We have discovered that three longevity mutants of the nematode Caenorhabditis elegans also exhibit increased intrinsic thermotolerance (Itt) as young adults.Mutation of the age-i gene causes not only 65% longer life expectancy but also Itt. The Itt phenotype cosegregates with age-i. Long-lived spe-26 and daf-2 mutants also exhibit Itt. We investigated the relationship between increased thermotolerance and increased life-span by developing conditions for environmental induction of thermotolerance. Such pretreatments at sublethal temperatures induce significant increases in thermotolerance and small but statistically highly significant increases in life expectancy, consistent with a causal connection between these two traits. Thus, when an animal's resistance to stress is increased, by either genetic or environmental manipulation, we also observe an increase in life expectancy. These results suggest that ability to respond to stress limits the life expectancy of C. elegans and might do so in other metazoa as well.A mechanistic understanding of the physiology of aging and its relationship to organismic life-span is the subject of considerable speculation. Mutations in any one of several genes in Caenorhabditis elegans result in significant extensions of mean and maximum life-span (1-5). The age-l(hxS46) mutation leads to a 65% increase in mean life-span and a 110% increase in maximum life-span with no detectable effect on development (6) and a marginal effect on fertility (2). Mutations that affect the organism's ability to form dauer larvae (dauers) also extend life-span. The dauer is an alternate developmental stage seen under conditions of poor nutrition or overcrowding (7); dauer-constitutive mutations, such as loss-of-function (lf) temperature-sensitive (ts) mutations in the daf-2 gene, result in dauer formation at the restrictive temperature under conditions that would not normally cause dauer formation, while dauer-defective If mutations in other genes cause failure to form normal dauers under any conditions (8). Analysis of these mutations has led to proposals for partially redundant, signal transduction pathways that control entry to and exit from the dauer state (9-12). Kenyon et al. (5) demonstrated that daf-2 mutants had twice the life expectancy of wild type when grown under conditions that allow the formation of normal adults. Life-span extension was suppressed by an lf mutation in the daf-16 gene. They postulated that mutation of daf-2 activates a life-span extension mechanism dependent on daf-16. This observation has been extended by Larsen et al. (13), who showed that the daf-23(m333) mutation also confers life-span extension, that the daf-12(m20) mutant acts synergistically with daf-2(el370) to extend life-span 4-fold, and that the daf-16(m26) mutation is probably epistatic to daf-2(el370) and daf-12(m20) mutations. Van Voorhies (4) demonstrated that two mutant alleles of spe-26(it118 and hc138) were long-lived (Age) and postulated that spermatogenesis reduces C. elegans life-span.In addi...

Age-synchronous cohorts of Caenorhabditis elegans were grown at 20 degrees C, then stressed at 30 degrees C or 35 degrees C. Intrinsic thermotolerance of wild type and age-1 mutant strains was assessed by measuring either progeny production or survival. In addition to increased life span (Age), mutation of age-1 results in a highly significant increased intrinsic thermotolerance (Itt) as measured by survival at 35 degrees C. Mean survival of Age strains is approximately 45% longer than that of non-Age strains for both sterile and nonsterile worms. Thermotolerance declines across the life span of both Age and non-Age strains, but Itt was observed at almost all ages. Unstressed age-1 animals showed a consistent and significant fertility deficit. Short thermal stresses can cause a dramatic reduction in progeny production for both Age and non-Age genotypes. Mutants of age-1 showed a small but consistent increased thermotolerance as measured by fertility. We propose that the enhanced ability of Age strains to cope with environmental stress may be mechanistically related to their lower age-specific mortality rates.

We present evidence for elevated levels of heat shock protein 16 (HSP16) in an intrinsically thermotolerant, long-lived strain of Caenorhabditis elegans during and after heat stress. Mutation of the age-1 gene, encoding a phosphatidylinositol 3-kinase catalytic subunit, results in both extended life span (Age) and increased intrinsic thermotolerance (Itt) in adult hermaphrodites. We subjected age-synchronous cohorts of worms to lethal and nonlethal thermal stress and observed the accumulation of a small (16-18 kd) heat-shock-specific polypeptide detected by an antibody raised against C. elegans HSP16. Strains carrying the mutation hx546 consistently accumulated HSP16 to higher levels than a wild-type strain. Significantly, overaccumulation of HSP16 in the age-1(hx546) strain following heat was observed throughout the adult life span. A chimeric transgene containing the Escherichia coli beta-galactosidase gene fused to a C. elegans HSP16-41 transcriptional promoter was introduced into wild-type and age-1(hx546) backgrounds. Heat-inducible expression of the transgene was elevated in the age-1(hx546) strain compared with the wild-type strain under a wide variety of heat shock and recovery conditions. These observations are consistent with a model in which Age mutations exhibit thermotolerance and extended life span as a result of elevated levels of molecular chaperones.

Monkeys experimentally infected with simian varicella virus (SVV) develop rash 10-14 days later. However, the route and the time of ganglionic infection are unknown. Using PCR, we analyzed DNA extracted from tissues of 13 monkeys 5 to 60 days after either intratracheal or intravenous inoculation with SVV. SVV DNA was detected in ganglia from four of five monkeys sacrificed 6 to 7 days after intratracheal inoculation. Further, analysis of ganglia from monkeys sacrificed at 10 days revealed that intravenous inoculation produced a higher proportion of SVV DNA-positive ganglia (63%) than that after intratracheal inoculation (13%), pointing to the role of hematogenous spread in ganglionic infection. Like other organs, monkey ganglia become infected with SVV before the appearance of rash.