RESVERATROL BENEFITS AND LIFESPAN EXTENSION

  Graph showing life extension in various species

extend the lifespan of yeast up to 70%

 Treatment of flies in early adulthood with 100 μM resveratrol was shown to extend mean lifespan [16]. The same dose of resveratrol was demonstrated to increase mean worm lifespan also, without any changes in fecundity

 https://www.sciencedirect.com/science/article/pii/S0925443915000216

Both aging accelerated as well as normal but shorter lived mice strains also experienced life extension

Beginning at two months of age, the mice were divided to receive a standard diet, or a diet supplemented with resveratrol. In SAMP8 mice fed a standard diet, the median life expectancy was 10.4 months in comparison with the SAMR1 group which survived a median of 17.8 months. However, in SAMP8 mice given resveratrol, median life expectancy increased to 14 months, and SAMR1 mice that received the compound experienced a median life span of 21.8 months. Maximum life span, determined by the longest-lived 20 percent of animals in each group, was also greater in animals that received resveratrol.

 https://www.lifeextension.com/newsletter/2013/3/resveratrol-increases-life-span-in-mice

In the new study — which compared the genetic crosstalk of animals on a restricted diet with those fed small doses of resveratrol — the similarities were remarkable, explains lead author Jamie Barger of Madison-based LifeGen Technologies. In the heart, for example, there are at least 1,029 genes whose functions change with age, and the organ’s function is known to diminish with age. In animals on a restricted diet, 90 percent of those heart genes experienced altered gene expression profiles, while low doses of resveratrol thwarted age-related change in 92 percent. The new findings, say the study’s authors, were associated with prevention of the decline in heart function associated with aging.

 https://news.wisc.edu/agent-in-red-wine-found-to-keep-hearts-young/

Despite lengthening the lifespan of most short lived species its been tried on, the reason resveratrol might not work as effectively in longer lived species could be due to the age related decline in NAD+ seen in longer lived species.  This is because resveratrol is believed to work primarily through the activation of multiple sirtuins, and sirtuins use NAD+, a decline in NAD+ hinders their function and resveratrol's effectiveness.

It is likely nad+ boosters like NMN, NR, Nicotinic Acid, Apigenin, among others may counter the age related declines in NAD+ enough that resveratrol may continue to function. 

In some studies in mice it was found resveratrol lengthened telomeres but did so more strongly in younger versus old animals.   This again could be due to the age related decline in NAD+

reference for telomere lengthening effect of resveratrol https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735524/

Comment on CR mimetic drugs and nutraceuticals potential

From what I understand, iirc, CR works even outside the parameters that can ever be found in nature.   That is IIRC, even up to 65% restriction resulted in 65% increase in lifespan in mice.   It is extremely unlikely, virtually impossible, that on 65% restriction on a famine you will find extraordinarily micronutrient fortified food with minimal effort(as large effort will also result in death from excessive calorie burning from activity) as provided in the lab.
   
I've also heard that on CR started on adult organisms, the transition into CR needs to be gradual and not sudden to actually confer benefits.   The food also has to be fortified to provide sufficient micronutrients.   Again it would seem to be that famines might occur quite sudden and drastic, and may reduce micronutrient availability.

Even in the lab it may be that the mechanism could even go further if not for the low calories compromising vital functions.    On higher lifeforms like man the minimal calories necessary to not jeopardize function may be even higher(I've heard of some severe calorie restriction individuals losing bone integrity), but the genetic expression flexibility may still remain.

What will tell the true limits of these pathways are the physical limits in terms of gene expression that they can ever reach with interventions such as drugs or nutraceuticals.  Which may be reached at 65% CR or could be higher had it been physically possible to survive on even less calories.   CR mimetics stimulate the pathways without jeopardizing function from insufficient calories.

We now know that things like NAD+ drop with age in some organisms which may be behind why resveratrol failed on healthy organism with longer lifespans of a few years after succeeding in many organisms of lower lifespans such as yeast, c. elegans, fruit flies, and some short lived fishes.   Sirtuin dependence on NAD+ would obviously be compromised if NAD+ levels fall too low.Since resveratrol works in part through sirtuins it's effects would be adversely affected through such age associated changes.  But ways to increase NAD+ are now known, some readily available some on the horizon.

source Josh Mitteldorf scienceblog comment

Excerpt from an old article on CR relating to humans

“Speaking of humans,” Fontana added, “if you are lean because you are exercising, of course you are doing good, because you’re preventing types of diabetes, some kinds of cardiovascular disease and maybe some types of cancers. But the data suggest that calorie restriction is more powerful. And the people on C.R. are more powerfully protected from diseases than the exercisers.”

Fontana connected his point to his continuing observations of some Calorie Restriction Society members. “In terms of cardiovascular diseases — the No. 1 cause of death; 4 out of 10 people die of it in the U.S. and Europe — we know that they will not die of cardiovascular death,” Fontana said. His subjects have cholesterol around 160, blood pressure around 100 over 60, high HDL, low triglycerides and very low levels of inflammation. “So these people won’t develop these diseases,” he said. “And I think that’s an important finding. Because every day doctors are publishing hundreds of papers on circulation research and medications that are lowering blood pressure or cholesterol by a small bit. And here we have such a powerful intervention that is basically cleaning out the arteries.” At Tufts, Susan Roberts, the lead investigator, echoed this position, saying that the study will probably have greater effects than the average clinical trial. “I don’t know why anyone would take drugs when they could do something like this,” Roberts said, referring to Calerie.-link

A nice article regarding CR in humans, this is only a small interesting bit.

On degrees of CR viable in longer lived animals

My next interview was so upsetting that it is difficult to write about, and it shows that CR can, in certain cases, lead to full-blown anorexia. I called Al at home; his voice was quiet and somewhat difficult to hear. I asked how many calories a day he ate (1,950, he said) and how much he weighed.

"Ninety-two," he answered. I hoped I'd heard wrong. "How tall are you?" I asked. "Five-four," he said. "But I used to be 5-feet-11." He paused. "Osteoporosis." His spine had compressed a full 7 inches—or perhaps he was bent over. I was glad we were on the phone and I couldn't see him.

Al, who is 59, said he began CR in 1989 after reading about it in a textbook co-written by CR guru Roy Walford. -link

It is likely that the CR performed here was more extreme and has now become more moderate.  Such examples suggest that extreme CR might not be recommendable for longer lived animals prone to bone loss over time.    

More moderate CR, combined with CR mimetics should be viable and not entail such side effects(adequate calcium intake and vitamin k2 should probably also be helpful).   Several CR mimetics are said to not be additive with maximal CR(around 65% restriction), but should likely have additive effect on more moderate CR.    An interesting compound that should hopefully be tested in mammals, is rhodiola, which is a compound that is additive with CR and even maximal CR in a species of insect.   The mechanisms of rhodiola are also of interest seeing as it can move some species' lifespan beyond maximal CR

Nice quote on gene expression and calorie restriction

 "Aging was accompanied by changes in gene expression associated with increased inflammation, cellular stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic metabolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks of ST-CR reversed the majority of these changes."-link

Effects seen in liver of rodents, reversal of most age related changes in gene expression, if I'm not mistaken.
LTCR long term calorie restriction
STCR short term calorie restriction

Nice sciencedaily article from earlier this year

Monkey caloric restriction study shows big benefit; contradicts earlier study

...The study of 76 rhesus monkeys, reported Monday in Nature Communications, was performed at the Wisconsin National Primate Research Center in Madison. When they were 7 to 14 years of age, the monkeys began eating a diet reduced in calories by 30 percent. The comparison monkeys, which ate as much as they wanted, had an increased risk of disease 2.9 times that of the calorie-restricted group, and a threefold increased risk of death.

"We think our study is important because it means the biology we have seen in lower organisms is germane to primates," says Richard Weindruch, a professor of medicine at the School of Medicine and Public Health, and one of the founders of the UW study. "We continue to believe that mechanisms that combat aging in caloric restriction will offer a lead into drugs or other treatments to slow the onset of disease and death."...

 Weindruch also points to some results from the NIA that seem to contradict the "no significant result" analysis. Twenty monkeys entered the NIA study as mature adults, 10 in the test group and 10 in the control group, and five of these (four test monkeys and one control monkey) lived at least 40 years. "Heretofore, there was never a monkey that we are aware of that was reported to live beyond 40 years," Weindruch says. "Hence, the conclusion that caloric restriction is ineffective in their study does not make sense to me and my colleagues."...-link

 Calorie restriction seems to be showing noticeable benefits on primates.

 

CR an artifact?

The most widely accepted theory is that this effect evolved to improve survival during times of famine. "But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact,"
  says Dr Adler.

Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system's ability to fight off disease and reduces the muscle strength necessary to flee a predator.-link 

I would also add that since the calorie restriction is done with dense nutrient enriched optimal nutrition, this is unlikely to occur in the wild.  Without optimal nutrition calorie restriction is said to fail to extend life, small amounts of nonenriched foodsource as found in the wild is in my opinion unlikely to provide optimal nutrition required for extension. edit: especially at levels that cr can work in some animals like 60+%, at 60% deprivation not only would the nutrient density likely be insufficient, but in an environment lacking resources the small amount of calories would be insufficient for exploration, cr appears to work and extend life even in calorie amounts beyond what would be sustainable in the wild.

CR mimic Resveratrol

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg⁻¹ day⁻¹), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.-link

Resveratrol seems to mimic some of the gene expression changes done by Calorie Restriction.

Calorie Restriction study comments

Regards humans in history. Humans present a very large population far larger than that of any study in CR. The greater number of centenarians in some populations has been attributed to moderate CR.

It is also likely that some humans may exhibit mutations conferring the benefits of CR, we would have to look at the gene expression of centenarians and supercentenarians to see if it is similar or not to that caused by CR. If the gene expression profiles are similar, even if only in some, it would be probable evidence for CR working in humans.

Also from what I've heard CR can work in some species of rodents all the way down to 50% and is rumored could work down at even lower levels if not for death by starvation. IF this is true a CR-mimetic could in theory break the 50% limit when it comes to changes in gene expression and might allow for even longer lifespan..

As for these two studies it would be interesting to see what the weights of the primates were compared to wild animals. It may be that in both cases the CR was too moderate, and both the CR and control fell within normal or slightly less than normal consumption levels for these animals.-fightaging

Also I should add regards the primate studies it would be interesting to note protein intake, and whether there was protein supplementation in the feed as it appears some primates require reduced protein intake for some of the effects of CR(IGF-1 levels)-link

 IT has to be seen what the normal levels of protein are for the animal in the wild, even if the calorie reduction also reduced protein, it may still have resulted in higher than normal protein intake for this type of animal.

It would also have to be seen the type of protein fed,  some types are said to raise IGF-1 which may mean that even the reduced IGF-1 might not have matched or gone below wild type.

Comment regarding negative result on primate studies, and human history potential for CR being implemented and effective as well as possible genetics mimicking CR.