Genes that control the timing of organ formation during development also control timing of aging and death, and provide evidence of a biological timing mechanism for aging, Yale researchers report in the journal Science.
"Although there is a large variation in lifespan from species to species, there are genetic aspects to the processes of development and aging," says Frank Slack, associate professor of molecular, cellular and developmental biology, and senior author of the paper. "We used the simple but genetically well-studied C. elegans worm and found genes that are directly involved in determination of lifespan. Humans have genes that are nearly identical."
A microRNA and the developmental-timing genes it controls, lin-4 and lin-14, affect patterns of cellular development at very specific stages. Slack's group found that mutations in these genes alter both the timing of the worm development stages and the worm lifespan. C. elegans has been the premier model organism for studying the genetics of aging, and has proved to be an excellent predictor of genes that also control mammalian aging.
To test the genes' functions, the scientists created mutations in both of them. Animals with a loss-of-function mutation in lin-4 had a lifespan that was significantly shorter than normal, suggesting that lin-4 prevents premature death. Conversely, over-expressing lin-4 led to a longer lifespan. They also found that a loss-of-function mutation in lin-14, the target of lin-4, caused a 31% longer lifespan.
According to Slack, the team's results are strong evidence of an "intrinsic biological clock" that runs for aging as well as for normal organ development. Other results from the study showed the developmental programs that these genes regulate are modulated through insulin signaling, demonstrating the connection between insulin-driven metabolism and aging.
"This microRNA is conserved in humans leading to the enticing idea of being able to beneficially affect the results of aging, including diseases of aging," says Slack. Work is under way to identify other microRNA regulators and genes they target, to determine where they function and whether they behave the same way in mice, and to see if they are altered in human diseases of aging.
Michelle Boehm co-authored this study which was funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health.
-- By Janet Rettig Emanuel
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