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Newfound mechanism in aging called a “surprising” advance

Dec. 28, 2012
Courtesy of Fred Hutchinson Cancer Research Center
and World Science staff

A newly iden­ti­fied mech­an­ism re­ported to un­der­lie the ag­ing pro­cess is be­ing called sur­pris­ing by oth­er sci­en­tist­s—who al­so say it has a good chance of pav­ing the way for fur­ther in­sights.

In find­ings re­ported in the Nov. 21 is­sue of the re­search jour­nal Na­ture, bi­ol­o­gists said the ag­ing pro­cess seems to have a lot to do with a de­clin­ing nutrient-stor­age ca­pa­city in cer­tain com­part­ments with­in cells.

Yeast cells, out­lined in blue, each con­tain one vac­u­ole, out­lined in red. The acid­i­ty of the vac­u­ole is in­di­cat­ed by the green dye: low­er acid­i­ty ap­pears as brighter green. (Cour­te­sy of Gott­sch­ling Lab, Hutch­in­son Can­cer Re­search Ctr.)
This stor­age fail­ure, they added, may cause cer­tain nu­tri­ents to build up where they're not needed and thus to flood in­to other ti­ny struc­tures of­ten called the “pow­er plants” of cells. That in turn could trig­ger a grad­u­al break­down in these struc­tures, called mi­to­chon­dria. This break­down, in turn, has been widely con­sid­ered a key part of the ag­ing pro­cess.

The find­ings, from bi­ol­o­gists at the Fred Hutch­in­son Can­cer Re­search Cen­ter in Se­at­tle, are gain­ing at­ten­tion from oth­er sci­en­tists. The work “raises new ques­tions that will serve as the jump­ing off point for fur­ther stud­ies,” wrote Mar­i­on Schmidt Al­bert Ein­stein Col­lege of Med­i­cine in New York and Bri­an K. Ken­ne­dy at the Buck In­sti­tute for Re­search on Ag­ing in Red­wood, Calif., in the Dec. 18 is­sue of the jour­nal Cur­rent Bi­ol­o­gy.

Al­though the re­search was done in yeast, si­m­i­lar mech­an­isms ex­ist in hu­man cells, bi­ol­o­gists said. The find­ings “should pro­vide new in­sights in­to the bi­ol­o­gy of the ag­ing pro­cess,” Schmidt and Ken­ne­dy wrote.

The Hutch­in­son Can­cer cen­ter re­search­ers, Dan­iel Gottschling and Ad­am Hughes, started the in­ves­ti­ga­t­ion by search­ing for the source of age-related dam­age in the cel­lu­lar “pow­er plants,” or mi­to­chon­dria. The mi­to­chon­dria gen­er­ate us­a­ble en­er­gy by us­ing the ox­y­gen we breathe in.

“Nor­mally, mi­to­chon­dria are beau­ti­ful, long tubes, but as cells get old­er, the mi­to­chon­dria be­come frag­ment­ed and chunky,” said Gottschling. “The changes in shape seen in ag­ing yeast cells are al­so ob­served in cer­tain hu­man cells, such as neu­rons and pan­cre­at­ic cells, and those changes have been as­so­ci­at­ed with a num­ber of age-related dis­eases in hu­mans.“

What causes mi­to­chon­dria to be­come dis­tort­ed and dys­func­tional as cells age had been a mys­tery. Gottschling and Hughes found that spe­cif­ic changes to a sep­a­rate stor­age com­part­ment called the vac­u­ole lead di­rectly to their mal­func­tion­ing.

The vac­u­ole – and its coun­ter­part in hu­mans and oth­er or­gan­isms, the ly­so­some – has two main jobs: dis­man­tling mo­le­cules called pro­teins that have out­lived out their use­ful­ness, and stor­ing mo­lec­u­lar build­ing blocks for the cell. To per­form those jobs, the vac­u­ole must be highly acid­ic in­side.

But Hughes and Gottschling found that the vac­u­ole be­comes less acid­ic fairly early in the yeast cel­l's life­span and that this change hin­ders the vac­u­ole's abil­ity to store cer­tain nu­tri­ents. This, in turn, dis­rupts the mi­to­chon­dria's en­er­gy source, caus­ing them to break down. When Hughes pre­vented the drop in vac­u­o­lar ac­id­ity, the mi­to­chon­dria's func­tion and shape were pre­served and the yeast cells lived long­er, they said.

“Un­til now, the vac­u­ole's role in break­ing down pro­teins was thought to be of pri­ma­ry im­por­tance. We were sur­prised to learn it was the stor­age func­tion, not pro­tein de­grada­t­ion, that ap­pears to cause mi­to­chon­drial dysfunc­tion in ag­ing yeast cells,” Hughes said.

The find­ing prompted Hughes and Gottschling to in­ves­t­i­gate the ef­fects of cal­o­rie re­stric­tion, which is known to ex­tend the life­span of yeast, worms, flies and mam­mals, on vac­u­o­lar ac­id­ity. They found that cal­o­rie re­stric­tion – that is, lim­it­ing the raw ma­te­ri­al cells need – de­lays ag­ing at least in part by boost­ing the ac­id­ity of the vac­u­ole.

“Now that we have pre­lim­i­nar­y ev­i­dence in yeast of how cal­o­rie re­stric­tion ex­tends life­span, our hope is that it can be trans­lated to high­er or­gan­isms like hu­mans,” Hughes said. Giv­en the si­m­i­lar­i­ties in the fun­da­men­tal bi­ol­o­gy of yeast and hu­man cells, the re­search­ers' newly de­fined link be­tween what cells “eat” and how they age could help clar­ify the events that lead to age-related dis­or­ders, they added.

Gottschling and Hughes spec­u­late that if the vac­u­ole's de­clin­ing ac­id­ity lim­its its abil­ity to store cer­tain nu­tri­ents and metabo­lites, these may build up in the cell, flood­ing the mi­to­chon­dria. Over­whelmed, the mi­to­chon­dria use up all their en­er­gy – es­sen­tially burn­ing out their mo­tors – tak­ing in the sur­plus. With no pow­er left to im­port the pro­teins they need to main­tain their el­e­gant shape and ex­e­cute their reg­u­lar du­ties, the mi­to­chon­dria lit­er­ally break down. Gottschling and his col­leagues are now in­ves­ti­gat­ing this hy­poth­e­sis in de­tail. They're al­so ex­plor­ing what trig­gers the in­i­tial drop in the vac­u­ole's ac­id­ity.

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A newly identified mechanism reported to underlie the aging process is being called surprising by other scientists—who also say it has a good chance of paving the way for further insights. In findings reported in the Nov. 21 issue of the research journal Nature, biologists said the aging process seems to have a lot to do with a declining nutrient-storage capacity in certain compartments within cells. This storage failure, they added, may cause certain nutrients to build up where they're not needed and thus to flood into tiny structures often called the “power plants“ of cells. That in turn could trigger a gradual breakdown in these structures, called mitochondria. This breakdown, in turn, has been widely considered a key part of the aging process. The findings, from biologists at the Fred Hutchinson Cancer Research Center in Seattle, are gaining attention from other scientists. The work “raises new questions that will serve as the jumping off point for further studies,“ wrote Marion Schmidt Albert Einstein College of Medicine in New York and Brian K. Kennedy at the Buck Institute for Research on Aging in Redwood, Calif., in the Dec. 18 issue of the journal Current Biology. Although the research was done in yeast, similar mechanisms exist in human cells, biologists said. The findings “should provide new insights into the biology of the aging process,“ Schmidt and Kennedy wrote. The Hutchinson Cancer center researchers, Daniel Gottschling and Adam Hughes, started the investigation by searching for the source of age-related damage in the cellular “power plants,“ or mitochondria. The mitochondria generate usable energy by using the oxygen we breathe in. “Normally, mitochondria are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky,“ said Gottschling. “The changes in shape seen in aging yeast cells are also observed in certain human cells, such as neurons and pancreatic cells, and those changes have been associated with a number of age-related diseases in humans.“ What causes mitochondria to become distorted and dysfunctional as cells age had been a mystery. Gottschling and Hughes found that specific changes to a separate storage compartment called the vacuole lead directly to their malfunctioning. The vacuole – and its counterpart in humans and other organisms, the lysosome – has two main jobs: dismantling molecules called proteins that have outlived out their usefulness, and storing molecular building blocks for the cell. To perform those jobs, the vacuole must be highly acidic inside. But Hughes and Gottschling found that the vacuole becomes less acidic fairly early in the yeast cell's lifespan and that this change hinders the vacuole's ability to store certain nutrients. This, in turn, disrupts the mitochondria's energy source, causing them to break down. When Hughes prevented the drop in vacuolar acidity, the mitochondria's function and shape were preserved and the yeast cells lived longer, they said. “Until now, the vacuole's role in breaking down proteins was thought to be of primary importance. We were surprised to learn it was the storage function, not protein degradation, that appears to cause mitochondrial dysfunction in aging yeast cells,“ Hughes said. The finding prompted Hughes and Gottschling to investigate the effects of calorie restriction, which is known to extend the lifespan of yeast, worms, flies and mammals, on vacuolar acidity. They found that calorie restriction – that is, limiting the raw material cells need – delays aging at least in part by boosting the acidity of the vacuole. “Now that we have preliminary evidence in yeast of how calorie restriction extends lifespan, our hope is that it can be translated to higher organisms like humans,“ Hughes said. Given the similarities in the fundamental biology of yeast and human cells, the researchers' newly defined link between what cells “eat“ and how they age could shed valuable light on the events that lead to age-related disorders in humans, they added. Gottschling and Hughes speculate that if the vacuole's declining acidity limits its ability to store certain nutrients and metabolites, these may build up in the cell, flooding the mitochondria. Overwhelmed, the mitochondria use up all their energy – essentially burning out their motors – taking in the surplus. With no power left to import the proteins they need to maintain their elegant shape and execute their regular duties, the mitochondria literally break down. Gottschling and his colleagues are now investigating this hypothesis in detail. They're also exploring what triggers the initial drop in the vacuole's acidity.