A pair of nematodes laid end to end would extend twiceas far as this hyphen in "life-span."

On that very subject, these millimeter-long backyardround-worms have an average life expectancy of threeweeks, from birth to death.

Caenorhabditis elegans, to call the minuscule, transparentinvertebrates by their full name, grow to maturity in 3.5days, by which time they can lay some 100 eggs per day,for ensuing generations of C. elegans.

Each grown-up nematode consists of 959 somatic cells,and counts an estimated 40,000 genes in its genome."That's not an awful lot less than for Homo sapiens,"observes molecular geneticist Thomas Johnson. "It makesC. elegans a good model for metazoa."

By metazoa, Johnson means all multicellular animals inwhich cells are differentiated and form tissues. As such,the lowly roundworm makes a good model for studyingsuch aspects of the human condition as longevity. Whichis what Johnson, a research faculty member at theUniversity of Colorado in Boulder, has been doing sincethe early 1980s.

In today's Proceedings of the National Academy ofSciences (PNAS), Johnson and his co-authors at theuniversity's Institute for Behavioral Genetics report on"Thermotolerance and extended life-span conferred bysingle-gene mutations and induced by thermal stress."

In other words, making things hot for nematodes makesthem live longer.

Age-1 Gene Confers Heat Tolerance, Long Life

Johnson has identified four mutant genes implicated inthe worm's longevity. Of these, the first-found is aptlynamed age-1. It was discovered, in another laboratory, byscreening the mutant progeny of worms that had beenpoint-mutated by chemical mutagen.

"We identified age-1 early in the '80s," Johnson toldBioWorld Today, "as a gene which, when mutated, leadsto a 65-percent longer-than-normal mean life-span, and110 percent maximum extension. It's not yet beencloned," he added, "but it does look as if age-1 isfunctioning in a signal-transduction pathway."

"All four of these genes," he said, "up-regulate the abilityof these animals to withstand lethal thermal stress. Sothey become more thermal-tolerant. The main thrust ofthis finding in PNAS," Johnson continued, "is that thereseems to be a unifying principal behind these longevitymutants."

Laboratory nematodes happily live out their allotted life-spans at 20o C (68o F). To teach his wormsthermotolerance 101, Johnson's group exposed four-dayold adults, both wild-type and age-1 mutants, to 35o Cheat shocks.

By 500 minutes of that big chill, all wild-type wormswere dead, whereas 80 percent of the age-1 mutants hadlearned their thermotolerance lesson and lived on.

Johnson's team has elicited life-prolonging responses inwild-type individuals as well, by pretreatment at 30o Cbefore the 35o C shock. Here, too, induction ofthermotolerance ran parallel with increased life-span. "Toour knowledge," Johnson wrote in PNAS, "there is noprevious report of single-gene mutations leading toincreased thermotolerance in any metazoan species."

"The field is really heating up," he told BioWorld, no punintended. "It's developed quite an interest inbiotechnology circles too." He already has been contactedabout the prospects for eventual application in mammals,including humans.

Not Diseases Of Aging _ Aging Itself

Johnson disclosed that "I'm currently involved veryheavily in a start-up that's going after longevity invertebrates."

That embryo biotech company is MRX Biosciences Inc.A retired motion picture magnate, Ralph Andrews byname, is putting it together, with Johnson as one of itsscientific consultants. As yet, MRX's laboratorypremises, Andrews told BioWorld Today, consists onlyof a "fabulous architectural rendering," and its locationwill "probably be in a country other than the U.S."Andrews is currently seeking private financing.

Geron Corp., of Menlo Park, Calif., comes to mind as apossible competitor, but Andrews points out that that firmfocuses on the diseases of aging, whereas MRX takes aimat the aging process itself. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.