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


Misfolded molecules gain prominence as culprits in aging

Jan. 6, 2011
Courtesy of the Salk Institute
and World Science staff

Mis­folded bi­o­log­i­cal mo­le­cules are un­der grow­ing sus­pi­cion as ma­jor cul­prits in the ag­ing pro­cess, ac­cord­ing to sci­en­tists at the pres­tig­ious Salk In­sti­tute for Bi­o­log­i­cal Stud­ies in La Jolla, Ca­lif.

This new thinking is emerg­ing as an off­shoot of a re­search ap­proach that orig­i­nally tend­ed to see aging as a re­sult of some­thing akin to burn­ing a can­dle at both ends. In this view, the chief prob­lem was over­ac­ti­vity in cel­lu­lar en­er­gy-gen­er­at­ing com­part­ments, called mi­to­chon­dria.

In­tes­ti­nal (green) and nerve (red) cells of the type stud­ied in an anal­y­sis of mi­to­chon­drrial func­tion and lon­gev­i­ty at the Salk In­sti­tute. (Im­age cour­te­sy K. Be­rend­zen, Salk In­sti­tute for Bi­o­log­i­cal Stud­ies )

It turns out, though, that mi­to­chon­dria are al­so in­volved in fold­ing large mo­le­cules called pro­tein­s—which are ubiq­ui­tous through­out the body—into spe­cif­ic forms so that they can prop­erly car­ry out their many func­tions. 

Over­ac­tive mi­to­chon­dria can lead to an in­crease in wrongly folded pro­teins, ac­cord­ing to An­drew Dillin at the Salk In­sti­tute and col­leagues, who re­port some of their lat­est re­search in the Jan. 7 is­sue of the jour­nal Cell.

Us­ing the round­worm Caenorhab­di­tis el­e­gans as a mod­el or­gan­ism, the group found that “per­turbing” mi­to­chon­drial func­tion in cer­tain worm cells led to cu­ri­ous ef­fects. The af­fect­ed cells, Dillin ex­plained, ap­par­ently sent a dis­tress sig­nal to oth­er bodily tis­sues, which re­sponded by launch­ing a con­cert­ed cam­paign to fix mis­folded pro­teins. This pro­cess seemed in turn to ex­tend the worms’ life­span.

The “ma­nipula­t­ion had to oc­cur with­in a crit­i­cal time win­dow in a wor­m’s life­span to get the max­i­mal ef­fec­t,” Dillin said, not­ing that ef­fects were long-lasting. “It was like you could ma­ni­pu­late mi­to­chon­dria in a 30-year-old hu­man and get an ex­tra 15 years, while in an 80-year-old, you might only gain two or three years.”

The dis­tress sig­nals trig­gered a flur­ry of ac­ti­vity fix­ing mis­folded pro­teins, known as the Un­folded Pro­tein Re­sponse, Dillin ex­plained. He de­scribes it as a an emer­gen­cy plan that cells launch when improp­erly folded pro­teins ac­cu­mu­late ex­ces­sive­ly, cre­at­ing a tox­ic situa­t­ion for cells. The Un­folded Pro­tein Re­sponse mo­bi­lizes a team of “helper” mo­lec­u­lar struc­tures that, like sales clerks at a Gap sweat­er ta­ble, re­fold the er­rant pro­teins.

To br­ing about the dis­tress sig­nals in the first place, Dillin and col­leagues ex­pe­ri­men­tally inac­tivated a gene called cco-1 in worms. The gene is re­spon­si­ble for the pro­duc­tion of a pro­tein es­sen­tial for chem­i­cal re­ac­tions col­lect­ively known as the Elec­tron Trans­port Chain, which are re­quired for mi­to­chon­dria to gen­er­ate en­er­gy—and thus, for cells to live.

The longe­vity ef­fect worked for worms in which cco-1 inac­tiva­t­ion af­fect­ed cells in the in­tes­tine or nerve cells, the sci­en­tists found. And the ef­fect van­ished when the Un­folded Pro­tein Re­sponse was chem­ic­ally blocked, they said, point­ing to the cru­cial role of this re­sponse in the longe­vity ef­fect.

The na­ture of the dis­tress sig­nal it­self is un­known, Dill­in said.

Be­fore 2000, Dillin said, bi­ol­o­gy text­books de­fined mi­to­chon­dria solely in terms of en­er­gy pro­duc­tion, “but we now rec­og­nize nu­mer­ous oth­er crit­i­cal ac­ti­vi­ties per­formed by mi­to­chon­dria.” For longe­vity, “it all comes down to pro­tein fold­ing,” he added. “That’s be­come the un­ify­ing theme in my lab.”

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Misfolded biological molecules are increasingly under suspicion as a big culprit in the aging process, according to scientists at the prestigious Salk Institute for Biological Studies in La Jolla, Calif. The findings arose as a curious detour from a research program that originally focused much of the blame for aging on cellular processes that scientists have likened to “burning the candle at both ends.” This idea had some common-sense appeal not only because of its simple parallels with James Dean-like tales of premature demise, but more concretely, because there has been extensive agreement that aging could be tied to overactivity in cellular energy-generating compartments, called mitochondria. It turns out, though, that mitochondria are also involved in folding large molecules called proteins—which are ubiquitous throughout the body—into specific forms so that they can properly carry out their many functions. Overactive mitochondria can lead to an increase in wrongly folded proteins, according to Andrew Dillin at the Salk Institute and colleagues, who report some of their latest research in the Jan. 7 issue of the journal Cell. Using the roundworm Ceanorhabditis elegans as a model organism, the group found that “perturbing” mitochondrial function in certain worm cells led to curious effects. The affected cells, Dillin explained, apparently sent a distress signal to other bodily tissues, which responded by launching a concerted campaign to fix misfolded proteins. This process seemed in turn to extend the worms’ lifespan. The “manipulation had to occur within a critical time window in a worm’s lifespan to get the maximal effect,” Dillin said, noting that effects were long-lasting. “It was like you could manipulate mitochondria in a 30-year-old human and get an extra 15 years, while in an 80-year-old, you might only gain two or three years.” The distress signals triggered a flurry of activity fixing misfolded proteins, known as the Unfolded Protein Response, Dillin explained. He describes it as a an emergency plan that cells launch when improperly folded proteins accumulate excessively, creating a toxic situation for cells. The Unfolded Protein Response mobilizes a team of “helper” molecular structures that, like sales clerks at a Gap sweater table, refold the errant proteins. To bring about the distress signals in the first place, Dillin and colleagues experimentally inactivated a gene called cco-1 in worms. cco-1 is responsible for the production of a protein essential for chemical reactions known as the Electron Transport Chain, which are required for mitochondria to generate energy—and thus, for cells to live. The longevity effect worked for worms in which cco-1 inactivation affected cells in the intestine or nerve cells, the scientists found. And the effect vanished when the Unfolded Protein Response was chemically blocked, they said, pointing to the crucial role of this response in the longevity effect. The nature of the distress signal itself is unknown, Dillin noted, though he calls the putative entity a “mitokine.” Before 2000, Dillin said, biology textbooks defined mitochondria solely in terms of energy production, “but we now recognize numerous other critical activities performed by mitochondria.” For longevity, “it all comes down to protein folding,” he added. “That’s become the unifying theme in my lab.”