We may not yet be able to compete with the likes of the bowhead whale, currently the longest-living mammal in existence with a lifespan of over 200 years, but for the bevy of life’s occupational hazards, we humans are pretty fit. (We’ve escaped the food chain, after all.) But aging still comes with the heavy baggage of cognitive decline, physical atrophy, and, inevitably, death. All of this is natural, of course, but scientists now argue they may have found a way to extend this finite timeline by startling orders of magnitude.
Published in Cell Reports, the study focuses on a commonly examined round worm, Caenorhabditis elegans. Scientists from the Buck Institute on Research and Aging used genetic mutations in two pathways, known for their role in longevity, in order to extend the lifespan of these worms five-fold. In human years, the team explained, the net result for humans would be an added three to four centuries of living.
To be clear, the new study involves worms — not even mammals. Any hope of increasing human lifespan must first go through numerous trials on mice models, and only then, if the researchers are successful, can the proposed gene therapies be used on humans. If they were to reach such a stage, lead researcher and Buck faculty, Dr. Pankaj Kapahi, points out, the mutations would hold great promise for aging therapies, much in the way human immunodeficiency virus (HIV) and cancer are currently treated.
"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," Dr. Kapahi said in a statement. "The same thing is likely happening in aging."
Dr. Kapahi says “likely” because one of the things scientists currently struggle to understand is how centenarians — people who live to be 100 years old and older — can achieve such longevity. Oftentimes, the centenarians themselves have vastly different success stories. Some attribute long life to maintaining a healthy diet, while others chalk it up to social support or religion. These factors may have an influence, but biologically something fundamentally different must be taking place. Aging occurs as a result of four key processes: telomere shortening, chronological aging, oxidative stress, and glycation. Telomere shortening is the gradual worsening of the cell’s blueprint because telomeres — the cap-like structures on the ends of chromosomes — fail to keep DNA from fusing together. Glycation refers to glucose binding to and inhibiting DNA, proteins, and lipids.
The current research could help explain why scientists are having such difficulty identifying single genes responsible for pushing centenarians past year 100, Dr. Kapahi explained. "It's quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives," he said.
To better understand the intricate process of round worm aging, the research team combined mutations in two pathways commonly used in aging studies, insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Together, these two pathways each usually make up 30 and 20 percent lifespan extensions, respectively — prompting expectations for a 130 percent increase in the round worms when they were employed together.
"Instead, what we have here is a synergistic five-fold increase in lifespan," Dr. 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."
In other words, Dr. Kapahi and his colleagues found that no single gene is responsible for increased life span; rather, that longevity is found in the interplay between multiple genes, owing to the feedback loop he mentions. Dr. Di Chen, associate professor at the Model Animal Research Center of Nanjing University, noted this loop originated along the worms’ germline, meaning it exists in the tissues that get passed on through generations, in the same way eye color passes between parent and child.
"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," Dr. Chen said. "The finding has implications for similar synergy between the two pathways in more complex organisms."
Initially, these organisms will be mice. Researchers must develop a better understanding of how the two mutant pathways can offset the deleterious effects of cellular aging. When humans age, for instance, their cells replicate a finite number of times — often between 50 and 70 across one lifetime — which means developing anti-aging therapies includes targeting specific cellular processes. As the TOR pathway regulates cell growth, and suppressed insulin signaling boosts key proteins responsible for stress resistance, the researchers believe future research targeting the tag-team could make great leaps in the field of aging.
"The idea would be to use mice genetically engineered to have suppressed insulin signaling,” Dr. Kapahi said, “and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway."
Source: Chen D, Kapahi P, Li P. Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans. Cell Reports. 2013.