MicroRNA gene that regulates lifespan found by Yale scientists

"The C. elegans lin-4 gene is also found in humans, conserved as human mir-125". This image shows an alignment between the C. elegans and human genes. Click here for a high resolution image.

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.

The effects of deleting or over-expressing the lin-4 microRNA on lifespan in C. elegans. Survival curve shows that losing lin-4 (blue) causes a short lifespan (50% of wild-type), while extra lin-4 (red) causes an extended lifespan (120% of wild-type) Click here for a high resolution image.

"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.

Old lin-4 mutants (right) show premature expression of an aging marker, lipofusin autofluorescence, compared to wild-type animals (left) of the same age Click here for a high resolution image.

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 loss–of-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.

"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," said Slack. Work is under way to identify other microRNAs 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 funded by a grant from the National Institute of General Medical Sciences of the NIH.

Citation: Science --: (December 23, 2005)