The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 6 • December 2010


Partial Caloric Restriction Mimic

Low Dose Resveratrol Partially Mimics Caloric
Restriction, Retards Some Aspects of Aging

Although high doses of resveratrol in some studies have been shown to extend lifespan in invertebrates and (at high doses, 22 or 186 mg/kg/day) has been shown to improve health and survival in mice fed a high fat diet,1 further work is needed to determine how resveratrol at lower doses, achievable with reasonable resveratrol supplementation would affect aging in mice on a normal (rather than high fat) diet.

A recent paper2 reports the results of just such a study. Male C57BL/6xC3H/He F1 hybrid mice were fed from middle age (14 months) to old age (30 months) with a low dose of resveratrol (4.9 mg/kg/day) or a CR (calorie restricted) diet and examined by genome-wide transcriptional profiles for genetic differences between these two groups and controls (fed the control diet with no supplemental resveratrol). These authors had previously reported that this CR regimen started at middle age in this strain leads to a 13% increase in average and maximum lifespan. As they did in their earlier study, the researchers reported in this study that CR had a large effect in opposing age-related changes: “CR reduced 921 (90%) age-related alterations in gene expression and 536 of these represented highly significant differences (P ≤ 0.01) in expression between the old control and old CR groups.”

The researchers report here that “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.” For example, the myocardial performance index, an overall assessment of cardiac function, increases significantly with age (reflecting decreasing cardiac function); resveratrol supplementation “almost completely prevented” this age-related change. This mouse dose of resveratrol is very roughly equivalent to a dose of 250 mg/day for an adult human.

Lesser effects on aging changes were found in skeletal muscle. Aging resulted in alteration of expression of 515 skeletal muscle genes, 136 (26%) of which were significantly (P ≤ 0.01) opposed by CR and resveratrol. In the neocortex, CR and resveratrol were reported to significantly inhibit only 19 and 13% respectively of the 505 highly significant age-related changes in gene expression. Both CR and resveratrol supplementation lowered blood glucose levels (P = 0.06 for CR, P = 0.07 for resveratrol). Unlike CR, however, low dose resveratrol did not reduce circulating IGF-1 (insulin-like growth factor-1) levels. Moreover, there was no decrease in the resveratrol-treated mice in spontaneous liver tumors, which were as abundant as in mice on the control diet, but rare in the CR mice.

Surprisingly, in this study, neither CR nor low dose resveratrol supplementation induced the activity of SIRT1, a longevity-associated gene. CR, but not resveratrol, did induce higher activity of PGC-1alpha, a master regulator of mitochondrial biogenesis.

Unfortunately, the researchers were unable to compare the effects of CR and low dose resveratrol on lifespan because the study involved the use of a long-lived strain and, as they killed the mice at 30 months of age, they could not evaluate effects on average or maximum lifespan. It wasn’t explained why all the mice were killed before at least some of them were allowed to live out their lives so as to capture the lifespan results. However, since the incidence of spontaneous liver tumors was decreased by CR but not by resveratrol and since higher circulating IGF-1 levels (reduced by CR but not by resveratrol) are generally considered a risk factor for cancer, it appears to us that the resveratrol supplemented mice may not have lived as long as the CR mice.

Another 2008 paper3 by a different group of researchers (the same group that published paper #1) compared the results of resveratrol supplementation in mice fed a standard diet (not high fat) ad lib versus mice fed every other day (EOD), a type of dietary restriction with similar but not identical effects to CR, calorie restriction. The usual EOD consists of a period (most often 24 hours) of ad lib feeding alternated with a day of fasting.4 In one human EOD study, subjects were allowed a liter of milk and 2–3 pieces of fruit on their “fasting” day.5 As the researchers3 explain. [a]lthough EOD feeding and conventional caloric restriction (reducing daily intake by ~40%, “CR”) share key features, including [in rodents] extending mean and maximum lifespan, preventing age-related disease, and improving insulin sensitivity, they have not been shown to work through a common mechanism.”

The purpose of the study was to determine whether resveratrol could mimic the age retarding effects of EOD. At 1 year of age, the mice were placed on a standard control diet (SD) or EOD feeding with or without resveratrol (low resveratrol was 100 mg/kg of food; high resveratrol was 400 mg/kg of food). (A typical adult human consumes about 500 grams of food per day on a dry weight basis.) They found that the long-term resveratrol treatment slows age-related degeneration and functional decline and mimics the gene expression patterns induced by EOD feeding, but without extending lifespan. For example, they observed reductions of osteoporosis, cataracts, vascular dysfunction, and declines in motor coordination. However, resveratrol did not reduce the incidence of lymphoma, a major cause of mortality in C57BL/6 mice. Another difference was that EOD strongly upregulated glutathione metabolism, whereas resveratrol had no effect. Surprisingly, the effect of resveratrol on SIRT1 in this study was not reported.

“In the context of the standard diet [SD], resveratrol did not increase overall survival or maximum lifespan … EOD feeding produced a trend toward increased longevity compared to the SD control group, but the effect did not reach statistical significance. Our results are consistent with the previous observation that the effect of EOD on longevity is diminished in older C57BL/6 mice, which is also true of DR [dietary restriction] by 40% restriction. Notably, EOD feeding in combination with the lower dose of resveratrol did extend both mean and maximal lifespan by 15% compared to SD controls.”3

References

  1. Baur et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-42 (2006)
  2. Barger et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6):e2264 (June 2008) [Open access freely available at www.plosone.org].
  3. Pearson et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157-168 (2008).
  4. Varady and Hellerstein. Do calorie restriction or alternate-day fasting regimens modulate adipose tissue physiology in a way that reduces chronic disease risk? Nutr Rev 66(6):333-42 (2008).
  5. Heilbronn et al. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr 81:69-73 (2005).

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