(This is part two of the report on lifespan and health involving a compound found in red wine)How the Study Was Done
This study examined three groups of mice, one on a standard diet (SD), another on a high calorie diet (HC) with 60 percent of calories coming from fat, and a third group of mice on the same high calorie diet but also treated with resveratrol (HCR). At middle age, or roughly 52 weeks of life, the researchers put the mice on the different diets.
Survival Benefit
At 60 weeks of age, the survival rates of HC and HCR fed mice groups began to diverge and remained separated by a three to four month span. At 114 weeks of age, 58 percent of the HC fed mice had died, compared to 42 percent of the HCR and SD groups. Presently, the team has found resveratrol to reduce the risk of death from the HC diet by 31 percent, to a point where it is not significantly increased over the SD group. [Note: Given that mice are still living, final calculations can't be made.] "The median lifespan increase we are seeing is about 15 percent at this point," says Sinclair. "We won't have final lifespan numbers until all of the mice pass away, and this particular strain of mouse generally lives for two-and-a-half-years. So we are around five months from having final numbers, but there is no question that we are seeing increased longevity."
The team also found that the HCR fed mice had a much higher quality of life, outperforming the HC fed mice on motor skill tests. "The mice on resveratrol have not been just living longer," says Sinclair. "They are also living more active, better lives. Their motor skills actually show improvement as they grow older."
Reversing Genetic Pathways Triggered by High Calorie Diet
The research team also wanted to see if resveratrol could reverse the changes in gene expression patterns triggered by high calorie diets. Using liver tissue of five mice at 18 months of age from each group, the team performed a whole-genome microarray and identified which genes were turned on or off. The researchers then used a database generated by the Broad Institute that groups individual genes into common functional pathways to see where there were major differences.
"We made a striking observation," says Sinclair. "Resveratrol opposed the effects of high caloric intake in 144 out of 153 significantly altered pathways. In terms of gene expression and pathway comparison, the resveratrol fed group was more similar to the standard diet fed group than the high calorie group."
Improved Health Biomarkers: Glucose and Insulin
In humans, high calorie diets can increase glucose and insulin levels leading to diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. In the HC fed mice, researchers found biomarkers that might predict diabetes, including increased levels of insulin, glucose and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group had significantly lower levels of these markers, paralleling the SD group.
For example, a standard diabetes glucose test on the HCR fed group found considerably higher insulin sensitivity, meaning the HCR group had a lower disposition toward diabetes than the HC fed group. Lower insulin levels also predict increased lifespan in mice.
Organ Protection: Heart and Liver
Three pathologists examined heart tissue from the SD, HC, and HCR mice, and while not knowing which organ belonged to which mouse group, they looked for subtle changes in the abundance of fatty lesions, degeneration and inflammation. On a relative scale of 0-4, the assessment produced mean scores of 1.6 for the SD group, 3.2 for the HC group, and 1.2 for the HCR group.
The researchers also found that the livers of mice at 18 months of age on the HC diet were greatly increased in size and weight. Liver tissue studies of these mice showed a loss of cellular integrity, and a build-up of lipids, which is common to high fat diets. In contrast, the HCR group had normal, healthy livers.
Links to Calorie Restriction Lifespan Model
The researchers also looked for metabolic ties to resveratrol's impact: pathway changes that mimicked those caused by calorie restriction. They examined AMP-activated kinase (AMPK), a metabolic regulator that promotes insulin sensitivity and fatty acid oxidation.
It's been shown in previous work that the lifespan of worms has been extended by the addition of copies the AMPK gene, and chronic activation of AMPK is seen on calorie-restricted diets. The researchers examined the livers of the HCR fed group and found a strong tendency for AMPK activation, as well as two downstream indicators of its activity.
Calorie restriction and exercise have also been previously shown to increase the number of mitochondria in the liver. Mitochondria generate energy in cells. Through electron microscopy, investigators showed that the livers of the HCR fed mice had considerably more mitochondria than the HC group, and were not significantly different from those of the SD group.
"This work demonstrates that there may be tremendous medical benefits to unlocking the secrets behind the genes that control our longevity," says Sinclair, "No doubt many more remain to be discovered in coming years."
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