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In mice, “youth” drug prolongs vigor but not life: report

July 3, 2008
Courtesy Cell Press
and World Science staff

Large doses of a red wine in­gre­di­ent can ward off many of the neg­a­tive ef­fects of ag­ing in mice who start tak­ing it at midlife, ac­cord­ing to a new re­port.

But those ben­e­fits, from the chem­i­cal known as res­ver­a­trol, come with­out nec­es­sarily pro­long­ing the ro­dents’ lives—the hoped-for re­sult it achieved in sim­pler an­i­mals, sci­en­tists say.

Grape skins and a va­riety of other plant pro­ducts con­tain res­ver­a­trol, but usu­ally only in very low con­cen­tra­tions. (Im­age cour­te­sy U.S.D.A.)


The new find­ings, by Da­vid Sin­clair at Har­vard Med­i­cal School and more than two doz­en col­leagues, ap­pear on­line July 3 in the re­search jour­nal Cell Me­tab­o­lism

The sci­en­tists found car­di­o­vas­cu­lar ben­e­fits, great­er mo­tor co­ordina­t­ion, re­duced cataracts, and bet­ter bone dens­ity in mice tak­ing res­ver­a­trol. The re­sults show ev­i­dence that the sub­stance mim­ics the doc­u­mented ben­e­fi­cial ef­fects of eat­ing spar­ing­ly, the re­search­ers said—many tis­sues show very si­m­i­lar gene ac­ti­vity either way.

“The qual­ity of life of these mice at the end of their days is much bet­ter,” said Raf­a­el de Cabo of the U.S. Na­tional In­sti­tute on Ag­ing, one of the re­search­ers. Res­ver­a­trol may “ex­tend pro­duc­tive, in­de­pend­ent life, rath­er than just ex­tend­ing life span.”

“I was most sur­prised by how broad the ef­fects were,” added Sin­clair. “Usu­ally, you fo­cus on slow­ing down or amel­io­rating one dis­ease at a time. In this case, res­ver­a­trol in­flu­ences a whole se­ries of seem­ingly un­re­lat­ed dis­eases as­so­ci­at­ed with ag­ing.” Sin­clair said he ex­pects some of the ef­fect seen in the mice would have even great­er im­pact if they hold in hu­mans. That’s be­cause, un­like peo­ple, mice usu­ally don’t die as a re­sult of heart dis­ease or suf­fer from weak­en­ing bones.

Ear­li­er stud­ies found that re­duc­ing cal­o­rie in­take by 30 per­cent to 50 per­cent, or eat­ing only every oth­er day, can de­lay the on­set of age-re­lat­ed dis­eases, im­prove stress re­sist­ance, and slow down func­tion­al de­cline. Al­though di­e­tary re­stric­tion has ben­e­fi­cial ef­fects in hu­mans, such a di­et is un­likely to be widely adopt­ed and would pose a sig­nif­i­cant risk to the frail, crit­ic­ally ill or eld­er­ly, the re­search­ers said.

There­fore, sci­en­tists hope to find com­pounds that pro­vide the ben­e­fits with­out cut­ting cal­o­ries. One con­tender has been sub­stances like res­ver­a­trol that ac­tivate a gene known as SIRT1. It and equiv­a­lent pro­teins have been linked to long life in many stud­ies in yeast to mam­mals, al­though its role in pro­long­ing life re­mains a mat­ter of con­si­der­able con­tro­ver­sy. 

Stud­ies have found res­ver­a­trol can ex­tend the lives of yeast, worms, flies, and fish, and im­proves the health and sur­viv­al of obese mice on a high-cal­o­rie di­et. In the new re­search, in­ves­ti­ga­tors placed one-year-old mice on a stand­ard con­trol di­et or ever­y-oth­er-day feed­ing with or with­out res­ver­a­trol. 

The res­ver­a­trol-fed mice did not live long­er in gen­er­al, al­though mice on a high-fat di­et plus res­ver­a­trol did avoid the short­ened life span that tends to come with such a fat­ty meal plan, Sin­clair said. Res­ver­a­trol treat­ment is al­ready be­ing tested in clin­i­cal tri­als for type 2 di­a­be­tes, the re­search­ers not­ed, and more po­tent mo­le­cules with ef­fects si­m­i­lar to res­ver­a­trol are al­so un­der de­vel­op­ment. The new find­ings in mid­dle-aged mice sug­gest that treat­ments with such drugs might ben­e­fit peo­ple who start tak­ing them in their late thir­ties or for­ties, the sci­en­tists said.

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Large doses of a red wine ingredient can ward off many of the negative effects of aging in mice who start taking it at midlife, according to a new report. But those benefits, from the chemical known as resveratrol, come without necessarily prolonging the rodents’ lives—the hoped-for result it achieved in simpler animals, scientists say. The new findings, by David Sinclair at Harvard Medical School and more than two dozen colleagues, appear online July 3 in the research journal Cell Metabolism. The scientists found cardiovascular benefits, greater motor coordination, reduced cataracts, and better bone density in mice taking resveratrol. The results show evidence that the substance mimics the documented beneficial effects of eating sparingly, the researchers said—the chemical induces very similar gene activity in many tissues. “The quality of life of these mice at the end of their days is much better,” said Rafael de Cabo of the U.S. National Institute on Aging, one of the researchers. Resveratrol may “extend productive, independent life, rather than just extending life span.” “I was most surprised by how broad the effects were,” added Sinclair. “Usually, you focus on slowing down or ameliorating one disease at a time. In this case, resveratrol influences a whole series of seemingly unrelated diseases associated with aging.” Sinclair said he expects some of the effect seen in the mice would have even greater impact if they hold in humans. That’s because, unlike people, mice usually don’t die as a result of heart disease or suffer from weakening bones. Earlier studies found that reducing calorie intake by 30% to 50%, or eating only every other day, can delay the onset of age-related diseases, improve stress resistance, and slow down functional decline. Although dietary restriction has beneficial effects in humans, such a diet is unlikely to be widely adopted and would pose a significant risk to the frail, critically ill, or the elderly, the researchers said. Therefore, scientists hope to find compounds that provide the benefits without cutting calories. One contender has been substances like resveratrol that activate a gene known as SIRT1. It and equivalent proteins have been linked to long life in many studies in yeast to mammals, although its role in prolonging life remains a matter of considerable controversy. Studies have found resveratrol can extend the lives of yeast, worms, flies, and fish. It also improves the health and survival of obese mice fed a high-calorie diet. In the new research, investigators placed 1-year-old mice on a standard control diet or every-other-day feeding with or without resveratrol. The resveratrol-fed mice did not live longer in general, although mice on a high-fat diet plus resveratrol did avoid the shortened life span that tends to come with such a fatty meal plan, Sinclair siad. Resveratrol treatment is already being tested in clinical trials for type 2 diabetes, the researchers noted, and more potent molecules with effects similar to resveratrol are also under development. The new findings in middle-aged mice suggest that treatments with such drugs might have benefits for people who start taking them in their late thirties or forties.