Hormesis and aging in Caenorhabditis elegans

Abstract

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.

Figure 1

Hormetic heat treatments induce both increased thermotolerance and improved survival. The similarity of the two dose-response curves is consistent with a relationship between stress resistance and aging. (Modified from Cypser and Johnson, 2002).

Figure 2

Short-term starvation extends lifespan in C. elegans. age-1 mutants display a relatively smaller effect size. Animals in experimental groups were transferred to liquid medium (S Basal) containing no food for 1 day or two days, then returned to survival medium (Johnson and Wood, 1982) for the duration of survival. Mean ± SEM (days) and p-value (log-rank) compared to unstarved control: For N2 (unstarved), 14.8 ± 0.3, NA; N2 (starved 1 day), 16.9 ± 0.4, p < 0.001; N2 (starved 2 days): 19.3 ± 0.3, p < 0.0001. For age-1 (unstarved), 25.3 ± 0.4, NA; age-1 (starved 1 day), 26.5 ± 0.4, p not significant; age-1 (starved 2 days), 28.8 ± 0.4, p < 0.0001.

Figure 3

Relative benefits derived from hormesis. Mean ± SEM (hours) and p-value by t-test from comparison of naïve and heat-pretreated animals (for N2): naive, 9.1 ± 0.4; pretreated, 16.9 ± 1.1, p < 0.0001, (for eat-2[ad465]): naive, 14.8 ± 0.8, pretreated, 19.8 ± 1.1, p < 0.001.

Figure 4

Genes of the insulin/IGF-2 signaling pathway are required for induced stress resistance and induced life extension. daf-18 appears to be required for heat-induced thermotolerance independently of daf-16. However, the daf-12, daf-16 and daf-18 mutants tested were all found to be defective for life extension induced by heat pretreatment. (Modified from Cypser and Johnson, 2003).