UCSF Finding Offers Insight Into Way Genes Regulate Aging And Life Span

In a study published in the October 16 issue of Cell, theyreport that a gene already known to play an important rolein controlling aging in roundworms does so not by actingwithin individual cells to control each cell's fate, but byacting within certain cells to coordinate the aging processof the whole organism.

"Our study indicates there is a mechanism that causes all ofthe cells in the animal to reach a consensus," said thesenior author of the study, Cynthia Kenyon, PhD, the HerbertBoyer Professor of Biochemistry and Biophysics at UCSF. "And that mechanism appears to be sparked into action byparticular genes acting within certain types of cells."

The researchers conducted their study on a gene known asdaf-2, which Kenyon's lab had previously determined plays asignificant role in controlling the aging process and lifespan of the roundworm known as nematode C. elegans.

Fertile roundworms with partially mutated, or "knocked out,"daf-2 genes grow to be active, fertile adults that live morethan twice as long as normal. And roundworms still in alarval stage of development, with more severely mutatedgenes, enter a state of extended prepubescence known asdauer diapause, in which larvae do not feed, are able towithstand harsh environmental conditions and live a longtime.

What the researchers have now discovered is that if thelevel of daf-2 activity is lowered in just a small group ofcells, the life span of the whole animal is extended."Somehow," said Kenyon, "this small group of cells allowsall the cells in the animal to live longer--even those thatcontain the normal gene."

The explanation, she said, appears to be that daf-2 acts inmultiple groups of signaling cells to control the productionor activity of a second signal that coordinates the growthand aging of individual cells, thereby regulating thedevelopment and life span of an individual," she said.

To determine how daf-2 functions, Javier Apfeld, a HowardHughes Medical Institute graduate student in Kenyon's lab,and Kenyon conducted what is known as a "mosaic" analysis,in which they diminished or eliminated daf-2 activity in awide variety of cell subtypes and observed whether thealteration prompted a corresponding change in the mutatedcells themselves or in other cells instead.

What they discovered was that there was not a one-to-onecorrespondence, or cell "autonomous" relationship, betweendaf-2 activity and a cell's behavior. Rather, cellsresponded "cell nonautonomously" to the gene, responding toa secondary message sent from signaling cells that weresensitive to the gene's actions.

"Our findings indicate that daf-2 does not act within eachcell to control that cell's fate," said Kenyon.

Moreover, the researchers determined that in animals withintermediate levels of daf-2 signaling activity, the animalsbecame either dauers or adults, further evidence that thereis a secondary mechanism that causes all of the cells in theanimal to reach a consensus on whether or not to proceedwith the aging process.

"In adult animals, by acting in signaling cells to controlthe production of a second signal, the daf-2 gene may beable to coordinate the aging process of all the cells in theanimal, so that they all age together at the same rate,"said Kenyon.

The researchers determined that one of the signaling celltypes that daf-2 acts within is nerve cells. It is alsopossible, said Kenyon, that the gene acts systemicallywithin both neural and nonneural cells, perhaps even inevery cell of the animal.

As many biological processes are known to be conservedbetween C. elegans and vertebrates, the finding offerspossible insight into the way that human aging iscontrolled. The possibility is particularly tantalizingbecause of several apparent similarities in the response ofboth C. elegans and rats and mice-a step closer tohumans--to low-calorie diets.

As with C. elegans, when rats and mice are fed low caloriediets they live longer than normal, and the first responsethey have on the molecular level is a drop in insulinlevels. The equivalent of the daf-2 gene in humans producesthe 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 actsin signaling cells, amongst other places, prompting secondsignals that then effect the behavior of other cells.

"It may be that the signaling cascade prompted by daf-2 incertain cells occurs in a similar way in the insulin/IGFfamily of receptors in mammals in response to caloricrestriction," said Kenyon.

If this is the case, she said, it may be that the hormonesignaling pathway in C. elegans hints at a similar processregulating aging in humans. "It may be that one portion ofthis pathway is involved in the control of aging, so thechallenge is to figure out which portion that is."

The UCSF research was funded by a grant from the NationalInstitute of Aging.