New Haven, Conn. -- 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," said 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 gene 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 an excellent predictor of genes that also control mammalian aging.
To test their functions, they made mutants in both of these genes. 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 lossof-function mutation in lin-14, the target of lin-4, caused the opposite effect -- a 31 percent longer lifespan.
According to Slack, their results are strong evidence of an "intrinsic biological clock" that runs for aging as well as for normal organ development. Included results showed the developmental programs that these genes regulate are modulated through insulin signaling, demonstrating the connection between insulin-driven metabolism and aging.
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