UC San Francisco researchers have made a significant finding in roundworms that may offer insight into the way in which genes regulate aging and life span in humans.
In a study published in the October 16 issue of Cell, they report that a gene already known to play an important role in controlling aging in roundworms does so not by acting within individual cells to control each cell's fate, but by acting within certain cells to coordinate the aging process of the whole organism.
"Our study indicates there is a mechanism that causes all of the cells in the animal to reach a consensus," said the senior author of the study, Cynthia Kenyon, PhD, 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 Kenyon's lab had previously determined plays a significant role in controlling the aging process and life span 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 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.
What the researchers have now discovered is 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," said Kenyon, "this small group of cells allows all the cells in the animal to live longer-'even those that contain the normal gene.' The explanation, she said, appears to be that daf-2 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," she said.
To determine how daf-2 functions, Javier Apfeld, a Howard Hughes 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 a wide variety of cell subtypes and observed whether the alteration prompted a corresponding change in the mutated cells themselves or in other cells instead.
What they discovered was that there was not a one-to-one correspondence, or cell "autonomous" relationship, between daf-2 activity and a cell's behavior. Rather, cells responded "cell nonautonomously" to the gene, responding to a secondary message sent from signaling cells that were sensitive to the gene's actions.
"Our findings indicate that daf-2 does not act within each cell to control that cell's fate," said Kenyon.
Moreover, the researchers determined that in animals with intermediate levels of daf-2 signaling activity, the animals became either dauers or adults. Further evidence that there is a secondary mechanism that causes all of the cells in the animal to reach a consensus on whether or not to proceed with the aging process.
"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," said Kenyon.
The researchers determined that one of the signaling cell types that daf-2 acts within is nerve cells. It is also possible, said Kenyon, that the gene acts systemically within both neural and nonneural cells, perhaps even in every cell of the animal.
As many biological processes are known to be conserved between C. elegans and vertebrates, the finding offers possible insight into the way that human aging is controlled. The possibility is particularly tantalizing 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," said Kenyon.
If this is the case, she said, it may be that the hormone signaling pathway in C. elegans hints at a similar process regulating aging in humans. "It may be that one portion of this pathway is involved in the control of aging, so the challenge is to figure out which portion that is."
The UCSF research was funded by a grant from the National Institute of Aging.
Journal
Cell