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New “longevity gene” spurs hopes of long life

May 2, 2007
Courtesy Salk Institute
and World Science staff

In stud­ies dat­ing back 70 years, mice and many oth­er spe­cies sub­sist­ing on a near-starvation di­et have con­sist­ent­ly lived as much as 40 per­cent long­er than nor­mal. But just why has been un­clear.

The round­worm Cae­nor­hab­di­tis el­e­gans, about 1 mm long, is a main­stay in many lab­o­ra­to­ries do­ing mo­lec­u­lar and ge­net­ic stud­ies. Be­cause many C. el­e­gans genes are si­m­i­lar to those of hu­mans, re­search­ers study the func­tions of such genes to gain in­sight in­to hu­man phys­i­ol­o­gy. (Im­age cour­te­sy NIH) 
Now, re­search­ers at the Salk In­sti­tute for Bi­o­log­i­cal Stu­d­ies in La Jolla, Calif., re­port they have have cracked the rid­dle, find­ing the first gene that specif­i­cally links this “ca­lor­ic re­stric­tion” reg­i­men to lon­gev­ity. 

“We fi­nal­ly have ge­net­ic ev­i­dence to un­rav­el the un­der­ly­ing mo­lec­u­lar pro­gram re­quired for in­creased lon­gev­i­ty in re­sponse to cal­o­rie re­stric­tion,” said the in­sti­tute’s An­drew Dil­lin, who led the study pub­lished on­line in the May 2 is­sue of the re­search jour­nal Na­ture. 

The find­ing opens the door to de­vel­op­ment of drugs that mim­ic cal­o­rie re­stric­tion’s ef­fects, he added. These could al­low peo­ple to reap health ben­e­fits with­out go­ing hun­gry. 

One com­pound that may fit this de­s­c­rip­tion, res­ver­a­trol, is al­ready mar­keted and has shown prom­ise in an­i­mal stud­ies. But it’s not clear wheth­er it acts specif­i­cally on the bi­o­chem­i­cal path­way of di­etary re­stric­tion—one of three sep­a­rate path­ways known to af­fect lon­gev­i­ty, Dil­lin said.

Ca­lor­ic re­stric­tion al­so is the on­ly strat­e­gy apart from di­rect ge­net­ic ma­ni­pu­la­tion that con­sist­ent­ly pro­longs life in an­i­mals, Dil­lin not­ed. It al­so cuts the risk of can­cer, di­a­be­tes, and car­di­o­vas­cu­lar dis­ease and staves off age-re­lat­ed neu­rode­gen­er­a­tion in lab­o­r­a­to­ry an­i­mals from mice to mon­keys.

The price: ca­lor­ic re­stric­tion requires cut­ting to around 60 per­cent of nor­mal cal­o­rie in­take while main­tain­ing a healthy di­et rich in vi­ta­mins, min­er­als, and oth­er nu­tri­ents, Dil­lin said. Al­though some peo­ple live by this reg­i­men, it’s too soon to say wheth­er it will ex­tend life­span in hu­mans, Dil­lin said.

In the quest for genes in­volved in the ca­lor­ic re­stric­tion re­sponse, grad­u­ate stu­dent Su­zanne Wolff and oth­ers in Dil­lin’s lab­o­r­a­to­ry stud­ied an ar­ray of genes re­lat­ed to ones pre­vi­ously linked to an­ti-ag­ing path­ways. They found that on­ly one gene, called pha-4, specif­i­cally af­fected the ca­lor­ic re­stric­tion re­sponse. In round­worms, they re­ported that loss of the gene, and the pro­tein mol­e­cule whose pro­d­uc­tion it en­codes, ne­gated ca­lor­ic re­stric­tion’s life-ex­tending ef­fect. Stim­u­lat­ing it en­hanced the ef­fect.

Dil­lin spec­u­lat­ed that the lon­gev­i­ty ben­e­fits of near-starvation may have evolved as a sys­tem to help an­i­mals live through stress­ful times. Pha-4 “may be the pri­mor­di­al gene that reg­u­lates nu­tri­ent sens­ing and helps an­i­mals live a long time through stress and di­etary re­stric­tion,” he added.

One oth­er gene, called sir-2, has been im­pli­cat­ed in the life- and health-prolonging re­sponse to cal­o­rie re­stric­tion, Dil­lin said. But while loss of sir-2 dis­rupts the cal­o­rie re­stric­tion re­sponse on­ly in yeast, it has no ef­fect on oth­er or­gan­isms, such as worms, Dil­lin added. Res­ver­a­trol is pro­posed to stim­u­late sir-2.

Be­sides ca­lor­ic re­stric­tion, the two oth­er mo­lec­u­lar path­ways af­fecting lon­gev­i­ty are called the in­sulin/IGF sig­nal­ing and the mi­to­chon­dri­al elec­tron trans­port chain path­ways, Dil­lin said. “It is still not clear where sir-2 fits in. It seems to med­dle with more than one path­way,” he added. “PHA-4 is spe­cif­ic for cal­o­rie re­stric­tion as it does not af­fect the oth­er path­ways.”

Hu­mans have three genes very si­m­i­lar to worm pha-4; they all be­long to a fam­i­ly of genes called Foxa, Dil­lin con­tin­ued. All three play roles in de­vel­op­ment and lat­er in the reg­u­la­tion of glu­ca­gon, a pan­cre­at­ic hor­mone that un­like in­su­lin boosts blood sug­ar le­vels and main­tains en­er­gy bal­ance, es­pe­cial­ly dur­ing fast­ing. Sci­en­tists might be able to ex­ploit the find­ings to cre­ate anti-ag­ing treat­ments—spe­cif­ic­ally, by find­ing ways to stim­u­late Foxa ac­tiv­i­ties, re­search­ers said. “Those are ex­per­i­ments we’re ac­tive­ly col­lab­o­rat­ing on,” said Si­ler Pan­ow­ski, a grad­u­ate stu­dent in Dil­lin’s lab­o­ra­tory.

* * *

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In studies dating back 70 years, mice and many other species subsisting on a near-starvation diet have consistently lived as much as 40 percent longer than normal. But just how this stringent existence extends lifespan has been unclear. Now, researchers at the Salk Institute for Biological Studies in La Jolla, Calif., report they have have cracked the puzzle, finding the first gene that specifically links this “caloric restriction” regimen to longevity. “We finally have genetic evidence to unravel the underlying molecular program required for increased longevity in response to calorie restriction,” said the institute’s Andrew Dillin, who led the study published online in the May 2 issue of the research journal Nature. The finding opens the door to development of drugs that mimic calorie restriction’s effects, he added. These could allow people to reap health benefits without going hungry. One such compound, called resveratrol, is already marketed and has shown promise in animal studies. But it’s not clear whether it acts specifically on the biochemical pathway of dietary restriction—one of three separate pathways known to affect longevity, Dillin said. Caloric restriction also is the only strategy apart from direct genetic mani pulation that consistently prolongs life in animals, Dillin noted. It also cuts the risk of cancer, diabetes, and cardiovascular disease, while staving off age-related neurodegen eration in labora tory animals from mice to monkeys. Caloric restriction involves cutting around 60 percent of normal calories while maintaining a healthy diet rich in vitamins, minerals, and other nutrients, Dillin said. Although some people live by this regimen, it’s too soon to say whether it will extend lifespan in humans, Dillin said. In the quest for genes involved in the caloric restriction response, graduate student Suzanne Wolff and others in Dillin’s labora tory studied an array of genes related to genes previously found to be involved in anti-aging pathways. They found that only one gene, called pha-4, specifically affected the caloric restriction response. In roundworms, they reported that loss of the gene and the protein molecule it encodes negated the lifespan-extending effects of caloric restriction. Stimulating it enhanced the effect. Dillin speculated that the longevity benefits of near-starvation may have evolved as a system to help animals live through stressful times. Pha-4 “may be the primordial gene that regulates nutrient sensing and helps animals live a long time through stress and dietary restriction,” he added. So far one other gene, called sir-2, has been implicated in the life- and health-prolonging response to calorie restriction, Dillin said. But while loss of sir-2 disrupts the calorie restriction response only in yeast, it has no effect on other organisms, such as worms, Dillin added. Resveratrol is proposed to stimulate sir-2. Besides caloric restriction, the two other molecular pathways affecting longevity are called the insulin/IGF signaling and the mitochondrial electron transport chain pathway, Dillin said. “It is still not clear where sir-2 fits in. It seems to meddle with more than one pathway,” he added. “PHA-4 is specific for calorie restriction as it does not affect the other pathways.” Humans have three genes very similar to worm pha-4, all belonging to what is called the Foxa family of genes, Dillin continued. All three play an important role in development and then later on in the regulation of glucagon, a pancreatic hormone that unlike insulin increases the concentration of blood sugar and maintains the body’s energy balance, especially during fasting.

Siler Panowski