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Qnas with Cynthia Kenyon QnAs QnAs with Cynthia Kenyon or more than a decade, devel- PNAS: Your work has shown that a protein opmental biologist Cynthia Kenyon called Target of Rapamycin (TOR) helps F has sought the essence of youth in mediate some of the effects of caloric re- the soil-dwelling roundworm Cae- striction. Does that make TOR a promis- norhabditis elegans. Through her studies on ing drug target for aging? genes that control aging in the worm, Ken- Kenyon: In yeast, worms, flies, and mice, yon, a member of the National Academy of inhibiting TOR extends life span. If you Sciences and a professor of biochemistry at feed mice an inhibitor of TOR called ra- the University of California, San Francisco, pamycin, they live longer, even if they don’t joined the quest for immortality that has receive rapamycin until they are already tickled the imagination ofthinkerssince time pretty old. But in humans, rapamycin acts immemorial. Kenyon’s work has uncovered as an immunosuppressant and can have aging-related genes that affect physiological undesirable side effects, so its potential as processes like metabolism, respiration, and an anti-aging drug is unclear. reproduction. Contradictory reports of ex- PNAS: Is there a tradeoff between re- perimental compounds purported to extend production and life span, as some evolu- life or delay aging in animals have often tionary theories might suggest? roiled this corner of biology. Kenyon offers Kenyon: I don’t think so; at least not in PNAS readers her views on the molecular worms. You can remove the whole re- underpinnings of aging. productive system, and the animal still has ’ PNAS: In the early 1990s you demonstrated a completely normal life span. So I wouldn t that altering genes in the roundworm can think of it as a tradeoff. But the repro- extend its life span. What does that finding Cynthia Kenyon. ductive system does make signals that con- mean for human life span extension? trol aging. We showed that worms with an Kenyon: ’ “empty gonad,” lacking germ cells, live Kenyon: We ve shown that mutations that We found that changing a single inhibit the function of sensory neurons can much longer than normal. A similar effect daf-2 fl gene called , which encodes a hormone extend the life span of roundworms. The was recently discovered in ies. receptor, drastically slows aging in the underlying molecular mechanism seems to PNAS: You’ve also shown that reducing roundworm. Humans have genes similar to involve daf-2 and daf-16. Several years later, daf-2 respiration has an effect on life span. , which encode receptors for the hor- others demonstrated a similar extension of mones insulin and insulin-like growth factor life span by blocking sensory neuron func- Kenyon: In nature, larger animals generally 1 (IGF-1).Other researchers have found that tion in fruit flies. Fruit flies live longer when tend to have lower metabolic rates and live some people who live to be a hundred harbor their calorie intake is restricted; the effect is longer than smaller ones. Several labora- mutations in the gene for the insulin-like diminished if the flies are allowed to smell tories, including ours, discovered that in- growth factor receptor, the human daf-2 ’ hibiting respiration extends the lifespan of the food. It s a cool phenomenon, but one fi counterpart. We also discovered that an- that isn’t completely understood. C. elegans, and this nding has now been other gene, called daf-16, is required for daf- repeated in flies and mice. There are 2 mutant roundworms to live long. daf-16 PNAS: How does restricting animals’ calo- a number of genes now known to link encodes a gene switch that turns on a slate of ric intake lead to some of the observed respiration and life span. We found one— genes involved in stress resistance, protein beneficial effects on aging? a gene switch—that senses cellular oxygen homeostasis, innate immunity, and metabo- Kenyon: In the old days people thought that levels and appears to mediate life exten- lism. These genes may extend life span by sion in response to reactive oxygen species protecting and repairing tissues. Others have caloric restriction helped extend life span because less metabolic activity meant less produced when respiration is reduced. We found that genetic variants in a human daf-16 ’ think that low levels of reactive oxygen counterpart called FOXO3A have been as- cellular damage to the animals. That s pro- bably not true. Now there’s a lot of evidence species might prompt the animal to mount sociated with exceptional longevity in Cali- a protective response that has a beneficial fornians, New Englanders, Ashkenazi Jews, suggesting that life span extension requires changes in gene regulation. Surprisingly, effect on life span. In fact, we and others Hawaiians of Japanese descent, Dutch, Ital- found that small amounts of paraquat, ians, Germans, and Chinese. These studies depending on how caloric restriction is ad- ministered, different regulatory systems can a chemical that generates reactive oxygen suggest that human life span is susceptible to species, can extend the roundworm’s life. the effects of this signaling pathway. But we be engaged to extend life span. Here are don’t know whether interventions can fur- three examples in the worm: Beginning ca- PNAS: In your opinion, is there a promising ther extend life span in people. loric restriction in middle age activates an candidate for an anti-aging drug? energy sensor, activating life span through ’ PNAS: Does the pathway also play a role in daf-16 changes. Feeding the worms every Kenyon: In my laboratory we re trying to age-related diseases? other day seems to extend life span through discover small molecules that activate the FOXO3A gene switch in human cells as Kenyon: fl daf-16 and daf-2. Keeping the worms calo- In worms, ies, and mice it is be- rically restricted all their life extends life a way to extend life span. Right now, there daf-2– coming clear that like mutations in span, not through daf-16, but through an- is no paradigm for evaluating the potential the insulin and IGF-1 signaling pathways other gene switch. of experimental compounds as human life- not only extend life span but also slow aging. extending drugs per se. But if we can show That translates into delayed onset and re- PNAS: Does caloric restriction work for that such compounds can alleviate age-re- duced severity of a number of age-related people? lated diseases, it makes sense to evaluate — diseases as seen in animal models of can- Kenyon: ’ their potential as drugs for those diseases. If cer, Alzheimer’s disease, and heart disease. There s some evidence to suggest that calorically restricted people have we are lucky, people taking these drugs will PNAS: Your work has revealed a link be- more youthful hearts. And there are on- age more slowly. tween sensory perception and aging in going clinical trials to test the effects of some animals. Can you explain the link? caloric restriction on human life span. Prashant Nair, Science Writer www.pnas.org/cgi/doi/10.1073/pnas.1114658108 PNAS Early Edition | 1of1 Downloaded by guest on September 28, 2021.
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