy intake decreases. That may indicate that the subjects who consumed more methionine also consumed more energy, but chose protein (and thus methionine) sources with low saturated fat content."(19)
 
This could happen with low-fat dairy, lower-fat cuts of meat, low-fat fish, or conceivably even more grain intake, though it's hard to get a meaningful increase in % dietary protein from grains. The "covariates used in the statistical models included saturated fat" which should in principle have zeroed any confounding effects; still, one wonders if the effect of Met might be even greater than that reported, if it were indeed blunted by their relatively low SFA intake of high Met consumers.

Not the homocysteine: Your initial thought will likely be to chalk this up to homocysteine. Aside from the fact that the causal connection of Hcy to cardiovascular disease is at this point on very shaky ground in general, it just won't wash as an explanation in this specific study. "In our study, however, plasma tHcy was inversely associated with methionine intake. In addition, in a recent randomized controlled trial, a six-month high-protein, high-methionine diet did not raise plasma tHcy concentrations compared with a low-protein, low-methionine diet . Similar results have been observed in other studies. ... One hypothesis [for this disconnect] is that the enzymes in the methionine cycle adapt to the high methionine intake and thus maintain a normal concentration of Hcy in circulation."(19)  Another, more likely one is the confounding of meat, methionine, and B₁₂ intakes. As noted in my post on supplementation for vegetarians, elevated Hcy is quite common in veg(etari)ans, as a dose-response curve (Hcy & B₁₂ deficiency  omnivores < lacto-ovos < vegans).
 
More protein is better:

However, ... total protein intake ... tended to decrease the risk."(19) Specifically, "The mean (±SD) intake of protein was 90.7 ± 25.1 g/day (15.5 ± 2.6% of energy)" and "The age and examination year adjusted [relative risks] of acute coronary event in quarters of energy-adjusted protein intake were 1.0 [for 12.9% of Calories from protein, which would average about 75 g protein/day], 0.89 [14.9%/ 87 g protein], 0.86 [16.1%/ 94 g protein], and 0.78 [18.0%/105 g protein].

If energy adjusted methionine intake was added in the models [to disentangle the fact that a higher intake of protein normally entails a higher intake of methionine, already separately shown to be a risk factor], the RRs for quarters of energy adjusted protein intake (excluding methionine) were 1.0, 0.76, 0.63, and 0.43. Further adjustments did not change the result.(19)

That's right: if you had average Met intake (~2 g/d), but were in the highest protein intake group (~94 g protein/d), you were less than half as likely to suffer an acute coronary event over the course of the next 14 years as a man with similar Met intake but only getting 75 g — which is already for most people more than the RDA.

"Interestingly, total protein intake was not associated with increased risk of acute coronary events, but rather tended to modestly decrease the risk, consistent with previous findings in women [20]." (19) This refers to findings from the Nurses' Health Study, which is amongst the highest-quality epidemiological studies ever produced (large, with prospective analysis of a relatively homogeneous cohort, very well-funded, long-term, repeated measures of dietary and metabolic outcomes along the way, etc etc). They found similar results extending to even higher absolute (as well as relative) protein intake, as is more typical of North American diets — and this in women, who are smaller and weigh less than the men in (19): "After age, smoking, total energy intake, percentages of energy from specific types of fat, and other ischemic heart disease risk factors were controlled for, high protein intakes were associated with a low risk of ischemic heart disease; when extreme quintiles of total protein intake were compared [14.7% vs 24.0% protein], the relative risk was 0.74 (95% CI: 0.59, 0.94). Both animal and vegetable proteins contributed to the lower risk. This inverse association was similar in women with low-or high-fat diets."(20)
 
In a much longer-term followup including data from both the Nurses’ Health Study (followed up from 1980 to June 1, 2012) and the all-male Health Professionals Follow-up Study (followup 1986 to January 31, 2012):
 

The median protein intake, as assessed by percentage of energy, was 14%for animal protein (5th-95th percentile, 9%-22%) and 4%for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was weakly associated with higher mortality, particularly cardiovascular mortality (HR, 1.08 per 10% energy increment; 95%CI, 1.01-1.16; P for trend = .04), whereas plant protein was associated with lower mortality (HR, 0.90 per 3% energy increment; 95%CI, 0.86-0.95; P for trend < .001). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors.(22)

 
Note that this was for total protein intake from each source, without consideration of what that higher protein intake replaced. Taking displacement effects into account:
 

Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat; 0.88 (95%CI, 0.84-0.92) from unprocessed red meat; and 0.81 (95%CI, 0.75-0.88) from egg.(22)

 
Similarly, in the Iowa Women’s Health Study,"Among women in the highest intake quintile, CHD mortality decreased by 30% from an isoenergetic substitution of vegetable protein for carbohydrate (95% confidence interval (CI): 0.49, 0.99) and of vegetable for animal protein (95% CI: 0.51, 0.98), following multivariable adjustment."(21)

To return to (19):
 

The risk was further decreased when the intake of methionine was taken into account in the models [of total protein intake vs. acute coronary event risk], which supports our findings of the risk increasing effects of high methionine intake. This could also explain why the increased risk associated with high methionine intake became more apparent only after total protein intake (excluding methionine) had been taken into account in the statistical models. In other words, the risk reduction associated with total protein intake masks the risk associated with its minor component, methionine. ...

in addition to the findings by Hu and colleagues [20][,] Very low levels of animal protein intake have been associated with increased risk of hemorrhagic stroke in women [29], and low total intake of protein with hemorrhagic stroke in Japan [30]. Furthermore, a significant inverse association between dietary protein and blood pressure in both sexes has been found in a meta-analysis of cross-sectional studies [31]. In addition, recent studies have found that short-term high protein diets decrease triglyceride and LDL cholesterol and increase HDL cholesterol concentrations or have no significant effect on blood lipid measures, although the concurrent weight loss may explain at least part of the effect [32]. However, it seems that high protein diets may be beneficial for cardiovascular health, although longer-term studies are needed for more definite evidence.(19)

There is also a provocative study (28) in which they showed that protein restriction (per se: 7% protein diet, vs. 21% normal rodent chow) or simple replacement of animal protein (lactalbumin, with or without casein) with the same amount of vegetal protein (wheat and corn gluten plus isolated soy protein) substantially inhibited the growth of a variety of implanted cancers in vivo, ostensibly independently of Calorie intake. However, it doesn't appear from reading the paper that they actually measured how much food the animals ate, or how much the animals weighed: the chow was isocaloric, but without measuring food intake you can't rule out crypto-CR. And, implanted cancer cells aren't as good a model as actual "spontaneous" (age-related) cancer incidence and mortality over a lifetime of feeding one diet vs. another.

In practice, a high-protein, low-methionine diet is one composed of a lot of non-grain vegetarian protein. All legume proteins are good, and lentils and favas are exceptionally noteworthy as being high %protein, low-Calorie, and unusually low-Met and low leucine even for a legume (see here and here on leucine moderation), per gram of protein and per Calorie. Dairy (aside from whey) is moderate in methionine; Quorn, despite being of vegetal source, is not very low — and not just because of its eggwhite content: the vegan version is ev is also pretty acceptable (certainly compared with meat).

Eggwhites, however, are very high-Met.
 
Additionally, tho' not enamored of vegans, gelatin is a very screwy protein, which contains no Trp and very little Met indeed; it is so messed up that it shouldn't be a major component of the diet (especially not if it isn't otherwise protein-packed), but if you add a small amount of supplemental Trp to gelatin or sugar-free Jell-O, the near absence of Met turns into a bonus.
 
Reminder on Protein, IGF-1, and CR
Additionally, although plant-sourced protein is in general good for one, and although I emphasize again that MetR ≠ PR, still people on CR should also engage in protein moderation to avoid overriding the reduction of IGF-1 induced by CR — ie, on CR, your protein should be at or a little above the RDA . Here again plant-based proteins are your friends, as vegetal protein is much less IGF-1-inducing than animal protein. In my own case, as I've noted before, even at ≈80 g protein and 16% of energy from mostly vegetal protein, my free and total IGF-1 levels were too low (and I attribute some negative health effects thereto), and I subsequently bumped it up to 20% protein, with the extra protein being either dairy or more highly-absorbable vegetal sources (tho' I have a hard time titrating my protein intake to get a consistent, agreeable IGF-1 profile).
 
A Plea for Rigor
Now, whatever you think of my review of the evidence and analysis, a plea. The life extension community is suffering from widespread confusion on this point that comes from — and is certainly perpetuated by — overly-loose use of language (and what I suspect is willful ignorance at best on the part of overly-zealous vegan propagandists). I have begged people over and over and over and over again to please, please, please, stop muddying the water by referring to limiting one's intake of some nutrient to RDAish levels as "restriction" of that nutrient. As we've seen, biogerontological studies of protein-, Met + Cys-, Leu-, Trp-, or Calorie restriction involve restricting consumption of these nutrients to levels far below the animals' "RDA" intake; with the exception of the Calories in CR, I don't practice or endorse that, and neither does anyone I know of (including a few folks who do, unfortunately, refer to what they do as "restriction" of that nutrient).

References
1: Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982 Mar 12;215(4538):1415-8. PubMed PMID: 7063854.

2: Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA. The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med. 2004 Apr 15;36(8):1043-57. PubMed PMID: 15059645.

"An additional group of mice were 151 subjected to CR at 14 months of age (as detailed in [39]) to serve as a positive control." Their reference (39) is this study from the same authors, which says "The restricted diet was nearly isocaloric to the normal diet, but enriched in protein, vitamins, and minerals to avoid malnutrition." They cite back to an earlier "Methods" guideline of theirs (PMID 10537025, "Controlling caloric consumption: protocols for rodents and rhesus monkeys"), which says even more explicitly, "The protein (casein), minerals, and vitamins are enriched in the [CR] diet such that nearly identical amounts of these components are fed to both [AL and CR] animals after a reduction in diet."

3: Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25. PubMed PMID: 15044709; PubMed Central PMCID: PMC397416.

"Control mice were fed 93 kcal per week of chemically defined control diet (AIN-93M, Diet No. F05312, Bioserv, Frenchtown, NJ). ... CR was introduced by reducing calories to 77 kcal per week of chemically defined CR diet for 2 weeks, followed by 52.2 kcal per week of CR diet thereafter (AIN-93M 40% Restricted, Diet No. F05314, Bioserv)." As is spelled out in the main investigators' own patent for "Methods of evaluating caloric restriction and identifying caloric restriction mimetics," "Mice on the control diet were fed 93 kcal per week fo the control diet (AIN-93M). Mice on the CR diets were fed 77 kcal per week of the CR diet or 52 kcal per week Of the CR diet (40% calorie restricted AIN-93M). ... Each mouse in the LT-CR [Long-Term CR] group 106 was subjected to a LT-CR dietary program with feeding of 52.2 kcal per week of a semi-purified CR diet (AIN-93M 40% Restricted, Diet No. F05314, BIO-SERV). The control diet program consist of about 14 gm/100 gm diet casein, about 0.2 gm/100 gm diet L-cysteine ... The CR diet consist of about 23.3 gm 100 gm diet casein, about 0.3 gm/100 gm diet cysteine ... Note that the 40% CR diet composition listed in Table 12 is for both the 52 kcal per week CR diet and the 77 kcal per week CR diet. The dietary composition for the diet in the reduction stage, where the diet includes a 77 kcal per week diet program, can be adjusted accordingly from the CR diet to obtain a 77 kcal per week diet. The CR diet was used for both 52 and 77 kcal per week CR diets." I'm sure you can do the math .

4: Pugh TD, Oberley TD, Weindruch R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res. 1999 Apr 1;59(7):1642-8. PubMed PMID: 10197641.

5: Davis TA, Bales CW, Beauchene RE. Differential effects of dietary caloric and protein restriction in the aging rat. Exp Gerontol. 1983;18(6):427-35. PubMed PMID: 6673988.

5a: Masoro EJ, Iwasaki K, Gleiser CA, McMahan CA, Seo EJ, Yu BP. Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein.
Am J Clin Nutr. 1989 Jun;49(6):1217-27. PMID: 2729159 [PubMed - indexed for MEDLINE]

6: Speakman JR, Mitchell SE, Mazidi M. Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Exp Gerontol.2016 Dec 15;86:28-38. doi: 10.1016/j.exger.2016.03.011. Epub 2016 Mar 19. Review.PubMed PMID: 27006163.

7: Malloy VL, Krajcik RA, Bailey SJ, Hristopoulos G, Plummer JD, Orentreich N. Methionine restriction decreases viseral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell. 2006 Aug;5(4):305-14. Epub 2006 Jun 26. PMID: 16800846

8: Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005 Jun;4(3):119-25. PubMed PMID: 15924568.

9: Pilar Caro, Jose Gomez, Ines Sanchez, Alba Naudi, Victoria Ayala, Monica López-Torres, Reinald Pamplona, and Gustavo Barja. Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuvenation Res. 2009 Dec;12(6):421-34. PubMed PMID 20041736.

10: Brown-Borg HM, Rakoczy SG, Wonderlich JA, Rojanathammanee L, Kopchick JJ, Armstrong V, Raasakka D. Growth hormone signaling is necessary for lifespan extension by dietary methionine. Aging Cell. 2014 Dec;13(6):1019-27. doi: 10.1111/acel.12269. Epub 2014 Sep 19. PubMed PMID: 25234161; PubMed Central PMCID: PMC4244257.

11: Plaisance EP, Greenway FL, Boudreau A, Hill KL, Johnson WD, Krajcik RA, Perrone CE, Orentreich N, Cefalu WT, Gettys TW. Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome. J Clin Endocrinol Metab. 2011 May;96(5):E836-40. doi: 10.1210/jc.2010-2493. Epub 2011 Feb 23. PubMed PMID: 21346062; PubMed Central PMCID: PMC3085194.

12: Durando X, Farges MC, Buc E, Abrial C, Petorin-Lesens C, Gillet B, Vasson MP, Pezet D, Chollet P, Thivat E. Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology. 2010;78(3-4):205-9. doi: 10.1159/000313700. Epub 2010 Apr 26. PubMed PMID: 20424491.

13: Thivat E, Farges MC, Bacin F, D'Incan M, Mouret-Reynier MA, Cellarier E, Madelmont JC, Vasson MP, Chollet P, Durando X. Phase II trial of the association of a methionine-free diet with cystemustine therapy in melanoma and glioma. Anticancer Res. 2009 Dec;29(12):5235-40. PubMed PMID: 20044642.

14: Durando X, Thivat E, Farges MC, Cellarier E, D'Incan M, Demidem A, Vasson MP, Barthomeuf C, Chollet P. Optimal methionine-free diet duration for nitrourea treatment: a Phase I clinical trial. Nutr Cancer. 2008;60(1):23-30. doi: 10.1080/01635580701525877. PubMed PMID: 18444132.

15: Thivat E, Durando X, Demidem A, Farges MC, Rapp M, Cellarier E, Guenin S, D'Incan M, Vasson MP, Chollet P. A methionine-free diet associated with nitrosourea treatment down-regulates methylguanine-DNA methyl transferase activity in patients with metastatic cancer. Anticancer Res. 2007 Jul-Aug;27(4C):2779-83. PubMed PMID: 17695447.

16: Epner DE, Morrow S, Wilcox M, Houghton JL. Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr Cancer. 2002;42(2):158-66. PubMed PMID: 12416254.

17: Epner DE. Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? J Am Coll Nutr. 2001 Oct;20(5 Suppl):443S-449S; discussion 473S-475S. Review. PubMed PMID: 11603655.
 
18: Davis TA, Bales CW, Beauchene RE. Differential effects of dietary caloric and protein restriction in the aging rat. Exp Gerontol. 1983;18(6):427-35. PubMed PMID: 6673988.
 
19: Virtanen JK, Voutilainen S, Rissanen TH, Happonen P, Mursu J, Laukkanen JA, Poulsen H, Lakka TA, Salonen JT. High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutr Metab Cardiovasc Dis. 2006 Mar;16(2):113-20. Epub 2005 Nov 2. PMID: 16487911

20: Hu FB, Stampfer MJ, Manson JE, Rimm E, Colditz GA, Speizer FE, Hennekens CH, Willett WC. Dietary protein and risk of ischemic heart disease in women. Am J Clin Nutr. 1999 Aug;70(2):221-7. PMID: 10426698 [PubMed - indexed for MEDLINE]

21: Kelemen LE, Kushi LH, Jacobs DR Jr, Cerhan JR. Associations of dietary protein with disease and mortality in a prospective study of postmenopausal women. Am J Epidemiol. 2005 Feb 1;161(3):239-49. PubMed PMID: 15671256.
 
22: Song M, Fung TT, Hu FB, Willett WC, Longo VD, Chan AT, Giovannucci EL. Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality. JAMA Intern Med. 2016 Oct 1;176(10):1453-1463. doi: 10.1001/jamainternmed.2016.4182. PubMed PMID: 27479196; PubMed Central PMCID: PMC5048552.
 
23: Ables GP, Perrone CE, Orentreich D, Orentreich N. Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS One. 2012;7(12):e51357. doi: 10.1371/journal.pone.0051357. Epub 2012 Dec 7. Erratum in: PLoS One. 2014;9(7):e104050. PubMed PMID: 23236485; PubMed Central PMCID: PMC3518083.
 
24: Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Smith AD, Drevon CA, Refsum H, Perrone CE. Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. J Lipid Res. 2011 Jan;52(1):104-12. doi: 10.1194/jlr.M010215. Epub 2010 Sep 25. PubMed PMID: 20871132; PubMed Central PMCID: PMC2999932.

25: Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Orentreich DS, Orentreich N, Refsum H, Perrone CE. Effect of taurine and N-acetylcysteine on methionine restriction-mediated adiposity resistance. Metabolism. 2013 Apr;62(4):509-17. doi: 10.1016/j.metabol.2012.10.005. Epub 2012 Nov 13. PubMed PMID: 23154184.

26: Perrone CE, Mattocks DA, Plummer JD, Chittur SV, Mohney R, Vignola K, Orentreich DS, Orentreich N. Genomic and metabolic responses to methionine-restricted and methionine-restricted, cysteine-supplemented diets in Fischer 344 rat inguinal adipose tissue, liver and quadriceps muscle. J Nutrigenet Nutrigenomics. 2012;5(3):132-57. doi: 10.1159/000339347. Epub 2012 Oct 9. PubMed PMID: 23052097.
 
27: Elshorbagy AK, Valdivia-Garcia M, Refsum H, Butte N. The association of cysteine with obesity, inflammatory cytokines and insulin resistance in Hispanic children and adolescents. PLoS One. 2012;7(9):e44166. doi: 10.1371/journal.pone.0044166. Epub 2012 Sep 11. PubMed PMID: 22984471; PubMed Central PMCID: PMC3439485.

28: Fontana L, Adelaiye RM, Rastelli AL, Miles KM, Ciamporcero E, Longo VD, Nguyen H, Vessella R, Pili R. Dietary protein restriction inhibits tumor growth in human xenograft models. Oncotarget. 2013 Dec;4(12):2451-61. PubMed PMID: 24353195; PubMed Central PMCID: PMC3926840.

[29] Iso H, Stampfer MJ, Manson JE, et al. Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women. Circulation 2001;103:856-63.

[30] Shimamoto T, Komachi Y, Inada H, et al. Trends for coronary heart disease and stroke and their risk factors in Japan. Circulation 1989;79:503-15.

[31] Liu L, Ikeda K, Sullivan DH, Ling W, Yamori Y. Epidemiological evidence of the association between dietary protein intake and blood pressure: a meta-analysis of published data. Hypertens Res 2002;25:689-95.

[32] Halton TL, Hu FB. The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review. J Am Coll Nutr 2004;23:373-85.

Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice.
Campus P, Maiolati M, Orsini C, Cabib S.
Behav Brain Res. 2016 Aug 6. pii: S0166-4328(16)30505-8. doi: 10.1016/j.bbr.2016.08.014. [Epub ahead of print]
PMID: 27506654
http://linkinghub.elsevier.com.sci-hub.cc/retrieve/pii/S0166432816305058
These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning.


The interaction of fasting, caloric restriction, and diet-induced obesity with 17β-estradiol on the expression of KNDy neuropeptides and their receptors in the female mouse.
Yang JA, Yasrebi A, Snyder M, Roepke TA.
Mol Cell Endocrinol. 2016 Aug 6. pii: S0303-7207(16)30298-2. doi: 10.1016/j.mce.2016.08.008. [Epub ahead of print]
PMID: 27507595
http://linkinghub.elsevier.com.sci-hub.cc/retrieve/pii/S0303720716302982
[This paper suggests that steroidal environment and energy state negatively regulate KNDy (Kisspeptin/Neurokinin B/Dynorphin) gene which plays an important role in the https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93gonadal_axis]


Effects of dietary supplementation with EPA and/or α-lipoic acid on adipose tissue transcriptomic profile of healthy overweight/obese women following a hypocaloric diet.
Huerta AE, Prieto-Hontoria PL, Fernández-Galilea M, Escoté X, Martínez JA, Moreno-Aliaga MJ.
Biofactors. 2016 Aug 10. doi: 10.1002/biof.1317. [Epub ahead of print]
PMID: 27507611
http://sci-hub.cc/doi/10.1002/biof.1317
α-lipoic acid, especially in combination with EPA, upregulated the expression of genes associated with lipid catabolism while downregulated genes involved in lipids storage.


Association of the TNF-alpha -308 G/A polymorphisms with metabolic responses secondary to a high protein/low carbohydrate versus a standard hypocaloric diet.
De Luis DA, Aller R, Izaola O, Romero E.
Nutr Hosp. 2016 Jun 30;33(3):267. doi: 10.20960/nh.267. Spanish.
PMID: 27513494
[i have no access to this paper's full texts.]
Carriers of -308 GG promoter variant of TNF-alpha gene have a better metabolic response than -308 GA obese with a high protein hypocaloric diet.

I have also spoken to multiple academics in the field of aging and caloric restriction research.

Many thanks, Kate

The internet is rife with advice for keeping the brain sharp as we age, and much of it is focused on the foods we eat. Headlines promise that oatmeal will fight off dementia. Blueberries improve memory. Coffee can slash your risk of Alzheimer’s disease. Take fish oil. Eat more fiber. Drink red wine. Forgo alcohol. Snack on nuts. Don’t skip breakfast. But definitely don’t eat bacon.

One recent diet study got media attention, with one headline claiming, “Many people may be eating their way to dementia.” The study, published last December in Neurology, found that people who ate a diet rich in anti-inflammatory foods like fruits, vegetables, beans and tea or coffee had a lower risk of dementia than those who ate foods that boost inflammation, such as sugar, processed foods, unhealthy fats and red meat.

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But the study, like most research on diet and dementia, couldn’t prove a causal link. And that’s not good enough to make recommendations that people should follow. Why has it proved such a challenge to pin down whether the foods we eat can help stave off dementia?

First, dementia, like most chronic diseases, is the result of a complex interplay of genes, lifestyle and environment that researchers don’t fully understand. Diet is just one factor. Second, nutrition research is messy. People struggle to recall the foods they’ve eaten, their diets change over time, and modifying what people eat — even as part of a research study — is exceptionally difficult.

For decades, researchers devoted little effort to trying to prevent or delay Alzheimer’s disease and other types of dementia because they thought there was no way to change the trajectory of these diseases. Dementia seemed to be the result of aging and an unlucky roll of the genetic dice.

While scientists have identified genetic variants that boost risk for dementia, researchers now know that people can cut their risk by adopting a healthier lifestyle: avoiding smoking, keeping weight and blood sugar in check, exercising, managing blood pressure and avoiding too much alcohol — the same healthy behaviors that lower the risk of many chronic diseases.

Diet is wrapped up in several of those healthy behaviors, and many studies suggest that diet may also directly play a role. But what makes for a brain-healthy diet? That’s where the research gets muddled.

Despite loads of studies aimed at dissecting the influence of nutrition on dementia, researchers can’t say much with certainty. “I don’t think there’s any question that diet influences dementia risk or a variety of other age-related diseases,” says Matt Kaeberlein, who studies aging at the University of Washington in Seattle. But “are there specific components of diet or specific nutritional strategies that are causal in that connection?” He doubts it will be that simple.

Worth trying

In the United States, an estimated 6.5 million people, the vast majority of whom are over age 65, are living with Alzheimer’s disease and related dementias. Experts expect that by 2060, as the senior population grows, nearly 14 million residents over age 65 will have Alzheimer’s disease. Despite decades of research and more than 100 drug trials, scientists have yet to find a treatment for dementia that does more than curb symptoms temporarily (SN: 7/3/21 & 7/17/21, p. 8). “Really what we need to do is try and prevent it,” says Maria Fiatarone Singh, a geriatrician at the University of Sydney.

Forty percent of dementia cases could be prevented or delayed by modifying a dozen risk factors, according to a 2020 report commissioned by the Lancet. The report doesn’t explicitly call out diet, but some researchers think it plays an important role. After years of fixating on specific foods and dietary components — things like fish oil and vitamin E supplements — many researchers in the field have started looking at dietary patterns.

That shift makes sense. “We do not have vitamin E for breakfast, vitamin C for lunch. We eat foods in combination,” says Nikolaos Scarmeas, a neurologist at National and Kapodistrian University of Athens and Columbia University. He led the study on dementia and anti-inflammatory diets published in Neurology. But a shift from supplements to a whole diet of myriad foods complicates the research. A once-daily pill is easier to swallow than a new, healthier way of eating.

Where diet fits 

Up to 40 percent of dementia cases could be prevented or delayed by modifying 12 risk factors. Targeting some of these risks reduces nerve cell loss in the brain; other interventions protect the brain’s ability to function and adapt even if some nerve loss has occurred, a concept called cognitive reserve. Diet plays a role in at least four of these risk factors.

Twelve modifiable risk factors for dementia

Reduce nerve cell damage 

• Minimize diabetes
• Treat hypertension  
• Prevent head injury
• Stop smoking
• Reduce air pollution
• Reduce midlife obesity 

Increase or maintain cognitive reserve

• Maintain frequent exercise 
• Reduce depression 
• Avoid excessive alcohol
• Treat hearing impairment 
• Maintain frequent social contact 
• Attain high level of education

Source: G. Livingston et al/Lancet 2020

Earning points

Suspecting that inflammation plays a role in dementia, many researchers posit that an anti-inflammatory diet might benefit the brain. In Scarmeas’ study, more than 1,000 older adults in Greece completed a food frequency questionnaire and earned a score based on how “inflammatory” their diet was. The lower the score, the better. For example, fatty fish, which is rich in omega-3 fatty acids, was considered an anti-inflammatory food and earned negative points. Cheese and many other dairy products, high in saturated fat, earned positive points.

During the next three years, 62 people, or 6 percent of the study participants, developed dementia. People with the highest dietary inflammation scores were three times as likely to develop dementia as those with the lowest. Scores ranged from –5.83 to 6.01. Each point increase was linked to a 21 percent rise in dementia risk.

Such epidemiological studies make connections, but they can’t prove cause and effect. Perhaps people who eat the most anti-inflammatory diets also are those least likely to develop dementia for some other reason. Maybe they have more social interactions. Or it could be, Scarmeas says, that people who eat more inflammatory diets do so because they’re already experiencing changes in their brain that lead them to consume these foods and “what we really see is the reverse causality.”

To sort all this out, researchers rely on randomized controlled trials, the gold standard for providing proof of a causal effect. But in the arena of diet and dementia, these studies have challenges.

Dementia is a disease of aging that takes decades to play out, Kaeberlein says. To show that a particular diet could reduce the risk of dementia, “it would take two-, three-, four-decade studies, which just aren’t feasible.” Many clinical trials last less than two years.

As a work-around, researchers often rely on some intermediate outcome, like changes in cognition. But even that can be hard to observe. “If you’re already relatively healthy and don’t have many risks, you might not show much difference, especially if the duration of the study is relatively short,” says Sue Radd-Vagenas, a nutrition scientist at the University of Sydney. “The thinking is if you’re older and you have more risk factors, it’s more likely we might see something in a short period of time.” Yet older adults might already have some cognitive decline, so it might be more difficult to see an effect.

Many researchers now suspect that intervening earlier will have a bigger impact. “We now know that the brain is stressed from midlife and there’s a tipping point at 65 when things go sour,” says Hussein Yassine, an Alzheimer’s researcher at the Keck School of Medicine of the University of Southern California in Los Angeles. But intervene too early, and a trial might not show any effect. Offering a healthier diet to a 50- or 60-year-old might pay off in the long run but fail to make a difference in cognition that can be measured during the relatively short length of a study.

And it’s not only the timing of the intervention that matters, but also the duration. Do you have to eat a particular diet for two decades for it to have an impact? “We’ve got a problem of timescale,” says Kaarin Anstey, a dementia researcher at the University of New South Wales in Sydney.

And then there are all the complexities that come with studying diet. “You can’t isolate it in the way you can isolate some of the other factors,” Anstey says. “It’s something that you’re exposed to all the time and over decades.”

Food as medicine?

In a clinical trial, researchers often test the effectiveness of a drug by offering half the study participants the medication and half a placebo pill. But when the treatment being tested is food, studies become much more difficult to control. First, food doesn’t come in a pill, so it’s tricky to hide whether participants are in the intervention group or the control group.

Imagine a trial designed to test whether the Mediterranean diet can help slow cognitive decline. The participants aren’t told which group they’re in, but the control group sees that they aren’t getting nuts or fish or olive oil. “What ends up happening is a lot of participants will start actively increasing the consumption of the Mediterranean diet despite being on the control arm, because that’s why they signed up,” Yassine says. “So at the end of the trial, the two groups are not very dissimilar.”

Second, we all need food to live, so a true placebo is out of the question. But what diet should the control group consume? Do you compare the diet intervention to people’s typical diets (which may differ from person to person and country to country)? Do you ask the comparison group to eat a healthy diet but avoid the food expected to provide brain benefits? (Offering them an unhealthy diet would be unethical.)

And tracking what people eat during a clinical trial can be a challenge. Many of these studies rely on food frequency questionnaires to tally up all the foods in an individual’s diet. An ongoing study is assessing the impact of the MIND diet (which combines part of the Mediterranean diet with elements of the low-salt DASH diet) on cognitive decline. Researchers track adherence to the diet by asking participants to fill out a food frequency questionnaire every six to 12 months. But many of us struggle to remember what we ate a day or two ago. So some researchers also rely on more objective measures to assess compliance. For the MIND diet assessment, researchers are also tracking biomarkers in the blood and urine — vitamins such as folate, B12 and vitamin E, plus levels of certain antioxidants.

Weighty survey 

Lengthy food frequency questionnaires (a snapshot of some questions below) are a common tool for assessing an individual’s eating habits over time. But the accuracy of results depends on how well participants can recall what they ate and how often.

NIH

Another difficulty is that these surveys often don’t account for variables that could be really important, like how the food was prepared and where it came from. Was the fish grilled? Fried? Slathered in butter? “Those things can matter,” says dementia researcher Nathaniel Chin of the University of Wisconsin–Madison.

Plus there are the things researchers can’t control. For example, how does the food interact with an individual’s medications and microbiome? “We know all of those factors have an interplay,” Chin says.

The few clinical trials looking at dementia and diet seem to measure different things, so it’s hard to make comparisons. In 2018, Radd-Vagenas and her colleagues looked at all the trials that had studied the impact of the Mediterranean diet on cognition. There were five at the time. “What struck me even then was how variable the interventions were,” she says. “Some of the studies didn’t even mention olive oil in their intervention. Now, how can you run a Mediterranean diet study and not mention olive oil?”

Another tricky aspect is recruitment. The kind of people who sign up for clinical trials tend to be more educated, more motivated and have healthier lifestyles. That can make differences between the intervention group and the control group difficult to spot. And if the study shows an effect, whether it will apply to the broader, more diverse population comes into question. To sum up, these studies are difficult to design, difficult to conduct and often difficult to interpret.

Kaeberlein studies aging, not dementia specifically, but he follows the research closely and acknowledges that the lack of clear answers can be frustrating. “I get the feeling of wanting to throw up your hands,” he says. But he points out that there may not be a single answer. Many diets can help people maintain a healthy weight and avoid diabetes, and thus reduce the risk of dementia. Beyond that obvious fact, he says, “it’s hard to get definitive answers.”

A better way

In July 2021, Yassine gathered with more than 30 other dementia and nutrition experts for a virtual symposium to discuss the myriad challenges and map out a path forward. The speakers noted several changes that might improve the research.

One idea is to focus on populations at high risk. For example, one clinical trial is looking at the impact of low- and high-fat diets on short-term changes in the brain in people who carry the genetic variant APOE4, a risk factor for Alzheimer’s. One small study suggested that a high-fat Western diet actually improved cognition in some individuals. Researchers hope to get clarity on that surprising result.

“I get the feeling of wanting to throw up your hands.”

Matt Kaeberlein

Another possible fix is redefining how researchers measure success. Hypertension and diabetes are both well-known risk factors for dementia. So rather than running a clinical trial that looks at whether a particular diet can affect dementia, researchers could look at the impact of diet on one of these risk factors. Plenty of studies have assessed the impact of diet on hypertension and diabetes, but Yassine knows of none launched with dementia prevention as the ultimate goal.

Yassine envisions a study that recruits participants at risk of developing dementia because of genetics or cardiovascular disease and then looks at intermediate outcomes. “For example, a high-salt diet can be associated with hypertension, and hypertension can be associated with dementia,” he says. If the study shows that the diet lowers hypertension, “we achieved our aim.” Then the study could enter a legacy period during which researchers track these individuals for another decade to determine whether the intervention influences cognition and dementia.

One way to amplify the signal in a clinical trial is to combine diet with other interventions likely to reduce the risk of dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, or FINGER, trial, which began in 2009, did just that. Researchers enrolled more than 1,200 individuals ages 60 to 77 who were at an elevated risk of developing dementia and had average or slightly impaired performance on cognition tests. Half received nutritional guidance, worked out at a gym, engaged in online brain-training games and had routine visits with a nurse to talk about managing dementia risk factors like high blood pressure and diabetes. The other half received only general health advice.

After two years, the control group had a 25 percent greater cognitive decline than the intervention group. It was the first trial, reported in the Lancet in 2015, to show that targeting multiple risk factors could slow the pace of cognitive decline.

Now researchers are testing this approach in more than 30 countries. Christy Tangney, a nutrition researcher at Rush University in Chicago, is one of the investigators on the U.S. arm of the study, enrolling 2,000 people ages 60 to 79 who have at least one dementia risk factor. The study is called POINTER, or U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk. The COVID-19 pandemic has delayed the research — organizers had to pause the trial briefly — but Tangney expects to have results in the next few years.

This kind of multi-intervention study makes sense, Chin says. “One of the reasons why things are so slow in our field is we’re trying to address a heterogeneous disease with one intervention at a time. And that’s just not going to work.” A trial that tests multiple interventions “allows for people to not be perfect,” he adds. Maybe they can’t follow the diet exactly, but they can stick to the workout program, which might have an effect on its own. The drawback in these kinds of studies, however, is that it’s impossible to tease out the contribution of each individual intervention.

Embracing complexity 

To untangle the role of diet in dementia, researchers are designing trials that intervene earlier in life and last longer. Some studies combine multiple interventions, like diet, exercise and brain training, as well as measure a wider range of outcomes.

Dementia and diet studies are due a makeover

Then	Now
Target one risk factor at a time	Target multiple risk factors and disease mechanisms simultaneously
Enroll individuals with substantial cognitive impairment	Enroll at-risk individuals who do not yet have symptoms of dementia
Trials last 6–12 months	Trials last 18–24 months
Focus on cognitive and functional outcome measures	Look at multiple outcome measures, including surrogate measures like biomarkers

Source: R. Stephen et al/Frontiers in Neurology 2021

Preemptive guidelines

Two major reports came out in recent years addressing dementia prevention. The first, from the World Health Organization in 2019, recommends a healthy, balanced diet for all adults, and notes that the Mediterranean diet may help people who have normal to mildly impaired cognition.

The 2020 Lancet Commission report, however, does not include diet in its list of modifiable risk factors, at least not yet. “Nutrition and dietary components are challenging to research with controversies still raging around the role of many micronutrients and health outcomes in dementia,” the report notes. The authors point out that a Mediterranean or the similar Scandinavian diet might help prevent cognitive decline in people with intact cognition, but “how long the exposure has to be or during which ages is unclear.” Neither report recommends any supplements.

Plenty of people are waiting for some kind of advice to follow. Improving how these studies are done might enable scientists to finally sort out what kinds of diets can help hold back the heartbreaking damage that comes with Alzheimer’s disease. For some people, that knowledge might be enough to create change.

“One of the reasons why things are so slow in our field is we’re trying to address a heterogeneous disease with one intervention at a time. And that’s just not going to work.”

Nathaniel Chin

“Inevitably, if you’ve had Alzheimer’s in your family, you want to know, ‘What can I do today to potentially reduce my risk?’ ” says molecular biologist Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association.

But changing long-term dietary habits can be hard. The foods we eat aren’t just fuel; our diets represent culture and comfort and more. “Food means so much to us,” Chin says.

“Even if you found the perfect diet,” he adds, “how do you get people to agree to and actually change their habits to follow that diet?” The MIND diet, for example, suggests people eat less than one serving of cheese a week. In Wisconsin, where Chin is based, that’s a nonstarter, he says.

But it’s not just about changing individual behaviors. Radd-Vagenas and other researchers hope that if they can show the brain benefits of some of these diets in rigorous studies, policy changes might follow. For example, research shows that lifestyle changes can have a big impact on type 2 diabetes. As a result, many insurance providers now pay for coaching programs that help participants maintain healthy diet and exercise habits.

“You need to establish policies. You need to change cities, change urban design. You need to do a lot of things to enable healthier choices to become easier choices,” Radd-Vagenas says. But that takes meatier data than exist now.

Questions or comments on this article? E-mail us at feedback@sciencenews.org

I'm new to the forums and very impressed with the level of engagement and sophistication. I wasn't expecting to be convinced that we don't have good evidence that CR works in humans on a CR forum, but I was.

That said, my read of some of the forum posts (and other evidence) is that:

• People tend to think that the evidence suggests fasting is probably good. That means shrinking your eating window down essentially as much as possible and possibly doing some extended (e.g., 5-day fasts).
  • Though Longo continues to insist that 12 hours of fasting and 12 hours of feeding is good. He seems to be an outlier.
  • David Sinclair is into OMAD and seems to think that fasting is the key but I think I've seen some stuff suggesting that he buys into CR but thinks it's too hard.
• People tend to be bullish on protein restriction as a strategy for slowing aging. So eating vegan, keeping protein around 10% of diet. Longo/Fontana stuff.
  • But some folks on the board seem to be vegan for ethical reasons. That's great, but I do worry that there may be motivated reasoning when it comes to the health effects of animal protein.
• Both of these things would tend to support the mechanistic stuff about mTor/IGF-1/etc. This is the very basic growth/longevity tradeoff model. Protein turns on pro-growth signaling but that's bad for longevity. Fasting/eating less protein promotes autophagy. Hormesis. Etc.

Now, I'd welcome feedback suggesting that, like Dean's post on CR in humans, the evidence for these propositions is weaker than some make it out to be. Of course, nothing is clear cut but the question is whether the totality of the evidence is strong enough that it's worth acting on. I used to think that was true of CR (though whether I had the willpower to actually do it was another question), but now I think the evidence is basically 50-50 on whether it'll work in humans relative to a diet that doesn't make you fat. So I'm not really going to put in extra effort to do CR.

But my impression is that, though the evidence is not slam dunk by any means on fasting/protein restriction, there's enough that it's worth doing.

Here's my issue, though. There's the Peter Attia view that we should prioritize preserving muscle mass for healthspan. (This seems to be what he currently thinks; Attia has changed his views a lot.) And indeed, there's good evidence that muscle mass is important for longevity/healtspan. And there are a lot of exercise researchers (Stuart Phillips, Layne Norton) who think eating high protein is important for longevity. Rhonda Patrick has had some of these kinds of people on her podcast recently. These kinds of folks talk a lot about frailty/sarcopenia.

Now, I know that Longo says increase protein after 65 for this reason. But Attia makes the point that we know muscle declines with age, so we want to be starting from as high of a baseline as possible. Which would imply building muscle early in life is optimal. 

The problem is that the muscle-building diet seems to be the exact opposite of the OMAD/protein restricted diet. There seems to be good evidence that ingesting protein leads to a transient increase in muscle protein synthesis, so the way optimal to build muscle is to eat protein (especially animal protein because it has lots of leucine!) at regularly spaced intervals (and do strength training, of course). And of course, that makes sense if the basic growth-longevity tradeoff model is right.

Have others thought about this? I expect that there is some unavoidable tradeoff here, as the growth-longevity model would imply. But does that mean that a shorter eating window isn't necessarily better? How much muscle mass is enough to avoid age-related issues? Might higher protein make more sense after strength training? One thought is that regular strength training will be enough so we shouldn't worry about muscle building on the diet side. But I'm not sure.

I'm 30/yo, male. I do OMAD for the longevity benefits and exercise a fair amount. I also strength train 3 times/week primarily for longevity. (I run a lot, too, more than I would if I were just concerned about longevity.) I eat a pretty high protein diet with lots of animal protein but am thinking about trying to reduce. My approach has pretty much been trying to split the difference by eating high protein for one meal, usually timed so that I eat as soon after strength training as possible. (I find that protein is good for satiety, so high protein diets may be better (at least for some) in reducing body mass.) But I am curious if/how others have tried to split the difference here.

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