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/

Forever young at heart, the power of resveratrol

 Taking into account the beneficial effects of RES on hypertension, obesity, inflammation, diabetes and dyslipidemia, RES could constitute an interesting pharmacological approach for the treatment of metabolic syndrome, which is associated with an increased risk of CVD development. Nevertheless, among the points to discuss for the interpretation of preclinical and clinical studies, not only the poor bioavailability and the dose of RES are critical, but also the length of RES treatment and the best time for initiating it (most studies showed effectiveness of RES when it was administered for short periods and as a pretreatment) [67]. Larger controlled human clinical trials are thus needed to investigate these points and to study the effects of long-term RES supplementation. Resveratrol and Cardiovascular Diseases (nih.gov)

In mice resveratrol has lengthened lifespan of obese mice abolishing practically abolishing lifespan negative effects of obesity, it has also lengthened lifespan of aging accelerated mice, of mice with mitochondrial defects, of normal aging but short lived strains of mice, of yeast, of short lived fish, and of a few other species.

It is able to elicit antiaging effects in multiple organs but most strongly in the heart, where iirc, it induces hundreds of gene expression changes opposed to aging and akin to calorie restriction(calorie restriction being one of the strongest youth resilience and health promoting antiaging interventions known.), this has already been shown in animals

Resveratrol presents a therapeutic agent with a novel mechanism of action that appears to benefit a variety of conditions related to CVD and HF. Ongoing studies will test the hypothesis that the addition of resveratrol in meaningful doses can help patients with CVD and/or HF. The Effects of Resveratrol in Patients with Cardiovascular Disease and Heart Failure: A Narrative Review (nih.gov)

Animal gene expression research

 Surprisingly, resveratrol opposed 947 (92%) of age-related changes in gene expression, and 522 of these represented highly significant differences in expression between the old control and old resveratrol groups (P≤0.01). Thus, resveratrol at doses that can be readily achieved through dietary supplementation in humans is as effective as CR in opposing the majority of age-related transcriptional alterations in the aging heart. Because the collection of such alterations in gene expression is a biomarker of aging, our results imply that similar to CR, middle-age onset resveratrol supplementation at low doses is likely a robust intervention in the retardation of cardiac aging. A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice (nih.gov)

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

resveratrol alzheimer's trial

 QUOTE:

“This is a single, small study with findings that call for further research to interpret properly.”

Patients who were treated with increasing doses of resveratrol over 12 months showed little or no change in amyloid-beta40 (Abeta40) levels in blood and cerebrospinal fluid. In contrast, those taking a placebo had a decrease in the levels of Abeta40 compared with their levels at the beginning of the study.

“A decrease in Abeta40 is seen as dementia worsens and Alzheimer’s disease progresses; still, we can’t conclude from this study that the effects of resveratrol treatment are beneficial,” Turner explains. “It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation. Resveratrol was measured in both blood and cerebrospinal fluid.”-link

END QUOTE

Resveratrol appears to show some effectiveness on initial trials and further research is to be done to confirm initial findings.

Resveratrol news 2014 december

For the new study, Sajish and Schimmel put TyrRS(tRNA synthetase called TyrRS) and resveratrol together and showed with tests including X-ray crystallography that resveratrol does indeed mimic tyrosine, well enough to fit tightly into TyrRS's tyrosine binding pocket. That binding to resveratrol, the team found, takes TyrRS away from its protein translation role and steers it to a function in the cell nucleus.

Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it grabs and activates the protein, PARP-1, a major stress response and DNA-repair factor thought to have a significance influence on lifespan. The scientists confirmed the interaction in mice injected with resveratrol. TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6.-machineslikeus link

 It seems that in addition to the previously known sirtuin 1 activity, resveratrol also activates other stress response mechanisms through TyrRS including SIRT6 and FOXO3A.    So resveratrol appears to be acting through more than one pathway and it also seems to activate some of these mechanisms at lower doses according to the linked article

A response to a post in josh mitteldorf's site

 "but only 15% to dogs and 5% or less in Rhesus monkey experiments reported last year. "

The 16% on dogs, was on 25% CR, iirc not maximal 65% CR.   Human igff1 levels have been influenced by protein intake, which may also affect other long lived species igf1 which may affect longevity

As for the primate study the earlier findings of small benefits were questioned this year.   It seems that not only have several monkeys who started CR in adulthood exceeded the maximum lifespan in captivity of the species studied, but those not on CR experienced triple the risk of death
http://www.news.wisc.edu/22672

Regards resveratrol, it has not only extended the life of fish, worms, yeast, obese mice, but also mitochondrially dysfunctional mice and several types of senescent accelerated mice strains.   It also tripled human cell survival upon exposure to gamma radiation.    Why it failed on normal mice, is a good question....  the fact that their nad goes drastically down with age, iirc, could be a culprit as this might handicap sirtuin activity which necesitates it, iirc, even in the presence of sirtuin activity enhancing compounds such as resveratrol. -Darian S, link to post in blog

Link to a nice list and info on resveratrol benefit

 The third story in my “top 10” list is another example of pathway synergy.  Combining exercise with Resveratrol supplementation enhances mitochondrial biogenesis more than is explainable due to summing the effects of the individual interventions.

Stories 2 and 3 convey a very powerful message for anti-aging interventions: combining interventions in seemingly independent pathways may produce positive effects that are much greater than additive.-link

Interesting post on another site about a list on aging things from 2013.  This one, 3rd on the list, shows resveratrol having a positive effect on rodents.

NOTE:  Regards the vitamin findings on the list, I consider them highly suspect even many researchers not associated to big pharma have a tendency to dismiss supplements(probably don't like taking pills even if it's cents a day).  It is also the case that it is extremely unlikely that in a large population none would have a deficiency in at least one nutrient given the diversity of diets, so at least some in the population should see benefits.   In addition those who're given a vitamin and don't normally take one might also engage in additional harmful lifestyle activity which may more than counter the benefits of vitamins and minerals.

Resveratrol snippet

Resveratrol has increased the lifespan of yeast, worms, fruit flies, fish, mice fed a high-calorie diet, genetically induced mitochondrially dysfunctional mice, and in senescence accelerated SAMP8 and SAMR1 mice.

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.

Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice

Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype.-link

In addition to extending the lifespan of obese mice, mice with alzheimer's like pathology and accelerated senescence mice, now with this study we see that in mice with genetic abnormality in the mitochondria lifespan's also extended.