Cypser JR et al. (2006) Exp Gerontol "Hormesis and aging in Caenorhabditis elegans."

Cypser JR, Johnson TE, Tedesco P

[Exp Gerontol, 2006]

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.

Cypser JR et al. (2003) Biogerontology "Hormesis in Caenorhabditis elegans dauer-defective mutants."

Cypser JR, Johnson TE

[Biogerontology, 2003]

We have shown that increased longevity and stress resistance can be induced by sub-lethal exposure to stressors(hormesis). Here we ask whether genes of the dauer formation pathway that are known to modulate life span in Caenorhabditis elegans are required for this hormesis. We find that loss-of-function mutations in any of three genes (daf-16, daf-18, or daf-12) not only reduce or abolish the ability to form dauers but also block the hormetic response increasing life span following sub-lethal heat stress. Indeed, the life expectancy of these dauer-defective mutants is decreased by the same pretreatments that increase the life expectancy of wild-type animals. Additionally, we find that daf-16 and daf-12 are not required for the induction of thermotolerance, but daf-18 is required for its full induction. Our results underscore the importance of the dauer-formation pathway in specifying life span by demonstrating a similar, but not identical, role in life extension attributed to hormesis.

Cypser JR et al. (1997) International C. elegans Meeting "STRESS RESISTANCE AND LIFE SPAN IN SELECTED STRAINS"

Johnson TE, Cypser JR

[International C. elegans Meeting, 1997]

Resistance to a variety of environmental stresses positively correlates with increased life expectancy in a variety of model organisms, including C. elegans. We have characterized the resistance of various strains to heat and ultraviolet light. The strains tested include single-gene mutants originally selected for longevity as well as transgenic strains carrying an integrated construct of heat shock protein 16 (hsp-16) promoter gene sequence coupled to the green fluorescent protein (GFP). We are exploring the use of the transgenic strains as reporters for longevity in double mutants based upon the surrogate phenotype of differential expression of GFP under conditions of environmental stress. We were unable to replicate the increased longevity or stress resistance for several mutant strains originally selected for increased longevity, including spe-10 (hc109). We have not thus far found any significant change in expression of GFP in response to heat in an age-1/GFP double mutant. However, it was found unexpectedly that one of three GFP reporter strains was long-lived and stress resistant in comparison to wild type. We will present details of these analyses.

Cypser JR et al. (2013) Exp Gerontol "Dietary restriction in C. elegans: recent advances."

Park SK, Cypser JR, Kitzenberg D

[Exp Gerontol, 2013]

The nematode Caenorhabditis elegans continues to serve as a useful model of life extension caused by dietary restriction. Using this model, downstream effectors of dietary restriction-induced longevity have been elucidated, including neuropeptides and cell-surface receptors. Although it remains possible that different forms of dietary restriction may utilize both specific and overlapping mechanisms to promote longevity, the nematode model has revealed roles for autophagy, metabolic energy-sensing and the hypoxic response. The nematode has also been used to identify specific tissues required for life extension via DR, including coelomocytes, intestine, and neurons.

Cypser JR et al. (2013) Mech Ageing Dev "Predicting longevity in C. elegans: fertility, mobility and gene expression."

Johnson TE, Wu D, Ishii T, Park SK, Tedesco PM, Cypser JR

[Mech Ageing Dev, 2013]

Expression level of an hsp-16.2::gfp transgene is a predictor of longevity in Caenorhabditis elegans. Here we examine fertility, movement and longevity, comparing high-expressing ("bright") and low-expressing ("dim") animals. There was no differential fertility between bright and dim individuals, suggesting that dim worms were not excessively frail. Worms with high hsp-16.2::gfp expression had improved mobility, consistent with improved health span. We predicted that the increased longevity of the bright worms would be associated with increased expression of protective genes such as those shown to be upregulated in Age mutants. However, few genes were differentially transcribed, although internal controls (hsp-16.2 and family members) were differentially expressed. Quite surprising was the observation that expression level of the transgenic reporter was inherited by the progeny: in seven experiments bright worms consistently produced progeny that were brighter. We tested and ruled out possible artifacts such as differential copy-number of the transgene as an explanation of this differential brightness. These results suggest that a robust physiological state does not depend heavily upon transcriptional differences for its establishment, consistent with proteostatic mechanisms underlying the differential longevity.

Cypser JR et al. (1999) Neurobiol Aging "The spe-10 mutant has longer life and increased stress resistance."

Johnson TE, Cypser JR

[Neurobiol Aging, 1999]

We investigated the life span of spe-10 mutant nematodes. We also tested resistance of spe-10 mutants to ultraviolet (UV) light, heat, and paraquat and examined the relationship between resistance to UV light and the fertility defect of these animals. The spe-10 mutation significantly increased mean life span. Additionally, the mutation significantly increased resistance to both UV light and to heat. Resistance to paraquat was not significantly different from that of wild-type, nor were any dauers formed at 27 degrees C. No significant correlation was found between the UV resistance and the fertility defect, nor was the UV resistance attributable to a hormetic effect. These results reinforce the importance of stress resistance in specifying increased life span and indirectly suggest that this fertility defect is not a direct cause of life span extension.

Johnson TE et al. (2002) J Gerontol A Biol Sci Med Sci "Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity."

Cypser JR, Johnson TE

[J Gerontol A Biol Sci Med Sci, 2002]

We demonstrate here that the nematode Caenorhabditis elegans displays broad hormetic abilities. Hormesis is the induction of beneficial effects by exposure to lock 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 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.

Johnson TE et al. (2000) Japanese Worm Meeting "Adaptive response extends the life span through signaling to DAF-16 in Caenorhabditis elegans"

Ishii N, Yanase S, Cypser JR, Johnson TE

[Japanese Worm Meeting, 2000]

Thermotolerance, UV resistance and resistance to reactive oxygen species (ROS) are closely connected with life span and aging in Caenorhabditis elegans. Short-term or lower dose exposure to heat shock, UV and ROS produce an adaptive response to oxidative stress. This adaptive response extends life span, presumably by decreasing the rate of aging. In this study, we found that life span in C. elegans was extended in conjunction with the adaptive response attributable to short-term exposure to high-concentrations of oxygen or heat shock. This extension depended on the developmental stage of the animals as well as the period of exposure to high-concentration oxygen. Moreover, different extensions of life span attributable to the adaptive response were observed for particular long-lived C. elegans mutants. Since the degree of the adaptive response is reflected in life expectancy, we attempted to identify genes critical to the adaptive response. One class of candidate genes is the hsp16 gene family, which encodes 16 kDa small heat shock proteins (sHSPs). Expression of the hsp16-1 and hsp16-48 genes was rapidly and clearly increased under the same conditions of oxygen exposure that increased life span via the adaptive response. The expression of these hsp16 genes differed between a short-lived strain and a long-lived strain. The expression of hsp16-1 was always strong in the short-lived mev-1 mutant, but was weak in the long-lived age-1 mutant. In addition, we found that the adaptive response was weaker and life expectancy was decreased in daf-16 mutant animals. This suggests that the relative intensity of adaptive response reflects resistance to oxidative stress, as expressed by the DAF-16 transcription factor. If the antioxidant genetic defense system is up regulated as part of the adaptive response, then the adaptive response should also be expected to increase life expectancy.

Michalski AI et al. (2001) Biogerontology "Heating stress patterns in Caenorhabditis elegans longevity and survivorship."

Johnson TE, Cypser JR, Michalski AI, Yashin AI

[Biogerontology, 2001]

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 degrees C have been investigated. Three experiments with 3-day-old worms were conducted with heat duration ranging between 0 and 12 hours. A statistically significant increase in life expectancy was observed in the groups heated for less than 2 hours, as compared to the unheated control groups. In different experiments P-values for the observed life spans under the hypothesis that heating has no influence on longevity were P < 0.004 after 0.5 hour heat, P < 0.012 after 1 hour heat and P < 0.055 after 2 hours of heating. A biphasic survival model with Gamma distributed frailty has been constructed to describe the survival of worms after heating. The increase in the remaining life expectancy is determined by more effective protection by heat-induced substances in the ages yanger than 27 days. The unheated control group demonstrated acquired heterogeneity of frailty with chronological age while the heat-induced substances defend the worms in a universal way and protect against the development of frailty.

Wu D et al. (2008) J Gerontol A Biol Sci Med Sci "The U-shaped response of initial mortality in Caenorhabditis elegans to mild heat shock: does it explain recent trends in human mortality?"

Johnson TE, Wu D, Yashin AI, Cypser JR

[J Gerontol A Biol Sci Med Sci, 2008]

U-shaped dose-response relationships (hormesis) have been documented in numerous biological, toxicological, and pharmacological investigations. For example, in response to a mild 35 degrees C heat shock, the longevity of Caenorhabditis elegans exhibits an inverted U-shaped dose-response. By applying the demographic concept of heterogeneity, we find that this U-shaped curve for longevity response is driven by a U-shaped dose-response of initial mortality. When worms are subjected to mild heat shock, the initial mortality decreases compared to the control. This initial mortality benefit increases with moderate increases in the length of heat shock, peaking at a point that coincides with the induction of damage to the worms. The dose of heat shock that coincided with this benefit in initial mortality did not affect the rate of increase in mortality.