When both genotype and environment are held constant, "chance" variation in the lifespan of individuals in a population is still quite large. Using isogenic populations of the nematode Caenorhabditis elegans we show that, on the first day of adult life, chance variation in the level of induction of a green fluorescent protein (GFP) reporter coupled to a promoter from the hsp-16.2 gene, predicts as much as a four-fold variation in subsequent survival. The same reporter is also a predictor of ability to withstand a subsequent lethal thermal stress. The level of induction of GFP is not heritable and GFP expression levels in other reporter constructs are not associated with differential longevity. HSP-16 alone is probably not responsible for the observed differences in survival but instead is likely reflective of a hidden, heterogeneous, but now quantifiable, physiological state that dictates the ability of the organism to deal with the rigors of living.Chance plays a large and probably ineradicable role in determining variation among individuals in age at death 1,2 . In humans, as well as populations of laboratory animals, 60-90% of the variation in age at death is independent of genotype 3 . In isogenic populations (where genetic variance is essentially zero), under a uniform environment, some individuals die early in life and others live quite long 1,4 . Differences in individual life span of Caenorhabditis elegans can reach as much as 50-fold 4,5 and still have almost as much variation in time of death as does the population of the United States 1,2,6 . Such observations make suspect the popular notion of a "genetic program that regulates longevity" 7 . Instead, geriatric, demographic and evolutionary evidence suggest an alternate paradigm of aging; one that encompasses a rich variety of often highly plastic processes, influenced by genetic, environmental, and stochastic phenomenon 1,2,6 . Here we demonstrate that the ability of individual isogenic worms to respond to stress on the first day of adult life has a large stochastic component and is a major predictor of their subsequent longevity.The optical transparency of C. elegans allows non-invasive visual assessment of living worms without compromising subsequent measurement of longevity. We used a chromosomallyintegrated transgenic strain (TJ375), containing the 400 bp hsp-16.2 promoter coupled to the gene encoding green fluorescent protein (GFP) and encoding no HSP-16.2 product itself (Fig. 1a). This reporter provides an accurate assessment of the total amount of native

Insulin-IGF receptor (InR) signaling has a conserved role in regulating lifespan, but little is known about the genetic control of declining organ function. Here, we describe progressive changes of heart function in aging fruit flies: from one to seven weeks of a fly's age, the resting heart rate decreases and the rate of stress-induced heart failure increases. These age-related changes are minimized or absent in long-lived flies when systemic levels of insulin-like peptides are reduced and by mutations of the only receptor, InR, or its substrate, chico. Moreover, interfering with InR signaling exclusively in the heart, by overexpressing the phosphatase dPTEN or the forkhead transcription factor dFOXO, prevents the decline in cardiac performance with age. Thus, insulin-IGF signaling influences age-dependent organ physiology and senescence directly and autonomously, in addition to its systemic effect on lifespan. The aging fly heart is a model for studying the genetics of age-sensitive organ-specific pathology.

We demonstrate here that the nematode Caenorhabditis elegans displays broad hormetic abilities. Hormesis is the induction of beneficial effects by exposure to low doses of otherwise harmful chemical or physical agents. Heat as well as pretreatment with hyperbaric oxygen or juglone (a chemical that generates reactive oxygen species) significantly increased subsequent resistance to the same challenge. Cross-tolerance between juglone and oxygen was also observed. The same heat or oxygen pretreatment regimens that induced subsequent stress resistance also increased life expectancy and maximum life span of populations undergoing normal aging. Pretreatment with ultraviolet or ionizing radiation did not promote subsequent resistance or increased longevity. In dose-response studies, induced thermotolerance paralleled the induced increase in life expectancy, which is consistent with a common origin.

Transgenic Caenorhabditis elegans expressing jellyfish Green Fluorescent Protein under the control of the promoter for the inducible small heat shock protein gene hsp-16-2 have been constructed. Transgene expression parallels that of the endogenous hsp-16 gene, and, therefore, allows direct visualization, localization, and quantitation of hsp-16 expression in living animals. In addition to the expected upregulation by heat shock, we show that a variety of stresses, including exposure to superoxide-generating redox-cycling quinones and the expression of the human beta amyloid peptide, specifically induce the reporter transgene. The quinone induction is suppressed by coincubation with L-ascorbate. The ability to directly observe the stress response in living animals significantly simplifies the identification of both exogenous treatments and genetic alterations that modulate stress response, and possibly life span, in C. elegans.

Hormesis has emerged as an important manipulation for the study of aging. Although hormesis is manifested in manifold combinations of stress and model organism, the mechanisms of hormesis are only partly understood. The increased stress resistance and extended survival caused by hormesis can be manipulated to further our understanding of the roles of intrinsic and induced stress resistance in aging. Genes of the dauer/insulin/insulin-like signaling (IIS) pathway have well-established roles in aging in Caenorhabditis elegans. Here, we discuss the role of some of those genes in the induced stress resistance and induced life extension attributable to hormesis. Mutations in three genes (daf-16, daf-18, and daf-12) block hormetically induced life extension. However, of these three, only daf-18 appears to be required for a full induction of thermotolerance induced by hormesis, illustrating possible separation of the genetic requirements for stress resistance and life extension. Mutations in three other genes of this pathway (daf-3, daf-5, and age-1) do not block induced life extension or induced thermotolerance; daf-5 mutants may be unusually sensitive to hormetic conditions.

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More than 40 single-gene mutants in Caenorhabditis elegans have been demonstrated to lead to increased lifespan (a rigorous, operational test for being a gerontogene) of 20% or more; these are referred to collectively as 'Age' mutants. Age mutants must change key functions that are rate-limiting determinants of longevity; moreover, important genes can be identified independently of prior hypotheses as to actual mode of gene action in extending longevity and/or 'slowing' of ageing. These Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Each of three well-studied mutants (age-1, clk-1, and spe-26) alters age-specific mortality rates in a fashion unique to itself. In age-1 mutants, the decreases in mortality rates are quite dramatic, with an almost tenfold drop in mortality throughout most of life. All Age mutants (so far without exception) increase the ability of the worm to respond to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies as well as random mutagenesis to identify novel genes that increase the worm's ability to resist stress. Two genes (daf-16 and old-1) are epistatic to the long-life phenotype of most mutants and also yield over-expression strains that are stress-resistant and long-lived. We have also used a variety of approaches to determine what transcriptional alterations are associated with increased longevity (and with ageing itself), including whole-genome expression studies using microarrays and GFP reporter constructs. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress. In mammals, both dietary restriction and hormesis are phenomena in which the endogenous level of resistance to stress has been upregulated; both of these interventions extend longevity, suggesting possible evolutionary conservation.

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