Gene Discovery In Roundworms May Offer Insight Into Human Aging

The discovery that a gene plays a coordinating role—by acting within certain cells rather than within all the individual cells of a roundworm—may offer insight into the way in which genes regulate life span in humans, a study in the October 16 issue of Cell claims.

A University of California at San Francisco research team, funded by a grant from the National Institute of Aging, reports that a consensus is reached amongst the cells in each animal and that the consensus is reached because of particular genes acting within certain types of cells.

"Our study indicates there is a mechanism that causes all of the cells in the animal to reach a consensus," says the senior author of the study, Dr. Cynthia Kenyon, the Herbert Boyer Professor of Biochemistry and Biophysics at UCSF. "And that mechanism appears to be sparked into action by particular genes acting within certain types of cells."

The researchers conducted their study on a gene known as daf-2, which had previously demonstrated its significant role in controlling the aging process and life span of the roundworm, known as nematode C. elegans. According to the researchers, fertile roundworms with partially mutated, or "knocked out," daf-2 genes grow to be active, fertile adults that live more than twice as long as normal. And roundworms still in a larval stage of development, with more severely mutated genes, enter a state of extended prepubescence known as dauer diapause, in which larvae do not feed, are able to withstand harsh environmental conditions and live a long time.

The latest study shows that if the level of daf-2 activity is lowered in just a small group of cells, the life span of the whole animal is extended. "Somehow, this small group of cells allows all the cells in the animal to live longer—even those that contain the normal gene," Dr. Kenyon says.

The explanation, she points out, is that the daf-2 gene acts in multiple groups of signaling cells to control the production or activity of a second signal that coordinates the growth and aging of individual cells, thereby regulating the development and life span of an individual.

"In adult animals, by acting in signaling cells to control the production of a second signal, the daf-2 gene may be able to coordinate the aging process of all the cells in the animal, so that they all age together at the same rate," Dr. Kenyon says.

The researchers determined that one of the signaling cell types that daf-2 acts within is nerve cells. It is also possible that the gene acts systemically within both neural and nonneural cells, perhaps even in every cell of the animal, the study states.

As many biological processes are conserved between C. elegans and vertebrates, the finding offers possible insight into the way that human aging is controlled. The possibility is particularly tantalizing, Kenyon claims, because of several apparent similarities in the response of both C. elegans and rats and mice—a step closer to humans—to low-calorie diets.

As with C. elegans, when rats and mice are fed low calorie diets they live longer than normal, and the first response they have on the molecular level is a drop in insulin levels. The equivalent of the daf-2 gene in humans produces the cell receptor for insulin and insulin-like growth factor (IGF), which plays a role in regulating food metabolism. And, just as in C. elegans, the human insulin receptor acts in signaling cells, amongst other places, prompting second signals that then effect the behavior of other cells.

"It may be that the signaling cascade prompted by daf-2 in certain cells occurs in a similar way in the insulin/IGF family of receptors in mammals in response to caloric restriction," says Dr. Kenyon.

For more information: Jennifer O'Brien, University of California at San Francisco, telephone: 415-476-2557. Email: jobrien@itsa.ucsf.edu.