Worm Breeder's Gazette 13(5): 82 (February 1, 1995)

These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

Stress Response and Lifespan

Gordon J. Lithgow, Tiffany M. White, Tom E. Johnson

Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, Colorado, 80309.

There are five published accounts of single-gene mutations
leading to an extended metazoan life span (Age). Four or
these were discovered in C. elegans (1-4), and the fifth
study (5), in drosophila, has neverbeen replicated. age-1(1),
daf-2(2) and spe-26(3) all extend lifespan at 20¡C anywhere
from 45percent to 100percent. rad-8 life-extension is
curious as it is limited to a 42percent increase at 1 6¡C
(4). C. elegans also happens to be the only system in which
a single gene mutation has been shown to confer increased
thermotolerance (survial at 35¡C) or Itt (6). That gene
is also age-1. We proposed that Itt may be mechanistically
related to Age in the following fashion; aging is the result
of the accumulation of conformationally altered protein
(CAP) which is produced by the action of reactive oxygen
species (ROS), a by-product of oxidative metabolism.
The accumulation of CAP can be prevented by the conversion
of ROS to non-ROS by antioxidant enzymes such as superoxide
dismutase and catalase or by refolding of CAP by molecular
chaperones or targeting of CAP for degradation. age-1
over-expresses SOD and catalase (7,8) and also over-expresses
hsp16 under stress conditions (see accompanying article).
We propose that age-1-associated Itt is a consequence
of hsp over-expression. We questioned whether any of the
other published Age mutants were consistent with this
Itt was assayed by shifting 2 agar plates of 25 four-day-old
adult hermaphrodites from 20¡C to 35¡C and assessing provoked
movement and pharyngeal pumping at various time intervals.
Animals lacking both of these characteristics were scored
as dead. We assayed two alleles of daf-2 and two alleles
of spe-26 and found that all were thermotolerant. daf-2(e
1370), daf-2(el368) and spe-26(hcl38) were significantly
different from N2 at the p < .0001 level and spe-26(it118)
at the p < .01 Ievel. A number of other daf-c mutations also
confer thermotolerance including daf-4 and daf-7. Although
we have not yet shown a causal relationship between the
thermotolerance phenotype and life span our results are
consistent with the notion that increased thermotolerance
is essential for life-span extension but, perhaps not
surprisingly, not sufficient. The figure shows a compilation
of life span data from different labs [age-1 and daf-2 are
from TEJ spe-26 from(2)j] and observed increases in themmotolerance.
(1) Friedman and Johnson, J. Geront. B.S. 4, B102. 1988.
(2) Van Voorheis, Nature. 360,
456. 1992. (3) Kenyon et al. Nature, 366, 461, 1993. (4)
Ishii et al. J. Geront. B. S. 49, B117,
1994. (5) Maynard Smith, Nature, 181, 496,1958 (6) Lithgow
et al. J. Geront. B.S. 49, B270,
1994. (7) Larsen, PNAS, 90, 8905, 1993. (8) Vanfleteren,
Biochem. J. 292, 605, 1993.