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Has CR ever been studied in a species larger than humans?

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All,

 

I was wondering if CR has ever been studied in large creatures? It seems that the effects of CR seem to scale down as the size of species goes up. For example, I believe we can double or triple the lifespan of flies and worms, and modestly extend maximum lifespan in larger species like dogs.  The evidence for humans is of course murky and the jury is still out on whether maximum lifespan will be effected, or just health span.

 

I'm wondering though if CR has ever been studied in a species physically larger than humans. Perhaps horses? Deer? Cows? Buffalo?

Edited by drewab

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Well, sort of.

 

1. I have a reference in my CR bibliography to cows, but no quote and the abstract is unavailable - even the title does not seem helpful (so I am not sure why I put it there years ago): Pinney DO, Stephens DF, Pope LS. Lifetime effects of winter supplemental feed level and age at first parturition on range beef cows. J Anim Sci. 1972 Jun;34(6):1067-74. PMID: 5027302

 

2. In elephants, reverse CR (obesity) correlates with shorter lives http://www.sciencedaily.com/releases/2014/07/140713155346.htm

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Drew,

 

I'm wondering though if CR has ever been studied in a species physically larger than humans. Perhaps horses? Deer? Cows? Buffalo?

 

Very good question!

 

[And now bizarrely and much later in the day, I get Scott's message (i.e. regarding Pinney et al and obesity-avoiding elephants) in my inbox and it seemingly shows up here (or at least I notice it showing up here) long after I researched and wrote the following. Amusingly, Scott writes "even the title [of Pinney et al] does not seem helpful (so I am not sure why I put it there years ago)". Oh well, it just goes to show how much the whole body of evidence supporting CR is just one big game of telephone... ]

 

It is often claimed that is has, with cows being the go-to large mammal. Cows are frequently included in lists of species shown to benefit from CR, both in the popular press, like this 2007 CBS News article featuring Paul and Meredith which say:

 

...research in animals such as mice, dogs, monkeys, even cows, has repeatedly shown that carefully restricting calories increases life spans.

 

as well as self-help books like Living to 100 and Beyond, which says on pg 29:

 

According to the Salk Institute, this concept [calorie restriction - DP] has been proven (in laboratory tests going back to the 1930s) to increase life span by as much as 40%. Subjects included fruit flies, spiders, rats, mice, dogs, cows, monkeys and the the worm C. elegans [ref].

 

Unfortunately, the reference at the end to the Salk Institute is this 2007 paper [5] in Nature where researchers from Salk discovered important things about C. elegans longevity pathway, which only says about other species (my emphasis):

 

The insulin/IGF-1 signalling (IIS) pathway is a key regulator of
the ageing process in worms, flies and mice, but its role in the regulation
of diet-restriction-mediated longevity remains ambiguous

 

The Salk public relations folks go a bit more out on a limb in their press release about the paper, saying (my emphasis):

 

In studies going back to the 1930's, mice and many other species subsisting on a severely calorie-restricted diet have consistently outlived their well-fed peers by as much as 40 percent.

 

Is this starting to sound like a game of telephone to anyone else? Once again, no actually evidence about cows found anywhere...

 

Heck, even the old CR Society homepage (up until a redesign in 2011) jumped on the cow CR bandwagon (my emphasis):

 

Since the 1930s extensive scientific research has shown that calorie restricted (CR) diets improve health and extend lifespans of nearly every species tested, including worms, spiders, rodents, dogs, cows and monkeys. We believe it is likely that people who carefully adopt a CR diet will see similar results.

 

I've addressed the less than compelling CR dog results before, and we know what happened subsequently with the monkeys... But what about those cows? I decided to continue my hunt for the elusive CR cows...

 

The extends lifespan link from the old CRS homepage points to an blog post by our old friend and CR practitioner Ian Goddard. Unfortunately for the credibility of the CRS, Ian doesn't mention any species by name. But he does give two references, saying (my emphasis):

 

Only one intervention has been proven to extend both the average and maximum lifespan of all animal species tested: reducing the consumption of dietary calories, or caloric restriction (CR). [ref1, ref2] 

 

Ian's reference ref1 is the seminal paper by Clive McCay from 1935, who discovered that CR seems to work in rodents. I didn't bother to see if that contained any reference to CR having been proven to work in other species (esp. cows!), since obviously it wouldn't have been shown back then.

 

Even more embarrassing, Ian's ref2 is a CR story in Scientific American from 2000 by none other than that most credible of science journalists, Gary Taubes, called The Famine of Youth. A piece apparently penned before he jumped on the paleo, saturated-fat apologist bandwagon. Gary, to his credit but without references, says (my emphasis):

 

This harsh regime [CR - DP] has been shown to work its life-extending magic on almost every species that's ever been tested--from paramecium and worms to spiders, insects, rodents and (although the data are still preliminary) primates.

 

Ironically considering the source, Gary's statement seems like the most accurate and least hyperbolic of all we've seen so far! We know now what actually happened with the primates, but Gary can be forgiven for his optimism back in 2000. Unfortunately, once again cows are nowhere to be seen... So the CR Society's claim that CR works in cows can apparently be traced back to a statement by Gary Taubes that doesn't mention cows anywhere! This is looking more embarrassing all the time...

 

OK - maybe I've been looking in the wrong place. You'd think the CRS would check its references for such a bold proclamation on its homepage, but whatever. Perhaps I need to look directly at the primary literature on CR instead. Somebody's got to have done something with cows at some point, right!?

 

This 2013 review article [1] titled Calorie restriction and its mimetics seems like as good a place as any to look, since it too boldly jumps on the cow CR bandwagon (my emphasis):

 

The effects of caloric restriction on longevity and health have been reproducibly investigated in a wide range of laboratory animals, yeast, worms, fruit flies, and rodents, as well as some wild animals including cows and dogs [2].

 

They appear to be basing their "Noah's ark" of CR animal species on reference [2] a review article by Fontana & Longo titled Extending healthy life span--from yeast to humans. That title sounds promising, and those are two highly-respected researchers. We must be onto something - Luigi's got to know something about cow CR, right?

 

Sadly, Fontana & Longo [2] mentions only a subset of the list from [1], leaving off both cows and dogs, but throwing in monkeys, all entirely without attribution or references:

 

 Indeed, dietary restriction (DR), a reduction in food intake without malnutrition, extends the average and/or maximum life span of various organisms including yeast, flies, worms, fish, rodents and rhesus monkeys.

 

Like Taubes, perhaps Luigi and Victor can be forgiven for playing a bit fast and loose with the list by including monkeys, since the disappointing CR primate results hadn't been published at the time of their review (2010).  But once again, we've come to a dead end. No cows here. Just more exaggerated, dead end references...

 

At this point in my research the idea that "CR works in cows" was beginning to look like one of those urban legends that everybody believes simply because they've heard it from someone else, because it seems like it could be plausible, and because they hope it is true since it would support their preconceived biases and make for a good story...

 

But I didn't want to leave any stone unturned, so I kept plugging away at my search.

 

The next cow sighting I made was in this 2011 special issue of the Journal of Molecular Aspects of Medicine [3] devoted to CR, and edited by our good friend and star CR researcher John Speakman. In it, Speakman et al. say:

 

However, the effect of CR on lifespan in invertebrates was not always positive. For example, it does not increase lifespan of house flies (Musca domestica) (Cooper et al., 2004) and in some rotifers and water striders it had a negative effect (Kirk, 2001; Kaitala, 1991). Among vertebrates CR was also shown to have beneficial effects on both median and maximal lifespan in mice (Mus musculus) (Weindruch, 1992), cows (Bos taurus) (Pinney et al., 1972) and dogs (Canis domesticus) (Lawler et al., 2008; Kealy et al., 2002; Lawler et al., 2005).

 

Pay dirt! - a reference specifically about cow CR, with the bold claim by someone as well-respected as John Speakman that CR has been shown to extend both median and maximal lifespan in cows. This I gotta see.

 

And no wonder it's been hard to track down, it's from way back in 1972. Almost lost in the annals of history. Fortunately nothing is lost these days with the web. The Pinney et al. reference is [4], titled Lifetime effects of winter supplemental feed level and age at first parturition on range beef cows.

 

But then to my chagrin, I discovered that I'm like that climber who struggles up the side of a mountain only to discover a McDonalds at the top with a road leading up the other side. Michael, in his magnum opus blog post on the CR primate study, cites Pinney et al. as his reference (236), saying (my emphasis):

 

CR has been shown to decelerate multiple degenerative aging processes in nearly every species and strain of organisms in which it has been tested, preserving youthful functionality and extending life in species ranging from yeasts, through small multicellular invertebrates, and most extensively to laboratory rodents — and although inconclusive, recent evidence also supports its effectiveness in dogs,((3) — and see (95) for additional analysis), possibly cattle,(236) and apparently (in a Czech study recalled but not available for citation(237,238)) in rabbits. 

 

Doh - I (along with everyone else) have been referring to the beasts in question colloquially as "cows", while Michael has to get all fancy pants and call them "cattle"... ☺. Oh well. At least I finally got to the bottom of it.

 

But wait a minute. What does Michael mean by "possibly cattle"? Is there more (or less) to Pinney et al than people have been saying all these years? Definitely worth looking at to see what the scoop is. So let's dive in, shall we?

 

You know these people don't have the animals ultimate welfare in mind when in the first paragraph of the full text they start talking about beef cow "performance":

 

A number of studies have indicated that ... nutrition of the beef cow can affect the performance of the cow and her offspring.

 

But hey, just because cows are a commodity to these livestock researchers (who hail from Oklahoma State and Texas A&M College of Agriculture), doesn't mean they can't conduct a good study. Let's give them the benefit of the doubt, and see what they did and what they found.

 

Here is the experimental design (my emphasis):

 

In October, 1948, a study was initiated using 90 Hereford weanling heifers procured from one herd. They were randomly allotted to six treatment groups of 15 heifers each. Each group was randomly assigned to one of six factorially arranged treatments. From early November to mid-April of each year, the groups were fed the following amounts of supplemental feed per head daily:
 
Low level (lots 1 and 2)--0.45 kg of 43% solvent process cottonseed meal
 
Medium level (lots 3 and 4)--1.13 kg of cottonseed meal
 
High level (lots 5 and 6)--1.13 kg of cottonseed meal plus 1.31 kg of whole oats.
 
This represents approximately 60, 120 and 200% of the presently recommended digestible protein allowances for the low, medium and high levels, respectively. Lots 1, 3 and 5 were exposed to bulls to calve first at 2 years of age (1950), while lots 2, 4 and 6 were exposed to calve first at 3 years of age (1951). All treatment groups were pasture mated to Hereford bulls during May, June and July of each year, with equal numbers of cows from each treatment combination being exposed to each bull, to minimize sire effects between treatments. Throughout the study, all cows grazed native grasses yearlong with a stocking rate of approximately 10 acres per cow.
 
Right off the bat there are a few things to notice about this study design. First, this was a study of supplemental feeding - all three (six) groups of cows were getting extra food in addition to the native grasses they were eating ad lib out in the pasture. Does that sound to you like any well-designed CR study you've ever read? Me neither.
 
Second, they don't even report the caloric content of the three different supplemental feeds, just that one condition represents less protein (and two, more protein) than is recommended. So it's a protein restriction study (sort of...). And what do they mean by 'recommended'? Clearly as cattle researchers interested in "beef cow performance" these folks aren't interested in necessarily maximizing cow longevity. In fact, it is almost certain that the "recommended" level of calories / protein for beef cows is far in excess of what would optimize their longevity, since they want to fatten them (and their calves) for market as quickly as possible.
 
Next, notice that all the cows were grazing outdoors year round and only given the three levels of supplemental feed for six months of the year (in winter). In fact, each of the cows (even the restricted ones) were given 10 acres of pasture containing "native grasses" to feed on year round. How's that compare with grass fed beef cattle today? It's pretty close to cow heaven. For example, in Missouri (a state a bit north of Oklahoma where this study was conducted), this rancher recommends "2 acres per head on a very good year and 4 on a dry year in an intensive grazing system." This wonderfully-titled document from the USDA called "Beef Cattle May Be Easy Way to Put Pastures to Work" says:
 
If your pasture land is covered with brush and scrub trees or rock, five or more acres per cow will be required.
 
Presumably the research farm in the Dept of Animal Sciences and Industry at Oklahoma State where this study was conducted did not have pastures "covered with brush, scrub trees or rocks", so at 10 acres per cow, the cows had it pretty good, at least compared with today's grass-fed beef cows, to say nothing of those languishing at this moment in crowded, manure-drenched fed-lots on factory farms - excuse me, "intensive animal agriculture facilities" or "industrial livestock facility" - to use the most popular euphemisms employed by those with something to hide.. But I digress.
 
So all the cows were living (and eating) pretty high on the hog, so to speak. But it's true from the yearly weight variation table (Table 1 - not shown) that the cows given the "low" amount of supplemental nutrition (who I'll refer to as the "CR cows" - despite the dubiousness of that label) were lighter relative to the "high" supplement group in the wintertime, losing more weight, or gaining a bit less weight, depending on (presumably) the severity of the winter. But the lightly-fed CR cows made up for it in summer, consistently gaining more weight during summertime than the cows given the high or medium amount of supplemental food in winter. The authors wrote:
 
An inverse relationship between winter gain and summer gain is evident, and highly significant differences (P<.005) occurred in summer gain due to winter feed level for the first five summers. As winter loss increased, summer gain increased. This compensatory gain has been widely documented, and is apparent in this data.
 
In short, at best we're looking at seasonal CR, with fewer calories in winter and compensatory overfeeding in the summer. So much for anything like a regular CR study design...
 
In fact, given these cows were grazing ad lib outdoors, its not at all clear which groups were eating the most total calories year round, a fact that is reflected in the weights of the six groups of cows (3 feed levels x 2 years of first mating, aka parturition) at age 8, the only point at which cow weight was reported:
 
XgZQ59a.png
 
As you can see, depending on the first year the cows were mated, the difference in weights between the three feeding groups was either 5 to 7.5% of total body weight. A pretty paltry difference, given that it's pretty common for CR mice to way 30-50% less than ad lib mice, and humans to lose a similar fraction of body weight when practicing CR (e.g. I went from 172 → 120 lbs, a difference of 36%). If fact, the authors observed "no statistically significant differences were seen in these weights".
 
There goes the whole idea that this was a CR study... But let's proceed.
 
In fact, not only weren't the weight differences statistically significant, the so-called "CR" cows (low group) weren't even consistently the thinnest! In the 3-year parturition group, the "medium" supplemented group weighed less than the "low" group.
 
But it gets worse...
 
What these researchers were interested in really was calf production. So they looked at all kinds of statistics about the calves from each of the six groups. Given the lack of a lower weight in the mothers, it's not surprising the calves didn't show any adverse effects either. In fact, if anything it was the opposite:
 
...the cows on the low winter feed level gave birth to a higher percent of calves, and lost less calves to weaning...
 
...neither winter feed level, nor age at first parturition, having any observable or significant effect on mean birth weights.'
 
No differences in 210-day weaning weights approached significance. The unweighted means show a slight advantage for the low winter feed level in four of the six calf crops reported.
 
So the so-called "CR cows" had more babies who were just as plump at birth, had fewer calves die prior to weaning, and had slightly chubbier calves at the time of weaning. Obviously these cows weren't CRed anywhere near the point of infertility, or an inability to produce enough milk to support her calves! 
 
But what about what we really care about, longevity? Here is the full table from above, this time including the "survival" data, highlighted in yellow:
 
EGc0Tg1.png
 
The study was started in 1948, so at the first headcount reported (in 1956), the cows were around 8 years old, and the second count (in 1957) the cows were 9 years old. Right off the bat you see the numbers of cows in each group are small, and the survivorship pattern is all over the map. In the 2-year parturition groups, it looks almost like the CR (Low) group is doing better, particularly relative to the overfed (High) group. But in the 3-year parturition group, the Low and High survivorship is virtually identical at both time points. So much for a survivorship advantage in CRed cows...
 
But believe it or not, it gets even worse...
 
You might ask, that's survivorship at two different time points. But what about lifespan - which is what we really care about? They computed that too. Here is the data in tabular form:

 

H0tUTB5.png

 
 
And here are the two "survival" curves for 2-year parturition groups (left) and 3-year parturition groups (right):
 
tCC7UuD.png
 
We see pretty much the same relationship in longevity as we saw in survivorship - with a seeming CR advantage for 2-year parturition cows and no real difference in the feeding groups for 3-year parturition cows. But those "survival" curves in the left graph look particularly encouraging - don't they!?. Maybe having kids young and going hungry in the winter is the way to go, if you're a cow?
 
But hold your horses (or cows). Appearances can be deceiving, in so many ways...
 
First, the authors say they didn't do any statistical analysis on the longevity data, for reasons I still have trouble parsing:
 
No statistical interpretation of these mean lifespans is made in that within treatment variance is related to treatment, and not normally distributed where a greater number of cows were still alive in some treatment groups at the termination of the study.
 
Aren't those the kind of differences that you're supposed to look at when computing longevity statistics? Of course "within treatment variance is related to treatment" - would you expect otherwise?
 
But it gets even worse.... Even the numbers they do give for lifespans are a crock.
 
Notice I've put "survival" in quotes above? There is a reason for that. It turns out, none of these cows were allowed to live out their natural lifespan. From the study's fine print (my emphasis):
 
Cows were removed from test only in the event that they failed for any reason to wean a calf in 2 successive years, or for conditions rendering them of no further productive value.
 
Catch that? Cows were being culled from the herd (and the experiment) when they were no longer having calves, or had "no further productive value". So much for living out their elder years grazing in peace on open pastures...
 
What were the reasons the cows were culled? (my emphasis):
 
Failure to wean a calf in 2 successive years is the most prevalent reason for removal of cows from test with four, seven and six cows being removed for this reason from the low, medium and high winter feed level groups, respectively. Cancer eye of the cows was the next largest reason for removal, with one, six and six cows being removed from the low, medium and high groups, respectively.
 
In short, the so-called CR cows appeared to have a so-called "longevity" advantage in the herd not because they actually lived longer, but because they were better at making babies and got less friggin' eye cancer - so the herdman didn't kill them off. Other reasons some of the cows in each group were culled included "crippled", "spoiled udder", and "died of calving difficulties". Do those seem like legitimate reasons to get rid of animals in a CR study? I don't think so either.
 
And I should note, in case it isn't clear - the data from those culled cows wasn't simply ignored and thrown out. The age at which they were culled was used in the 'lifespan' computation!
 
Oh yeah, and there was one other reason for culling - emaciated condition:
 
it is interesting that the herdsman's notations indicated that nearly all of the "emaciated" cows removed for this reason, came from the two low feed level treatment groups [specifically - 7 from 'Low' group and 1 from 'Medium' feed group - DP]
 
Catch that? If cows were too thin as judged by the herdsman, because, like, maybe they were actually calorie restricted, they were friggin' killed off and eliminated from the study! So it was only the chubby cows in the so-called CR condition (who were probably better at foraging for food and so weren't as skinny) that were contributing to the apparent longevity advantage <sic> resulting from CR <sic>.
 
Oh yeah - one other thing. The so-called "longest lived" cows in this study had an average "lifespan" of 14.65 years. That must be pretty impressive for this breed of cattle (Hereford) right? Nope. From the Hereford page on The Cattle Site (my emphasis):
 
These cattle are known for their vigor and foraging ability and for their longevity, many females live and produce calves beyond the age of 15 years.
 
Ouch...
 
Despite how utterly (☺) meaningless their results were in general, and how completely irrelevant they were to CR, the authors nevertheless blather on about CR in the discussion section, saying (my emphasis):
 
 Restricted dietary energy in the early life of the rat has been shown to favor a longer lifespan (Ball, Barnes and Visscher, 1947; McCay et al.,1935, 1939, 1943). Later research (Berg and Simms, 1960), indicated that less severe restrictions in the complete diet throughout life, resulted in a longer lifespan, less disease and reduced tumor incidence in the rat. Arnett (1963) using monozygotic beef cattle twins, indicated longer survival for "normally-fed" twin-mates as compared to grossly "over-fed" twin-mates. Also, Hansson et al. (1953) observed this phenomenon with dairy cows when comparing restricted to normally fed cows. J. H. Hughes et al. (Unpublished data) reported some advantage in survival rate of beef cows on two lower planes of winter supplemental feed as compared to two higher levels However, he states that no definite conclusions concerning longevity could be made with the small number of observations made.
 
How's that for a knockdown argument for the efficacy of CR in cows!? Not... 
 
It's no wonder Michael was guarded in his endorsement of the claim that CR works in cattle. I wonder if he's ever actually read the paper he references, since it seems to me that if he had, he'd have been too embarrassed to even mention cows, unless his standard for evidence is a lot lower than I imagine...
 
The researchers even acknowledge the meaninglessness of their own findings, and bemoaned the small number of cows in their study:
 
Additional numbers of observations would facilitate the drawing of meaningful conclusions. However, this type of data is extremely meager, and will probably be no more plentiful in the foreseeable future.
 
Now, 45 years later, we can see just how much of an understatement that last remark was.
 
In short, the widely promulgated rumor that CR works in cows is a complete load of manure. We can therefore add cows to the list of large mammals (currently including dogs and monkeys) where, despite attempts to show otherwise and widespread claims to the contrary, there is no good evidence that CR extends lifespan relative to a healthy, obesity-avoiding diet.
 
--Dean
 
------------

[1] BMB Rep. 2013 Apr;46(4):181-7. Review.

 

Caloric restriction and its mimetics.

 

Lee SH, Min KJ.

  PMID:  23615

 

-----------

[2] Science. 2010 Apr 16;328(5976):321-6. doi: 10.1126/science.1172539.

 
Extending healthy life span--from yeast to humans.
 
Fontana L(1), Partridge L, Longo VD.
 
Author information: 
(1)Division of Geriatrics and Nutritional Science, Washington University School
of Medicine, St. Louis, MO 63110, USA. lfontana@dom.wustl.edu
 
Comment in
    Science. 2010 Aug 27;329(5995):1012-3; author reply 1013-4.
    Science. 2010 Aug 27;329(5995):1014-5; author reply 1015.
 
When the food intake of organisms such as yeast and rodents is reduced (dietary
restriction), they live longer than organisms fed a normal diet. A similar effect
is seen when the activity of nutrient-sensing pathways is reduced by mutations or
chemical inhibitors. In rodents, both dietary restriction and decreased
nutrient-sensing pathway activity can lower the incidence of age-related loss of 
function and disease, including tumors and neurodegeneration. Dietary restriction
also increases life span and protects against diabetes, cancer, and
cardiovascular disease in rhesus monkeys, and in humans it causes changes that
protect against these age-related pathologies. Tumors and diabetes are also
uncommon in humans with mutations in the growth hormone receptor, and natural
genetic variants in nutrient-sensing pathways are associated with increased human
life span. Dietary restriction and reduced activity of nutrient-sensing pathways 
may thus slow aging by similar mechanisms, which have been conserved during
evolution. We discuss these findings and their potential application to
prevention of age-related disease and promotion of healthy aging in humans, and
the challenge of possible negative side effects.
 
DOI: 10.1126/science.1172539 
PMCID: PMC3607354
PMID: 20395504
 
---------
[3] Mol Aspects Med. 2011 Jun;32(3):159-221. doi: 10.1016/j.mam.2011.07.001. Epub
2011 Aug 10.
 
Caloric restriction.
 
Speakman JR(1), Mitchell SE.
 
 
Restricting the intake of calories has been practiced as a method for increasing 
both the length and quality of life for over 500 years. Experimental work
confirming the success of this approach in animals has accumulated over the last 
100 years. Lifelong caloric restriction (CR) may extend life by up to 50% in
rodents, with progressively less impact the later in life it is started. This
effect is matched by profound impacts on age related diseases including reduced
risk of cancer, neurodegenerative disorders, autoimmune disease, cardiovascular
disease and type II diabetes mellitus. The disposable soma theory of ageing
suggests that CR evolved as a somatic protection response to enable animals to
survive periods of food shortage. The shutdown of reproductive function during CR
is consistent with this suggestion, but other features of the phenomenon are less
consistent with this theory, and some have suggested that in rodents it may be
mostly an artifact of domestication. CR induces profound effects on animals at
all levels from the transcriptome to whole animal physiology and behavior.
Animals under CR lose weight which is disproportionately contributed to by white 
adipose tissue. Generally animals on CR change their activity patterns so that
they are more active prior to food delivery each day but total activity may be
unchanged or reduced. Considerable debate has occurred over the effects of CR on 
resting metabolic rate (RMR). Total RMR declines, but as body mass and body
composition also change it is unclear whether metabolism at the tissue level also
declines, is unchanged or even increases. Body temperature universally decreases.
Hunger is increased and does not seem to abate even with very long term
restriction. Circulating adipokines are reduced reflecting the reduction in white
adipose tissue (WAT) mass under restriction and there is a large reduction in
circulating insulin and glucose levels. There are profound tissue level changes
in metabolism with a generalized shift from carbohydrate to fat metabolism. Four 
pathways have been implicated in mediating the CR effect. These are the insulin
like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the
adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the
target of rapamycin (TOR) pathway. These different pathways may interact and may 
all play important roles mediating different aspects of the response. Exactly how
they generate the health benefits remains open for debate, however CR results in 
reduced oxidative stress and enhanced autophagy, both of which could be essential
components of the beneficial effects. Most data about the effects of CR in
mammals comes from work on rodents. There is limited work on non-human primates
that shows promising effects and one randomized controlled trial in humans where 
physiological markers of the CR response are consistent with the responses in
mice and rats. There are also populations of humans voluntarily restricting
themselves. Humans on long term restriction report similar negative side effects 
to those observed in animals - perpetual hunger, reduced body temperature leading
to a feeling of being cold, and diminished libido. Considerable effort has been
directed in recent years to find drugs that mimic the CR response. Promising
candidates are those that intersect with the critical signaling pathways
identified above and include biguanides such as metformin that target the insulin
signaling pathway, stilbenes (e.g. resveratrol) that affect sirtuin activity and 
drugs such as rapamycin that interact with mTOR signaling. Whether it will ever
be possible to find drugs that capture the health benefits of CR without the
negative side-effects remains unclear. Moreover, even if such drugs are developed
how the current licensing system for drug use in western societies would cope
with them may be a further obstacle to their use.
 
Copyright © 2011 Elsevier Ltd. All rights reserved.
 
DOI: 10.1016/j.mam.2011.07.001 
PMID: 21840335 
 
---------
[4] Nature. 2007 May 31;447(7144):550-5. Epub 2007 May 2.
 
PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans.
 
Panowski SH(1), Wolff S, Aguilaniu H, Durieux J, Dillin A.
 
Author information: 
(1)The Salk Institute for Biological Studies, Molecular and Cell Biology
Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
 
Comment in
    Nature. 2007 May 31;447(7144):536-7.
    Gastroenterology. 2007 Nov;133(5):1729-30.
 
Reduced food intake as a result of dietary restriction increases the lifespan of 
a wide variety of metazoans and delays the onset of multiple age-related
pathologies. Dietary restriction elicits a genetically programmed response to
nutrient availability that cannot be explained by a simple reduction in
metabolism or slower growth of the organism. In the nematode worm Caenorhabditis 
elegans, the transcription factor PHA-4 has an essential role in the embryonic
development of the foregut and is orthologous to genes encoding the mammalian
family of Foxa transcription factors, Foxa1, Foxa2 and Foxa3. Foxa family members
have important roles during development, but also act later in life to regulate
glucagon production and glucose homeostasis, particularly in response to fasting.
Here we describe a newly discovered, adult-specific function for PHA-4 in the
regulation of diet-restriction-mediated longevity in C. elegans. The role of
PHA-4 in lifespan determination is specific for dietary restriction, because it
is not required for the increased longevity caused by other genetic pathways that
regulate ageing.
 
DOI: 10.1038/nature05837 
PMID: 17476212
 
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[5] J Anim Sci. 1972 Jun;34(6):1067-74.
 
Lifetime effects of winter supplemental feed level and age at first parturition
on range beef cows.
 
Pinney DO, Stephens DF, Pope LS.
 
 
Abstract
 
Ninety Hereford females were used in factorially arranged treatment groups to study the lifetime effects of three levels of winter supplemental feed and two ages at first parturition on the beef cow and her performance under range conditions. Winter supplemental feed level significantly affected winter and summer weight gains in the early years of the study. Mature cow size and body weight were not significantly affected by either winter feed level or age at first parturition. However, body weight and height were greatest for the later calving cows receiving the high level of winter supplemental feed, and least for those cows calving first at 2 years of age and receiving the low winter supplemental feed level. No differences in birth or weaning weights of the calves were noted; however, average calving date was delayed by the low winter supplemental feed level. The difference in the early years of the study being approximately 7 to 12 days later for the low level fed cows as compared to those receiving the high winter supplemental feed level. Percent calf crop born and weaned favored those cows receiving the low winter feed level, with the difference in percent calf crop weaned due to winter feed level approaching significance (P<.10). Total pounds of calf weaned per cow during her lifetime was significantly affected (P<.025) by winter supplemental feed level, with the average cow on the low winter supplemental feed level weaning 340 and 478 kg more calf than the average cow on the medium or high winter feed level, respectively. Although not statistically significant, the average cow calving first at 2 years of age weaned 154 kg more calf than the average cow calving first at 3 years of age.
 
At the termination of the study, the average lifespan of cows on test was 14.65, 13.07 and 10.88 years for the low, medium and high winter feed level groups, calving at 2 years of age, respectively; and 13.51, 12.73 and 13.06 years, respectively, for the same winter feed level groups calving first at 3 years of age. Reasons for removal of cows from test, and the possible relationship between nutritional level and lifespan were discussed.
 
PMID: 5027302  [PubMed - indexed for MEDLINE]
doi:10.2527/jas1972.3461067x

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