The timing gene lin-4 controls aging in worms.


The same genes that regulate timed events during development also regulate aging and lifespan in C. elegans, according to Michelle Boehm and Frank Slack (Yale University, New Haven, CT).

The lin-4 microRNA is required for the correct timing of cell fate specification at larval stage L2. It acts by blocking the expression of lin-14, a putative transcription factor. But both genes are also expressed in the adult. The Yale duo engineered temperature-sensitive mutations that allowed expression changes after the proteins had functioned in development. Mutants with decreased lin-4 activity lived half a normal lifespan, whereas lin-14 mutants lived 31% longer than normal. This biological clock seems to regulate adult lifespan in the same way it regulates development: via lin-4 repression of lin-14.

Further experiments suggested that lin-4 and lin-14 exert their effect on lifespan by linking into a well-characterized insulin-like signaling pathway. This pathway, regulated by the protein Daf-2, combats aging by fighting damage from heat-shock and oxidative stress. Both lin-4 and lin-14 are widely conserved genes, so the Yale group is examining whether the murine homologues also control aging.

The function of lin-14—and whether this function is the same in both development and aging—is not known. But Slack notes that the involvement of heterochronic genes in adulthood is not surprising, as many events in adulthood occur in a timed manner, including reproduction, signs of aging, and death.


Boehm, M., and F. Slack.