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Multiple Stressors in Caenorhabditis elegans Induce Stress Hormesis and Extended Longevity

^a Institute for Behavioral Genetics, University of Colorado, Boulder

Thomas E. Johnson, Institute for Behavioral Genetics, 1480 30th Street, Boulder, CO 80303 E-mail: johnsont{at}colorado.edu.

Decision Editor: John A. Faulkner, PhD

	Abstract

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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.

HORMESIS is the induction of beneficial effects by exposure to low doses of chemical or physical agents that are harmful at higher doses. Hormesis has been observed in response to a broad variety of harmful physical agents and environmental stressors ^(1)(2)(3). Beneficial effects may manifest as increased resistance to a subsequent lethal dose of the same stressor ⁽⁴⁾⁽⁵⁾ or a different stressor ^(6)(7)(8). However, diverse environmental stressors are thought to share a common mechanism of oxidative damage to macromolecules ^(9)(10)(11). Beneficial effects on normal life expectancy have been reported in yeast ⁽¹²⁾, house flies ⁽¹³⁾, Drosophila ⁽⁵⁾, nematodes ^(4)(14)(15), and mice ⁽¹⁶⁾.

The nematode worm Caenorhabditis elegans lends itself well to studies of aging because of its short life span, large brood size, and ability to self-fertilize without concomitant inbreeding depression ^(17)(18), which permits the production of large numbers of genetically identical individuals. These traits have enabled the discovery of over 40 single-gene mutations in the worm that extend life span between 10% and 400% ⁽¹⁹⁾. Strikingly, most or all of these mutants also display greater resistance to one or more forms of environmental stress ^{(20)(21)(22)(23)(24)(25)}. This positive correlation between stress resistance and life span prompted us to investigate C. elegans as a model system for the study of life extension by means of hormesis.

We have tested several stressors to determine whether they can induce resistance to subsequent stress and life extension. Furthermore, we asked whether two different oxidative stressors induce cross-tolerance. Selye ^(26)(27) observed that diverse disease states displayed a set of common symptoms, and he defined the study of the physiological effects of stress and stress resistance. Selye observed that exposure to one stressor frequently resulted in subsequent resistance not merely to the same stressor but also to multiple stressors, and he proposed the existence of a general adaptive response ⁽²⁶⁾ mediating resistance to many stressors. Cross-tolerance between two different oxidative stressors is consistent with such a general adaptive response.

	Methods

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Maintenance of Strains
All animals were either wild type (N2) or TJ1060 [fer-15(b26);spe-9(hc88)], a temperature-sensitive sterile strain that facilitates the handling of large numbers of animals throughout the reproductive period without confounding parents and progeny ⁽²⁸⁾. Strains were maintained as frozen stocks as described ⁽¹⁷⁾, until needed. All assessments of stress resistance and survival were performed on solid nematode growth medium (NGM) with a spot of Escherichia coli OP50 for food ⁽²⁹⁾. Age-synchronized groups of animals were produced by placing reproductive adults onto a fresh NGM plate for 8 hours or less and permitting the eggs laid to develop into adults 3 days later when maintained at 20°C. All animals were raised at 20°C and were pretreated at 3.5 to 4.5 days of age as young adults.

Pretreatments and Challenges
We exposed animals to 35°C for 2 hours followed by 12 hours recovery at 20°C before the 35°C challenge. Wild-type animals were used to test thermotolerance and TJ1060 was used to monitor life span.

Oxygen pretreatment consisted of exposure to 100% O₂ (Airgas, Radnor, PA) at 40 psi for 8 hours, using a steel pressure vessel, at 20°C. The steel pressure vessel was flushed with pure oxygen for 60 seconds at the beginning of each exposure to ensure a concentration of 100% O₂. After pretreatment, worms were permitted to recover for 12–16 hours at 20°C under normal atmospheric oxygen, and then they were exposed to the appropriate challenge. Oxygen challenges were 100% O₂ at 40 psi for 20–24 hours at 20°C, using the same source of oxygen and pressure vessel.

Juglone pretreatment was at a concentration of 236 µM juglone for 10–20 minutes. Plates were prepared by dissolving 21 mg of juglone (Sigma, St. Louis, MO) in 10 ml of 100% EtOH and immediately mixing this with 500 ml of liquefied NGM at 54°C and pouring the mixture into plastic petri plates. After 30 minutes, each plate was spotted with 40 µl of 10⁹/ml OP50. The plates were dried in a fume hood for 1 hour and used between 2 and 3 hours after the mixture was poured. For pretreatment, animals were transferred to a juglone plate for 10–20 minutes, washed off the plate with S Basal ⁽²⁹⁾ collected by centrifugation, washed again in S Basal, recentrifuged, and then transferred to a plain, prespotted NGM plate for 24 hours of recovery at 20°C. The juglone challenges were performed similarly (at 472 µM) and worms were scored dead or alive every 30–60 minutes after transfer.

For ultraviolet (UV) pretreatment, worms were irradiated with germicidal UV light (254 nm), which generates DNA lesions—that is, cyclobutane dimers and (6-4) photoproducts. The animals were irradiated in a Stratalinker 2400 (Stratagene, La Jolla, CA) on fresh NGM plates without food, and then they were transferred to fresh NGM plates with food for recovery. After 24–48 hours of recovery, both control and experimental animals were transferred to fresh NGM plates without food and exposed to 500 J/m² or 2000 J/m² of UV irradiation as challenge; their subsequent survival was followed, as described ⁽²³⁾.

For gamma irradiation we chose conditions ⁽¹⁴⁾ previously shown to be hormetic. Wild-type animals were irradiated with 10,000 rad at the rate of 200 rad/min from a ¹³⁷Cs gamma source, and subsequent survival was followed as described in the paragraphs that follow.

Longevity Assessments
All animals were maintained at 20°C and transferred to fresh plates daily until the cessation of egg-laying to avoid confounding of generations. (TJ1060 animals produce a smaller, but not negligible, number of offspring than wild type raised at 20°C, effectively reducing the number of days requiring transfer of animals.)

Statistical Analysis
Comparisons between survival curves were made by the log-rank test ⁽³⁰⁾, in which lost animals were treated as censored data. Comparisons of means were made by independent, two-tailed t tests of the means. All errors presented are standard errors of the mean. All statistical calculations were made by using the Statsoft Statistica 99 software package (Statsoft, Tulsa, OK).

	Results

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Heat-Induced Thermotolerance and Life Extension
We found that 2 hours at 35°C induced subsequent thermotolerance maximally, and these results have been confirmed in numerous studies (Fig. 1). Pretreatment for 1 hour at 35°C produced a more muted response. Pretreatments for 3 hours resulted in a mixed pattern of thermotolerance, in which pretreated animals were initially less thermotolerant than naive controls but subsequently displayed increased thermotolerance. Pretreatment for 4 hours caused an overall reduction in thermotolerance compared with that of naive controls throughout all or almost all of the challenge. Animals pretreated for longer times displayed prompt mortality when challenged with 35°C. The dose dependency of induced thermotolerance was very similar to that of the life extension previously observed in response to various periods at 35°C ⁽¹⁵⁾. Pretreatments of 1 or 2 hours of 35°C were beneficial (caused hormesis); 3 hours produced no benefit; a moderate detriment was observed in response to 4 hours, and longer pretreatments severely reduced subsequent survival (Fig. 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. A, Effect of varying length of heat pretreatment on subsequent thermotolerance; + or - indicate presence or absence of pretreatment. Thermotolerance of controls and pretreated groups were as follows. Pretreatment of 1 hour: experiment 1—control 9.0 ± 0.2 hours (n = 27), pretreated 9.7 ± 0.3 hours (n = 33), p not significant; experiment 2—control 9.9 ± 0.3 hours (n = 20), pretreated 11.7 ± 0.4 hours (n = 22), p < .001. Pretreatment of 2 hours: experiment 1—control 9.0 ± 0.2 hours (n = 27), pretreated 11.1 ± 0.4 hours (n = 29), p < .01; experiment 2—control 9.9 ± 0.3 hours (n = 20), pretreated 12.7 ± 0.5 hours (n = 19), p < .05. Pretreatment of 3 hours: experiment 1—control 9.0 ± 0.2 hours (n = 27), pretreated 9.1 ± 0.4 hours (n = 28), p not significant; experiment 2—control 9.9 ± 0.3 hours (n = 20), pretreated 10.3 ± 0.6 hours (n = 23), p not significant. Pretreatment of 4 hours: experiment 1—control 9.0 ± 0.2 hours (n = 27), pretreated 7.1 ± 0.4 hours (n = 28), p < .001; experiment 2—control, 9.9 ± 0.3 hours (n = 20), pretreated 8.8 ± 0.4 hours (n = 20), p < .06. B, Effect of varying length of heat pretreatment on life span and thermotolerance. All results are normalized by dividing by control survival run at the same time. Relative survival and thermotolerance of pretreated groups were as follows: 1 hour—1.16 ± 0.02 (n = 476), 1.08 ± 0.03 (n = 55, p not significant); 2 hours—1.13 ± 0.02 (n = 495), 1.23 ± 0.04, (n = 48, p < .03); 3 hours—0.96 ± 0.03 (n = 283), 1.01 ± 0.04 (n = 51, p not significant); 4 hours—0.91 ± 0.02 (n = 484), 0.79 ± 0.04, (n = 48, p not significant); 8 hours—0.32 ± 0.005 (n = 584), 0.56 ± 0.00 (n = 33, p < .00001).

View larger version (21K): [in this window] [in a new window]   Figure 2. Pretreatment with juglone increases subsequent juglone resistance. A, Controls survived 1.7 ± 0.1 hours (n = 36) compared with 2.1 ± 0.2 hours for pretreated (n = 19; p < .03). B, Controls survived 0.8 ± 0.05 hours (n = 59) compared with 1.4 ± 0.1 hours for pretreated (n = 99; p < .00001).

View larger version (26K): [in this window] [in a new window]   Figure 3. A, Pretreatment with hyperbaric oxygen increases subsequent resistance to hyperbaric oxygen; + or - indicate control or pretreated, respectively. Surviving fractions were as follows. Experiment 1—controls 0.11 (n = 9), pretreated 0.87 (n = 8); experiment 2—controls 0.28 (n = 37), pretreated 0.50 (n = 27); experiment 3—controls 0.32 (n = 40), pretreated 0.72 (n = 21); for three experiments combined—controls 0.28 (n = 86); pretreated 0.62 (n = 56, p < .00001 by independent t test of means). B, C, Pretreatment with hyperbaric oxygen increases life expectancy. B, Controls (n = 30) had a life expectancy of 15.2 ± 0.8 days compared with 18.5 ± 1.3 days for the pretreated (n = 33, p < .01). C, controls (n = 23) had life expectancy of 13.4 ± 0.5 days compared with 16.5 ± 0.6 days for pretreated (n = 38, p < .02).

View larger version (30K): [in this window] [in a new window]   Figure 4. A, Pretreatment with low doses of ultraviolet (UV) radiation does not increase resistance to subsequent UV irradiation of 500 J/m2 (n = 14–24; no comparisons significant). B, Pretreatment with moderate doses of UV radiation does not increase resistance to subsequent UV irradiation of 2000 J/m2 (n = 8–10; no comparisons significant except control [mean survival, 3.8 ± 0.3 days] compared with pretreatment with 500 J/m2 [mean survival, 2.2 ± 0.4 days, p < .01]). C, Effect of 137Cs gamma irradiation on life expectancy of C. elegans (control, n = 18; pretreated group 1, n = 24; pretreated group 2, n = 23; no comparisons significant).

Cross-Induction of Juglone and Oxygen Resistance
Pretreatment with either juglone or oxygen also resulted in subsequent resistance to the other stressor, suggesting an underlying unity of response. In these experiments, pretreatment with juglone increased subsequent oxygen resistance by 79%, 25%, and 146% (Fig. 5). Conversely, pretreatment with hyperbaric oxygen increased subsequent resistance to juglone. In three experiments, pretreatment with hyperbaric oxygen increased juglone survival by 27%, 47%, and 4%, respectively (Fig. 5).

View larger version (25K): [in this window] [in a new window]   Figure 5. Cross-tolerance between juglone and hyperbaric oxygen. A, Pretreatment with hyperbaric oxygen increases subsequent juglone resistance. Experiment 1—controls survived 2.8 ± 0.1 hours (n = 41) compared with 5.0 ± 0.3 hours for pretreated (n = 20, p < .00001); experiment 2—controls survived 0.8 ± 0.1 hours (n = 59) compared with 1.0 ± 0.05 hours for pretreated (n = 157, p < .03); experiment 3—controls survived 1.3 ± 0.1 hours (n = 99) compared with 3.2 ± 0.1 hours for pretreated (n = 87, p < .00001). B, Pretreatment with juglone increases subsequent resistance to hyperbaric oxygen. Control and pretreated surviving fractions are as follows: experiment 1—controls 0.07 (n = 56), pretreated 0.34 (n = 58); experiment 2—controls 0.39 (n = 61), pretreated 0.86 (n = 73); experiment 3—controls 0.55 (n = 58), pretreated 0.59 (n = 100); for three experiments combined—controls 0.34 (n = 175), pretreated 0.61 (n = 231, p < .00001 by independent t test of means).

	Discussion

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Juglone induced a cross-tolerance to subsequent O₂ challenge of 27% while the reciprocal pairing produced an 81% benefit in juglone resistance, the largest effect observed. The large variation in juglone sensitivity observed between experiments may be caused by the rapid decay of juglone efficacy after the juglone plates are poured. We have observed that plates used more than 3 hours after pouring have virtually no toxicity, whereas those used 1 hour after pouring can kill all animals within 2 hours. Thus it is not surprising to see wide differences in toxicity between experiments.

Numerous examples of cross-tolerance have been reported in other organisms. Some cases include exotic stressors such as hypergravity ⁽⁷⁾, cadmium and fin wounding ⁽⁸⁾, and ischemia ⁽³⁶⁾, whereas others represent tolerance induced by oxygen ⁽⁶⁾. Such cross-tolerance is consistent with the proposals of Selye ^(26)(27) who postulated that any systemic stress provokes physiological responses that are general and not specific to the physical nature of the stressor. These responses were further theorized to promote adaptation of the individual to subsequent environmental challenges, and they were collectively called the general adaptive syndrome. Selye emphasized the generality of the response to diverse stressors. We propose that in C. elegans many stressors induce a physiological response leading to subsequent resistance to several stressors. Specifically, we propose that the observed cross-tolerance between oxygen and juglone supports the work of Yanase and colleagues ⁽⁶⁾ and is consistent with an elevated resistance to all forms of oxidative stress. Other stressor combinations (heat and oxygen, and heat and juglone) also produce cross-tolerance (Cypser and Johnson, manuscript in preparation). The effect of O₂ on life extension is also consistent with the suggestion of Harman ⁽³⁷⁾ that oxidative stress is the major proximal cause of aging. This effect of O₂ on survival was not manifested until 5–10 days after pretreatment. These observations are consistent with the observed effect of sublethal heat pretreatment early in life ⁽¹⁵⁾. Furthermore, we have found that age-specific mortality of a large population of C. elegans is reduced throughout a majority of the life span following heat treatment in early adulthood (Cypser and Johnson, unpublished results). It seems that brief, early exposure to moderate stress can permanently remodel a component of the aging process and manifest itself in differential survival once the mortality of both groups is significantly different from zero. One possible mechanism for such a remodeling is chromatin remodeling, perhaps accomplished by histone modification.

However, not all forms of stress induce subsequent stress resistance. We found no hormetic response to UV or gamma irradiation. Although Johnson and Hartman ⁽¹⁴⁾ reported life extension in response to this dose of ¹³⁷Cs gamma irradiation, we were not able to replicate their observations. This may be because of differences in the conditions of gamma radiation treatment used. The doses (including 10 krad) used by Johnson and Hartman were administered at a rate of 2.7 krad/min, whereas we used a gamma radiation source that delivered only 0.2 krad/min. There are numerous UV-sensitive mutants of C. elegans ⁽³⁸⁾. However, it may be that C. elegans, as a native soil organism, lacks a UV response element that would serve to increase UV stress resistance because worms are not regularly exposed to UV in their natural habitat. Alternatively, the lack of response to UV may derive from the frequency used (254 nm), which represents the UVC portion of the electromagnetic spectrum; sunlight contains a greater fraction of longer wavelength UVB and UVA radiation. It also seems clear that the molecular responses to ultraviolet light are at least partly distinct from the responses to oxidative stress ^(39)(40). Other types of stressors, including heavy metals, herbicides ⁽⁴¹⁾, fungicides ^(42)(43), and microwave radiation ⁽⁴⁴⁾, have been reported to induce a stress response in C. elegans. Hormesis likely depends upon changes in the regulation of genes critical for stress resistance such as those of the JNK ⁽⁴⁵⁾ and dauer formation ⁽⁴⁶⁾ pathways, as well as heat shock proteins (⁽⁶⁾; for a review, see ⁽⁴⁷⁾,⁽⁴⁸⁾). A subset of the genes so regulated seems likely to play a causal role in hormetic life extension. The identification of those genes may lead to novel interventions that directly extend life span.

	Acknowledgments

 
This work was supported by grants from the National Institutes of Health (PO1 AG08761, RO1-AG12423, RO1-AG16219, and KO2-AA00195) and by gifts from the Ellison Medical Foundation.

Received August 15, 2001

Accepted November 8, 2001

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