New “longevity gene” spurs hopes of long life
May 04,2007 00:00 by Bend_Weekly_News_Sources

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.

Now, re­search­ers at the Salk In­sti­tute for Bi­o­log­i­cal Stu­d­ies in La Jolla, Calif., re­port they 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 glucagons, 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.

Courtesy Salk Institute and World Science staff