"Long before it's in the papers"
January 27, 2015


“Longevity gene” may be unrelated to longevity

Sept. 21, 2011
Courtesy of the Wellcome Trust
and World Science staff

Pro­teins thought to boost life­span in sev­er­al test or­gan­isms—and said to be stim­u­lat­ed by cer­tain “anti-aging” prod­uct­s—don’t really af­fect longe­vity, new re­search sug­gests.

That does­n’t mean life­span can­not be ex­tend­ed, sci­en­tists said; it just means any tech­niques that have suc­ceeded in do­ing so were probably not work­ing through those pro­teins.

The round­worm C. ele­gans, used in some ag­ing studies. (Im­age cour­tesy free.ed.gov)

Pre­vi­ous stud­ies had linked the nat­u­ral molecules, known as sir­tu­ins, to age­ing and longe­vity in or­gan­isms in­clud­ing yeast, nem­a­tode worms and fruit flies, of­ten used as mod­els for the bi­ol­o­gy of hu­man age­ing. Re­search­ers had shown that when the or­gan­is­ms over­pro­duced sir­tuin, they lived long­er, by as much as 50 per­cent in the case of nem­a­todes.

Oth­er re­search iden­ti­fied a link be­tween sir­tu­ins and di­e­tary re­stric­tion – a sharp cut­back in calo­ries eat­en, a meth­od known to ex­tend life­span in many or­gan­isms, in­clud­ing some mam­mals. Re­search sug­gested that it works by ac­ti­vat­ing the pro­duc­tion of sir­tu­ins. The stud­ies caused much in­ter­est among sci­en­tists and oth­ers. Some dubbed the sir­tuin-producing gene the “longe­vity gene.” 

Pills and “anti-age­ing” creams have al­so been launched con­tain­ing res­ver­a­trol, a sub­stance found in red wine and thought to ac­ti­vate sir­tu­ins. 

But sub­se­quent re­search has cast doubt on the claims that res­ver­a­trol ac­ti­vates sir­tu­ins. A study pub­lished Sept. 21 in the jour­nal Na­ture, led by Da­vid Gems and col­leagues at Uni­vers­ity Col­lege Lon­don, pro­vides al­most con­clu­sive ev­i­dence that the ef­fects on an­i­mal longe­vity seen in ear­li­er ex­pe­ri­ments were un­con­nect­ed to sir­tuin, the in­ves­ti­ga­tors said.

“These re­sults are very sur­pris­ing. We have re-ex­am­ined the key ex­pe­ri­ments link­ing sir­tuin with longe­vity in an­i­mals and none seem to stand up to close scru­ti­ny. Sir­tu­ins, far from be­ing a key to longe­vity, ap­pear to have noth­ing to do with ex­tending life,” Gems said. “But I think this is good news in a way: af­ter all, re­vis­ing old ideas can be as im­por­tant as pre­sent­ing new ones to as­sure sci­en­tif­ic prog­ress. This work should help to re­di­rect sci­en­tif­ic ef­forts to­ward those pro­cesses that really do con­trol age­ing.”

Gems and col­leagues, with re­search­ers at the Uni­vers­ity of Wash­ing­ton, Se­at­tle, and Sem­mel­weis Uni­vers­ity, Bu­da­pest, ex­am­ined two strains of nem­a­tode worm, each from a dif­fer­ent pri­or stu­dy. These were ma­ni­pu­lated to have a hy­per­ac­tive sir­tuin gene. They did live long­er than nor­mal worms, but af­ter pre­cau­tions were tak­en to en­sure that the only dif­fer­ence be­tween the nor­mal and test worms was high­er sir­tuin lev­els, the longe­vity ef­fect was found to van­ish. 

Thus some­thing else must have caused the longe­vity, the sci­en­tists pro­pose. In one of the two orig­i­nal strains, they iden­ti­fied this as a muta­t­ion in a gene in­volved in nerve cell de­vel­op­ment.

Work­ing with col­leagues at the Uni­vers­ity of Mich­i­gan, the U.K. re­search­ers then ex­am­ined an en­gi­neered ver­sion of the fruit fly, Dro­soph­i­la melanogaster, in which sir­tuin lev­els were al­so raised. The same or­gan­ism had been the sub­ject of ear­li­er re­search which seemed to show that over­ac­tiva­t­ion of sir­tu­ins in­creased longe­vity.

Gems and col­leagues pro­pose ge­net­ic fac­tors oth­er than sir­tu­ins genes were the cause of the longe­vity. They al­so cre­at­ed a new strain of fruit fly with even high­er sir­tuin lev­els, but found that this was­n’t long-lived ei­ther.

The re­search­ers al­so pre­pared syn­thet­ic fruitfly sir­tuin and tested wheth­er it could be ac­ti­vated by res­ver­a­trol, as pre­dicted by pre­vi­ous claims. But nei­ther the U.K. or U.S. lab­o­r­a­to­ries, each us­ing sev­er­al tech­niques, could show any ac­tiva­t­ion. Fi­nal­ly, the teams re-tested the claim that di­e­tary re­stric­tion in­creases life­span by ac­ti­vat­ing sir­tu­ins. Tak­ing mu­tant fruit flies that lacked the sir­tuin gene, the re­search­ers showed that di­e­tary re­stric­tion still in­creased life­span. So di­e­tary re­stric­tion was work­ing in­de­pend­ently of sir­tu­ins, they said.

* * *

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Proteins thought to boost lifespan in several test organisms—and said to be stimulated by some “anti-aging” products—don’t really affect longevity, new research suggests. That doesn’t mean lifespan cannot be extended, the scientists said; it just means any techniques that have succeeded in doing so were probably not working through those proteins. Previous studies had linked the natural molecules, known as sirtuins, to ageing and longevity in organisms including yeast, nematode worms and fruit flies, often used as models for the biology of human ageing. Researchers had shown that when the organism’s genes overproduced sirtuin, it lived longer, by as much as 50% in the case of nematodes. Other research identified a link between sirtuins and dietary restriction – a sharp cutback in calories eaten, a method known to extend lifespan in many organisms, including some mammals. Research suggested that it works by activating the production of sirtuins. The studies caused much interest among scientists and others. Some dubbed the sirtuin-producing gene the “longevity gene.” “Anti-ageing” creams have also been launched containing resveratrol, a substance found in red and thought to activate sirtuins. But subsequent research has cast doubt on the claims that resveratrol activates sirtuins. A study published Sept. 21 in the journal Nature, led by David Gems and colleagues at University College London, provides almost conclusive evidence that the effects on animal longevity seen in earlier experiments were unconnected to sirtuin, the investigators said. “These results are very surprising. We have re-examined the key experiments linking sirtuin with longevity in animals and none seem to stand up to close scrutiny. Sirtuins, far from being a key to longevity, appear to have nothing to do with extending life,” Gems said. “But I think this is good news in a way: after all, revising old ideas can be as important as presenting new ones to assure scientific progress. This work should help to redirect scientific efforts toward those processes that really do control ageing.” Gems and colleagues, with researchers at the University of Washington, Seattle, and Semmelweis University, Budapest, examined two strains of nematode worm, each from a different prior study. These were manipulated to have a hyperactive sirtuin gene. They did live longer than normal worms, but after precautions were taken to ensure that the only difference between the normal and test worms was higher sirtuin levels, the longevity effect was found to vanish. Thus something else must have caused the longevity, the scientists propose. In one of the two original strains, they identified this as a mutation in a gene involved in the development of nerve cells. Working with colleagues at the University of Michigan, the U.K. researchers then examined an engineered version of the fruit fly, Drosophila melanogaster, in which sirtuin levels were also raised. The same organism had been the subject of earlier research which seemed to show that overactivation of sirtuins increased longevity. Gems and colleagues propose genetic factors other than sirtuins genes were the cause of the longevity. They also created a new strain of fruit fly with even higher sirtuin levels, but found that this wasn’t long-lived either. The researchers also prepared synthetic fruitfly sirtuin and tested whether it could be activated by resveratrol, as predicted by previous claims. But neither the U.K. or U.S. laboratories, each using several techniques, could show any activation. Finally, the teams re-tested the claim that dietary restriction increases lifespan by activating sirtuins. Taking mutant fruit flies that lacked the sirtuin gene, the researchers showed that dietary restriction still increased lifespan. So dietary restriction was working independently of sirtuins, they said.