Scientists at the Buck Institute say they have combined mutations in two pathways well known for lifespan extension and found a synergistic five-fold extension of longevity in the nematode C. elegans. The research (“Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans”), which appears online in Cell Reports, 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 Pankaj Kapahi, Ph.D., said single mutations in TOR (in this case rsks-1) usually result in a 30% lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms, when added together, would be expected to extend longevity by 130%.

“Instead, what we have here is a synergistic five-fold increase in lifespan,” continued Dr. Kapahi. “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.”

“Our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms,” wrote the investigators.

Dr. Kapahi added that 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 explained. “The same thing is likely happening in aging.”

Dr. Kapahi believes 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,” he noted.

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