A new study using a single compound to increase the lifespan of obese mice, found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets–some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small 1) ___, resveratrol has been shown to offer survival benefits in a mammal. Mice are much closer evolutionarily to humans than any previous model organism treated by this molecule, which offers hope that similar impacts might be seen in humans without negative side-effects. After six months, resveratrol essentially prevented most of the negative effects of the high calorie diet in mice. Resveratrol is found in red wines and produced by a variety of plants when put under stress. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30%, and fish by almost 60%. It has also been shown to protect against Huntington’s disease in two different animal models (worms and mice).”The healthspan benefits we saw in the obese mice treated with resveratrol, such as increased insulin sensitivity, decreased glucose levels, healthier heart and liver tissues, are positive clinical 2) ___ and may mean we can stave off in humans, age-related diseases such as type 2 diabetes, heart disease, and 3) ___, but only time and more research will tell,” says Harvards David Sinclair MD, who is also a co-founder of Sirtris, a company which is currently in a phase 1b trial in humans with diabetes using an enhanced, proprietary formulation of 4) ___. [Harvard has license and equity interests with Sirtris, which is not a public company.] Investigators identified resveratrol while looking for compounds that activate Sir2, an 5) ___ linked to lifespan extension in yeast and other lower organisms. “The median lifespan increase, in mice, we are seeing is about 15% 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 6) ___ of life, outperforming the HC fed mice on motor skill tests. “The mice on resveratrol have not just been living longer,” says Sinclair. “They are also living more active, better lives. Their motor skills actually show improvement as they grow older.” Mice on a rotarod also showed improved motor function with age over its HC fed counterparts. Researchers watched how well the mice did walking on a rotarod, similar to walking on a log in the water, a common measure of balance and motor coordination. “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. “The research team found that levels of PGC-1alpha were three-fold lower in the HCR fed mice than in the HC mice, consistent with what would be expected when SIRT1 was being activated by resveratrol. This work demonstrates that there may be tremendous 7) ___ benefits to unlocking the secrets behind the genes that control our longevity.

ANSWERS: 1) molecule; 2) indicators; 3) cancer; 4) resveratrol; 5) enzyme; 6) quality; 7) medical

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