Gauging Aging
Authors: Beckman Mary 
Published: August 2003

Like a family album that records how the years unfold, snapshots through the microscope reveal how worms change over time. By analyzing ripening
Caenorhabditis elegans
, researchers have now documented how nematodes age normally, providing criteria with which to uncover short-lived mutants that grow old quickly. Using this technique, they've found a gene whose identity suggests what many baby boomers already know: Aging is stressful.

When researchers discover life-extending mutations, they crack open the champagne. When they find mutations that cut life short, however, they pour a stiff one; distinguishing whether the organisms are aging fast or succumbing to an unrelated illness poses a significant challenge. Garigan and colleagues turned to Nomarski microscopy, a technique that shows minute details of living animals, to watch worms wizen. Their goal: to define normal aging in order to assess which mutants age rapidly and which ones wither by other means.

First, the group tracked normal worms. The membrane surrounding the nucleus in their cells gradually blurred, and the animals' tissues curdled like cottage cheese. To quantify the process, the team rated the worms on a numeric scale from "youthful and unsullied" to "nearly unrecognizable" because of extreme degeneration. The researchers then used statistics to show that tissue deteriorated in a predictable fashion.

Next they found that two different life-extending mutations slowed tissue disintegration: Nuclear membranes in long-lived
daf-2
mutants appeared sharp for at least 20 days, whereas they started to fade in normal 5-day-old worms. This success motivated the converse experiment, in which the researchers tested whether they could discriminate briskly aging worms from sick ones. They screened all 2500 genes on chromosome I and found five whose absence caused worms to blink out of existence faster than normal. Four of the genes spawned maladies that seemed unrelated to aging: Rotted tissue appeared more like whey than curds. The last gene,
hsf-1
, caused 5-day-old worms to fill with cavities and cottage cheese-like tissue, thereby resembling normal 10- or 15-day-olds. This gene encodes heat shock factor (HSF), a protein switch that helps the animal fix or dispose of disfigured proteins. Previous data suggest that this renovation system staves off aging in
yeast
,
worms
, and
fruit flies
. Taken together, the data suggest that the organism normally stays young by stemming stress-induced molecular havoc, says molecular biologist and co-author Cynthia Kenyon of the University of California, San Francisco.

The work addresses an oft-neglected aspect of aging-related studies, says molecular geneticist Monica Driscoll of Rutgers University, Piscataway, New Jersey. Instead of focusing on how long an animal lives, she says, researchers should be detailing "what aging looks like" so they can judge when they've foiled the process. Just because an animal kicks around for twice as long as normal doesn't mean it's living a productive life, she says. The work opens new avenues toward mutants that accelerate aging, with
hsf-1
leading the way; their mutations reveal genes that presumably inhibit the process when left unperturbed. Until now, "we didn't have good criteria for what aging is," says Driscoll. With advances like this, appraising aging might turn out to be as easy as scrutinizing a Polaroid for gray hairs.

--Mary Beckman; suggested by Hanyu Liang and Arlan Richardson

D. Garigan, A.-L. Hsu, A. G. Fraser, R. S. Kamath, J. Ahringer, C. Kenyon, Genetic analysis of tissue aging in
Caenorhabditis elegans
: A role for heat-shock factor and bacterial proliferation.
Genetics
161
, 1101-1112 (2002).
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