James R. Cypser

Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans

We review the status of the hypothesis that interventions that increase the resistance to stress offer the potential for effective life prolongation and increased health. The work focuses on research in the nematode worm Caenorhabditis elegans and describes both published and unpublished results consistent with this hypothesis. Correlation between stress resistance and longevity among many gerontogene mutants is provided.

Hormesis and aging in Caenorhabditis 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.

Ageing and survival after different doses of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans

Stress experiments performed on a population of sterilised nematode worms (Caenorhabditis elegans) show a clear hormesis effect after short exposure and clear debilitation effects after long exposure to heat shock. An intermediate duration of exposure results in a mixture of these two effects. In this latter case the survival curves for populations in the stress and control groups intersect. In this paper we develop an adaptation model of stress and apply it to the analysis of survival data from three such stress experiments. We show that the model can be used to explain empirical age-patterns of mortality and survival observed in these experiments. We discuss possible biological mechanisms involved in stress response and directions for further research.

Heating stress patterns in Caenorhabditis elegans longevity and survivorship

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 °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.

Hormesis and debilitation effects in stress experiments using the nematode worm Caenorhabditis elegans: the model of balance between cell damage and HSP levels

In this article, we discuss mechanisms responsible for the effects of heat treatment on increasing subsequent survival in the nematode worm Caenorhabditis elegans. We assume that the balance between damage associated with exposure to thermal stress and the level of heat shock proteins produced plays a key role in forming the age-pattern of mortality and survival in stress experiments. We propose a stochastic model of stress, which describes the accumulation of damage in the cells of the worm as the worm ages. The model replicates the age trajectories of experimental survival curves in three experiments in which worms were heat-treated for 0, 1, 2, 4, 6, or 8h. We also discuss analytical results and directions of further research. The proposed method of stochastic modelling of survival data provides a new approach that can be used to model, analyse and extrapolate experimental results.

Hormesis in Caenorhabditis elegans dauer-defective mutants

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.

The spe-10 mutant has longer life and increased stress resistance☆

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.

Molecular Genetic Mechanisms of Life Span Manipulation in Caenorhabditis elegans

Abstract: Aging and a limited life span are fundamental biological realities. Recent studies have demonstrated that longevity can be manipulated and have revealed molecular mechanisms underlying longevity control in the soil nematode Caenorhabditis elegans. Signals from both neurons and the gonad appear to negatively regulate longevity. One tissue‐specific signal involves an insulin‐like phosphatidylinositol 3‐OH kinase pathway, dependent upon the DAF‐16 forkhead transcription factor. These signals regulate mechanisms determining longevity that include the OLD‐1 (formerly referred to as TKR‐1) receptor tyrosine kinase. Interestingly, increased resistance to environmental stress shows a strong correlation with life extension.

Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans

Exposure to mild heat-stress (heat-shock) can significantly increase the life expectancy of the nematode Caenorhabditis elegans. A single heat-shock early in life extends longevity by 20% or more and affects life-long mortality by decreasing initial mortality only; the rate of increase in subsequent mortality (Gompertz component) is unchanged. Repeated mild heat-shocks throughout life have a larger effect on life span than does a single heat-shock early in life. Here, we ask how multiple heat-shocks affect the mortality trajectory in nematodes and find increases of life expectancy of close to 50% and of maximum longevity as well. We examined mortality using large numbers of animals and found that multiple heat-shocks not only decrease initial mortality, but also slow the Gompertz rate of increase in mortality. Thus, multiple heat-shocks have anti-aging hormetic effects and represent an effective approach for modulating aging.

Genetic Dissection of Late-Life Fertility in Caenorhabditis elegans

The large post-reproductive life span reported for the free-living hermaphroditic nematode, Caenorhabditis elegans, which lives for about 10 days after its 5-day period of self-reproduction, seems at odds with evolutionary theory. Species with long post-reproductive life spans such as mammals are sometimes explained by a need for parental care or transfer of information. This does not seem a suitable explanation for C elegans. Previous reports have shown that C elegans can regain fertility when mated after the self-fertile period but did not report the functional limits. Here, we report the functional life span of the C elegans germ line when mating with males. We show that C elegans can regain fertility late in life (significantly later than in previous reports) and that the end of this period corresponds quite well to its 3-week total life span. Genetic analysis reveals that late-life fertility is controlled by conserved pathways involved with aging and dietary restriction.