Combining mutants results in 5-fold lifespan extension in C. elegans

(Press-News.org) Contact information: Kris Rebillot
krebillot@buckinstitute.org
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Buck Institute for Age Research
Combining mutants results in 5-fold lifespan extension in C. elegans Research highlights possibility of combination therapy for aging What are the limits to longevity? New research in simple animals suggests that combining mutants can lead to radical lifespan extension. Scientists at the Buck Institute combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans. The research, done at the Buck Institute and published online in Cell Reports on December 12, 2013, introduces the possibility of combination therapy for aging and the maladies associated with it.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Lead scientist and Buck faculty Pankaj Kapahi, PhD, said single mutations in TOR (in this case RSKS-1) usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms – added together they would be expected to extend longevity by 130 percent. "Instead, what we have here is a synergistic five-fold increase in lifespan," Kapahi said. "The two mutations set off a positive feedback loop in specific tissues that amplified lifespan. Basically these worms lived to the human equivalent of 400 to 500 years."

Kapahi said the research points to the possibility of using combination therapies for aging, similar to what is done for cancer and HIV. "In the early years, cancer researchers focused on mutations in single genes, but then it became apparent that different mutations in a class of genes were driving the disease process," he said. "The same thing is likely happening in aging." Kapahi said this research could help explain why scientists are having a difficult time identifying single genes responsible for the long lives experienced by human centenarians. "It's quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives."

Former Buck postdoctoral fellow Di Chen, PhD, now an associate professor at the Model Animal Research Center, Nanjing University, China, lead author of the study, said that the positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. "The germline was the key tissue for the synergistic gain in longevity – we think it may be where the interactions between the two mutations are integrated," Chen said. "The finding has implications for similar synergy between the two pathways in more complex organisms."

Kapahi said ideally the research would move into mice as a way of determining if the lifespan-extending synergy extends into mammals. "The idea would be to use mice genetically engineered to have suppressed insulin signaling, and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway."

### Other Buck Institute researchers involved in the study include Patrick Wai-Lun Li, Emma Lynn Thomas, and Simon Melov. Other contributors include Benjamin A. Goldstein and Alan Hubbard from the School of Public Health, University of California, Berkeley and Waijiao Cai, from the Institute of Traditional Chinese and Western Medicine, Huashan Hospital, Fudan University, Shanghai. The work was supported by the National Institutes of Health (P30AG025708)( RO1AG038688), (RL1AAG032113) and (3RL1AG032113-03S1); the American Federation for Aging Research and the Hillblom Foundation.

Citation: "Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans"; publishing online December 12, 2013 in Cell Reports.

About the Buck Institute for Research on Aging The Buck Institute is the U.S.'s first independent research organization devoted to Geroscience – focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending "Healthspan", the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: http://www.thebuck.org.