Early life stress (ELS), or exposure to adverse events during childhood, increases the risk of psychological or cognitive problems in adulthood. While pharmacological treatments are common, they may disrupt brain development, highlighting the need for safer alternatives. This study used Caenorhabditis elegans to examine whether regular physical activity would ameliorate long-term effects of ELS. Results showed that physical activity enhanced stress resistance in adults, suggesting a therapeutic potential by promoting greater resilience to stressors.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":null,"dataTable":null,"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/1fe40822c2a879c81a7ed83812c81178.jpg"},"imageCaption":"(A) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Welch's ANOVA, F(3, 72.21)=19.96, p<0.0001). Post hoc Dunnett's T3 tests showed that the ELS + SE group significantly differed from Control (p<0.0001), ELS (p<0.0001), and Control + SE (p<0.0001) groups.
(B) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference between groups was also observed, (Kruskal-Wallis test, H(3)=22.41, p<0.0001). Dunn's multiple comparisons test showed that the ELS + SE group significantly differed from Control (p=0.0153) and ELS (p=0.0005) groups, while no significant difference was observed when compared to Control + SE group (p>0.999).
","imageTitle":"Effects of physical activity on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20ºC on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20°C unless otherwise specified.
Early life-stress: Synchronized L1 larvae were maintained at 20°C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise (SE) following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20ºC.
Two distinct groups were subjected to the SE protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily SE session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + SE group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four SE sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naꞵ et al. (2021). A stopwatch was started immediately to record the time required for complete paralysis.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 ºC for 6 hours, following the protocol described by Naꞵ et al. (2021). After the heat shock, worms were returned to 20 ºC. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress experiments, several groups violated normality assumptions. To account for this, non-parametric tests were performed. For the heat stress dataset, a Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons. For the osmotic stress dataset, a Welch's ANOVA was performed, followed by Dunnett's T3.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the indiviudal is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can be lead to cognitive deficits and an increased lifetime risk of psychiatric disorders , including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Importantly, the increased sensitivity to stressors may occur due to alterations in the development of brain circuits involved in stress regulation. For example, ELS can disrupt the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system (Alkon et al., 2014; Loman & Gunnar, 2010), leading to physiological dysregulation in response to environmental stressors, which may include altered cortisol secretion (Gunnar & Quevedo, 2007), heightened or blunted autonomic reactivity (McLaughlin et al., 2015), and immune or inflammatory disturbances (Miller et al., 2011). ELS may also alter other brain regions integral to stress responses, including the prefrontal cortex, hippocampus, amygdala, and striatum (Fareri & Tottenham, 2016; McEwen & McEwen, 2017). All these alterations may often lead to maladaptive behavioral responses such as increased fearfulness, hypervigilance, emotional dysregulation, diminished social competence, and ineffective coping strategies (Cicchetti & Toth, 2016; Tottenham, 2012), ultimately increasing the risk for mental health disorders, including anxiety, depression, and substance abuse later in life (Teicher & Samson, 2016; Peña et al., 2025).
Given the long-term impact of ELS, it would be important to develop therapeutic interventions early in life to mitigate this impact. Current pharmacological strategies often involve the use of antidepressants and/or anxiolytics to deal with mental health problems observed during childhood or adolescence whether they are due to ELS or not. This approach, however, does not necessarily take into consideration the underlying causes of these mental health problems, but most importantly, it could have unforeseeable consequences in the developing brains of these individuals. Although they may relieve symptoms, antidepressants can also cause anxiety, insomnia, restlessness, nausea, abdominal pain, and dry mouth (Strawn et al., 2023). In the worst case, these medications have serious harm in children and adolescents doubling the risk of suicidal thinking and aggressive behavior when compared with adults (Sharma et al., 2016; Friedman, 2014; Schneeweiss et al., 2010).
A potential non-pharmacological intervention for the long-term effects of ELS is to engage in physical activity. Studies have suggested that it is an effective therapeutic strategy for depression and anxiety (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). Interestingly, it has been found that lack of exercise and sedentary behavior can contribute to stress, anxiety and depression (Lee and Kim, 2019) further highlighting the importance of physical activity in improving mental health. It is, therefore, necessary, to evaluate the therapeutic potential of physical activity routines in individuals at risk of developing mental health problems due to early life stress. To evaluate this therapeutic potential, we decided to use the nonparasitic nematode, Caenorhabditis elegans. This nematode is a simple and useful organism that has been used as an in vivo model to study human diseases and to evaluate potential treatment strategies for those diseases. Interestingly, there is evidence that physical activity in C. elegans improves learning abilities, and protects against neurodegeneration (Laranjeiro et al., 2017; Schmidt et al., 2021). Taken together, these traits make it a suitable model to evaluate non-pharmacologic approaches to reduce the long-term consequences of ELS.
Our main objective was to investigate whether physical activity can mitigate the long-term effects of ELS by enhancing stress resistance in C. elegans. To achieve this, ELS was induced through starvation during early larval development, and a recurrent swimming exercise (SE) protocol was implemented as a form of physical activity. To assess the independent and combined effects of ELS and SE, four experimental groups were established: a control untreated group, a control + SE group, an ELS only group, and an ELS + SE group. Once the worms reached adulthood, osmotic and heat stress resistance assays were performed for all groups.
In the osmotic stress assay, we observed a significant overall difference between groups. Specifically, our results indicated a higher resistance to osmotic stress in the ELS + SE group compared to the others. No significant differences were observed among the other group comparisons (Figure 1A). In the heat stress assay, a significant difference between groups was also observed, with higher heat stress resistance in animals that underwent physical activity, regardless of ELS exposure (Figure 1B). Taken together, these results indicate that physical activity significantly modulates stress responses, enhancing stress resistance and resilience in animals with and without ELS exposure.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of ELS. Given that ELS in humans has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021), strategies that enhance stress resilience would be of great benefit for individuals (Nishimi et al., 2021). By promoting adaptive responses to future stressors, physical activity may reduce the risk of developing anxiety, depression, and other mental health conditions. Furthermore, enhanced stress resilience can improve overall well-being by enabling individuals to cope more effectively with life challenges and maintain greater overall life satisfaction. Our findings demonstrate that swimming exercise throughout early developmental stages increases stress resistance in adult C. elegans, even on those animals not exposed to ELS, suggesting a non-specific benefit of this non-pharmacological approach. Exercise is known to modulate neuroendocrine function, enhance synaptic plasticity, and promote mental health in humans (Phillips, 2017; de Sousa Fernandes et al., 2020; Smith & Merwin, 2021), and our data extend this evidence by showing stress-buffering effects in a simple model system. Thus, early-life swimming exercise may act as a preventive intervention to improve resilience following early adversity. Future studies should identify the molecular mechanisms underlying this protective effect, as well as determine whether these benefits persist across different forms of stress and later developmental stages.
","references":[{"reference":"Alkon A, Boyce WT, Tran L, Harley KG, Neuhaus J, Eskenazi B. 2014. Prenatal Adversities and Latino Children’s Autonomic Nervous System Reactivity Trajectories from 6 Months to 5 Years of Age. PLoS ONE 9: e86283.
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","pubmedId":"","doi":"10.1002/9781119125556.devpsy311"},{"reference":"de Sousa Fernandes MS, Ordônio TF, Santos GCJ, Santos LER, Calazans CTr, Gomes DA, Santos TM. 2020. Effects of Physical Exercise on Neuroplasticity and Brain Function: A Systematic Review in Human and Animal Studies. Neural Plasticity 2020: 1-21.
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","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M. 2017. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biology 15: 10.1186/s12915-017-0368-4.
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","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson’s disease.. microPublication Biology.
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","pubmedId":"","doi":"10.1002/dev.20531"}],"title":"Physical activity enhances stress resistance in adult Caenorhabditis elegans exposed to Early Life Stress
","reviews":[{"reviewer":{"displayName":"Anne Hart"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"69345298-0334-42a8-a437-11de0d8aa8ec","decision":"revise","abstract":"Early-life exposure to adverse conditions, like starvation, can lead to long-term vulnerability to stress. In this study, we used Caenorhabditis elegans to evaluate whether swimming exercise during early-life starvation could counteract this detrimental effect. Larvae subjected to swimming while starving showed enhanced resistance to osmotic and heat stress in adulthood. These findings suggest that this type of physical activity during early life stress can promote long-term resistance to environmental challenges. Given that many cellular stress response pathways are conserved across species, this study provides an insight into how early behavioral interventions might enhance stress resilience later in life.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":null,"dataTable":null,"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/c465f9ac2c0816ba421b67242f397cd8.jpg"},"imageCaption":"(A) Timeline of experiments for starved animals. Synchronized L1 larvae were transferred to unseeded NGM plates to induce starvation. After 72 hours on starvation, a subset of animals underwent a 15-min swimming session per day for four consecutive days (Starved + Swimming group), while another subset remained on unseeded NGM plates (Starved group). One day after the final swimming session, all animals were transferred to seeded NGM plates to resume normal development at 20 °C. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(B) Timeline of experiments for control (unstarved) animals. Synchronized L1 larvae were either transferred directly to seeded NGM plates with Escherichia coli OP50 (Control group) or subjected to four 15-min swimming sessions on a single day before transfer to seeded plates. All animals were maintained at 20 °C and allowed to develop normally. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(C) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Kruskal Wallis test, H (3) = 45.23, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that Starved + Swimming animals took significantly longer to paralyze in comparison to Control (p < 0.0001****), Control + Swimming (p = 0.0006***) and Starved animals (p < 0.0001****). No significant differences were found between Control and Control + Swimming (p = 0.1117), Control and Starved (p > 0.9999) or Control + Swimming and Starved (p = 0.4175).
(D) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference was observed between groups, (Kruskal-Wallis test, H (3) = 22.41, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that a significantly higher percentage of Starved + Swimming animals survived the heat shock in comparison to Starved (p = 0.0005***) and Control animals (p = 0.0153*). A significantly higher percentage of Control + Swimming animals also survived in comparison to Control (p = 0.0472*) and Starved animals (p = 0.0041**). No significant differences were observed between Control and Starved animals (p > 0.9999) or Control + Swimming and Starved + Swimming animals (p > 0.9999).
","imageTitle":"Effects of swimming on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20 °C on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20 °C unless otherwise specified.
Starvation: Synchronized L1 larvae were maintained at 20 °C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20 °C.
Two distinct groups were subjected to the swimming protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily swimming session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + Swimming group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four swimming sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, between 100-150 worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naβ et al. (2021). A stopwatch was started immediately to record the time required for all animals to completely paralyze. We performed six independent trials, with 6-9 plates per group per trial.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 °C for 6 hours, following the protocol described by Naβ et al. (2021). After the heat shock, worms returned to 20 °C. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead. Heat stress resistance was assessed in five independent trials with 3-6 plates per group per trial. In some trials, plates with overcrowded animals were excluded from the analysis. An average of 740 animals per group was analyzed across the trials. Where feasible, experimenters were blinded to treatment during scoring of both stress resistance assays.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress resistance experiments, several groups violated normality assumptions. To account for this, the non-parametric tests Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons test.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the individual is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can lead to cognitive deficits and an increased lifetime risk of psychiatric disorders, including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Physical activity is a non-pharmacological intervention known to improve stress resilience and reduce symptoms of anxiety and depression (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). While these benefits have been documented, less is known about how physical activity influences long-term outcomes when it occurs in the context of early-life adversity. To address this, we used Caenorhabditis elegans to test whether swimming, as a form of physical activity during early-life starvation, affects stress resistance in adulthood. For the starved group, C. elegans L1 larvae were transferred to unseeded NGM plates to induce starvation. Maintaining animals under these conditions leads to developmental arrest at the L1 larval stage (Jobson et al. 2015). Three days after the onset of starvation, animals were subjected to a daily 15-minute swimming session for four consecutive days (Figure 1A). After each session, they were returned to unseeded NGM plates to maintain starvation conditions. The day after the last swimming session, animals were transferred to seeded NGM plates to resume development. Once they reached adulthood, we assessed osmotic and heat stress resistance.
For unstarved control groups, animals were maintained on seeded NGM plates throughout the experiment. A subset of those animals underwent four 15-minute sessions, administered at two-hour intervals on the first day after synchronization at the L1 stage. Once they reached adulthood, osmotic and heat stress resistance assays were performed (Figure 1B). Although we recognize that the swimming schedules of starved and unstarved control animals may elicit distinct physiological responses, we wanted to ensure that all animals were at the same developmental stage during exercise. Applying the same swimming schedule to both groups would have resulted in unstarved animals swimming across different developmental stages, introducing greater variability in physiological and behavioral responses.
Our results showed that starved animals that underwent swimming sessions exhibited significantly higher osmotic stress resistance compared to starved animals that did not swim and unstarved controls (Figure 1C). In the heat stress assay, animals that underwent swimming sessions showed increased heat stress resistance regardless of whether they had experienced starvation or not (Figure 1D). These findings suggest that swimming exercise during early life can enhance stress resistance in adulthood. Although swimming may transiently reduce feeding, resembling a form of dietary restriction, which can enhance stress resistance in C. elegans (Greer et al., 2007), our results suggest that this alone does not account for the observed effects. Unstarved animals that underwent swimming and had normal access to food showed an increase in heat stress resistance consistent with the idea that reduced feeding during exercise may partially contribute to this effect. These animals, however, did not exhibit increased resistance to osmotic stress, suggesting that reduced feeding alone may not be sufficient to induce general stress resilience. In contrast, starved animals that underwent swimming exhibited enhanced resistance to both osmotic and heat stress, while starved animals that did not swim showed a significantly lower resistance. These results indicate that swimming during early-live adversity enhances stress resistance possibly through mechanisms that cannot be explained solely by reduced feeding during exercise.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of early life adversity. In humans, ELS has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021). Strategies that enhance stress resilience, particularly non-pharmacological ones, may offer broad benefits for mental and physical health (Nishimi et al., 2021). In this study, we showed that swimming exercise during early developmental stages increases stress resistance in adult C. elegans, including animals not exposed to starvation, suggesting a general benefit of early-life physical activity. While this model does not represent the full complexity of human psychological or physiological stress, many cellular and molecular stress response pathways are conserved. Our results, therefore, provide a foundation for investigating how early behavioral interventions, such as physical activity, may promote long-term resilience to environmental challenges. Future studies should explore the mechanisms underlying these effects and examine whether similar benefits extend across different stressors and developmental stages.
","references":[{"reference":"Birnie MT, Baram TZ. 2025. The evolving neurobiology of early-life stress. Neuron 113: 1474-1490.
","pubmedId":"","doi":"10.1016/j.neuron.2025.02.016"},{"reference":"Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. 2007. An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17: 1646-1656.
","pubmedId":"","doi":"10.1016/j.cub.2007.08.047"},{"reference":"Heim C, Nemeroff CB. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49: 1023-1039.
","pubmedId":"","doi":"10.1016/s0006-3223(01)01157-x"},{"reference":"Jobson MA, Jordan JM, Sandrof MA, Hibshman JD, Lennox AL, Baugh LR. 2015. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 201: 201-212.
","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Levin RY, Liu RT. 2021. Life stress, early maltreatment, and prospective associations with depression and anxiety in preadolescent children: A six-year, multi-wave study. Journal of Affective Disorders 278: 276-279.
","pubmedId":"","doi":"10.1016/j.jad.2020.09.072"},{"reference":"Naß J, Kampf CJ, Efferth T. 2021. Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs. Molecules 26: 1827.
","pubmedId":"","doi":"10.3390/molecules26071827"},{"reference":"Nishimi KM, Koenen KC, Coull BA, Chen R, Kubzansky LD. 2021. Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study. Proceedings of the National Academy of Sciences 118: 10.1073/pnas.2102619118.
","pubmedId":"","doi":"10.1073/pnas.2102619118"},{"reference":"Peña CJ. 2025. Early-life stress sensitizes response to future stress: Evidence and mechanisms. Neurobiology of Stress 35: 100716.
","pubmedId":"","doi":"10.1016/j.ynstr.2025.100716"},{"reference":"Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al., De Volder. 2022. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. Journal of Affective Disorders 301: 145-153.
","pubmedId":"","doi":"10.1016/j.jad.2022.01.011"},{"reference":"Porta-de-la-Riva M, Fontrodona L, Villanueva A, Cerón Jn. 2012. Basic Caenorhabditis elegans Methods: Synchronization and Observation. Journal of Visualized Experiments : 10.3791/4019.
","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson’s disease.. microPublication Biology.
","pubmedId":"","doi":"10.17912/micropub.biology.000413."}],"title":"Swimming exercise during early-life starvation enhances adult stress resistance in Caenorhabditis elegans
","reviews":[{"reviewer":{"displayName":"Anne Hart"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Karen Yook (Ed)"},"openAcknowledgement":false,"submitted":null},{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1772072638678"}]},{"id":"022b75ca-97e8-4810-b040-2d80c1608cf1","decision":"accept","abstract":"Early-life exposure to adverse conditions, like starvation, can lead to long-term vulnerability to stress. In this study, we used Caenorhabditis elegans to evaluate whether swimming exercise during early-life starvation could counteract this detrimental effect. Larvae subjected to swimming while starving showed enhanced resistance to osmotic and heat stress in adulthood. These findings suggest that this type of physical activity during early life stress can promote long-term resistance to environmental challenges. Given that many cellular stress response pathways are conserved across species, this study provides an insight into how early behavioral interventions might enhance stress resilience later in life.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":null,"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/6778ce42c556ced950c8ab3c0ed15c9f.jpg"},"imageCaption":"(A) Timeline of experiments for starved animals. Synchronized L1 larvae were transferred to unseeded NGM plates to induce starvation. After 72 hours on starvation, a subset of animals underwent a 15-min swimming session per day for four consecutive days (Starved + Swimming group), while another subset remained on unseeded NGM plates (Starved group). One day after the final swimming session, all animals were transferred to seeded NGM plates to resume normal development at 20 °C. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(B) Timeline of experiments for control (unstarved) animals. Synchronized L1 larvae were either transferred directly to seeded NGM plates with Escherichia coli OP50 (Control group) or subjected to four 15-min swimming sessions on a single day before transfer to seeded plates. All animals were maintained at 20 °C and allowed to develop normally. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(C) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Kruskal Wallis test, H (3) = 45.23, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that Starved + Swimming animals took significantly longer to paralyze in comparison to Control (p < 0.0001****), Control + Swimming (p = 0.0006***) and Starved animals (p < 0.0001****). No significant differences were found between Control and Control + Swimming (p = 0.1117), Control and Starved (p > 0.9999) or Control + Swimming and Starved (p = 0.4175).
(D) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference was observed between groups, (Kruskal-Wallis test, H (3) = 22.41, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that a significantly higher percentage of Starved + Swimming animals survived the heat shock in comparison to Starved (p = 0.0005***) and Control animals (p = 0.0153*). A significantly higher percentage of Control + Swimming animals also survived in comparison to Control (p = 0.0472*) and Starved animals (p = 0.0041**). No significant differences were observed between Control and Starved animals (p > 0.9999) or Control + Swimming and Starved + Swimming animals (p > 0.9999).
","imageTitle":"Effects of swimming on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20 °C on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20 °C unless otherwise specified.
Starvation: Synchronized L1 larvae were maintained at 20 °C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20 °C.
Two distinct groups were subjected to the swimming protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily swimming session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + Swimming group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four swimming sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, between 100-150 worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naβ et al. (2021). A stopwatch was started immediately to record the time required for all animals to completely paralyze. We performed six independent trials, with 6-9 plates per group per trial.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 °C for 6 hours, following the protocol described by Naβ et al. (2021). After the heat shock, worms returned to 20 °C. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead. Heat stress resistance was assessed in five independent trials with 3-6 plates per group per trial. In some trials, plates with overcrowded animals were excluded from the analysis. An average of 740 animals per group was analyzed across the trials. Where feasible, experimenters were blinded to treatment during scoring of both stress resistance assays.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress resistance experiments, several groups violated normality assumptions. To account for this, the non-parametric tests Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons test.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early-life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the individual is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can lead to cognitive deficits and an increased lifetime risk of psychiatric disorders, including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Physical activity is a non-pharmacological intervention known to improve stress resilience and reduce symptoms of anxiety and depression (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). While these benefits have been documented, less is known about how physical activity influences long-term outcomes when it occurs in the context of early-life adversity. To address this, we used Caenorhabditis elegans as a model system in which swimming has been characterized as an exercise paradigm that shares central features of mammalian exercise, including elevated muscle metabolic activity and post-exercise fatigue, as well as altered carbohydrate and lipid metabolism (Laranjeiro et al. 2017). We, therefore, decided to test whether swimming during early-life starvation affects stress resistance in adulthood.
To induce early-life starvation, synchronized C. elegans L1 larvae were transferred to unseeded NGM plates. Maintaining animals under these conditions leads to developmental arrest at the L1 larval stage (Jobson et al. 2015), ensuring that animals remain in an early-life developmental state. Three days after the onset of starvation, animals were subjected to a daily 15-minute swimming exercise session for four consecutive days (Figure 1A). After each session, they were returned to unseeded NGM plates to maintain starvation conditions. The day after the last swimming session, animals were transferred to seeded NGM plates to resume development. Once they reached adulthood, we assessed osmotic and heat stress resistance.
Animals that were not subjected to starvation (unstarved controls) were maintained on seeded NGM plates throughout the experiment. A subset of these animals underwent four 15-minute swimming exercise sessions, administered at two-hour intervals on the first day after synchronization at the L1 stage. Once they reached adulthood, osmotic and heat stress resistance assays were performed (Figure 1B). Although we recognize that the swimming schedules of starved and unstarved control animals may elicit distinct physiological responses, we wanted to ensure that all animals were at the same developmental stage during exercise. Applying the same swimming schedule to both groups would have resulted in unstarved animals undergoing exercise across different developmental stages, introducing greater variability in physiological and behavioral responses.
Our results showed that starved animals that underwent swimming sessions exhibited significantly higher osmotic stress resistance compared to starved animals that did not swim and unstarved controls (Figure 1C). In the heat stress assay, animals that underwent swimming sessions showed increased heat stress resistance regardless of whether they had experienced starvation or not (Figure 1D). These findings suggest that swimming exercise during early life can enhance stress resistance in adulthood. Although swimming may transiently reduce feeding, resembling a form of dietary restriction, which can enhance stress resistance in C. elegans (Greer et al., 2007), our results suggest that this alone does not account for the observed effects. Unstarved animals that underwent swimming and had normal access to food showed an increase in heat stress resistance consistent with the idea that reduced feeding during exercise may partially contribute to this effect. These animals, however, did not exhibit increased resistance to osmotic stress, suggesting that reduced feeding alone may not be sufficient to induce general stress resilience. In contrast, starved animals that underwent swimming exhibited enhanced resistance to both osmotic and heat stress, while starved animals that did not swim showed a significantly lower resistance. These results indicate that swimming during early-live adversity enhances stress resistance possibly through mechanisms that cannot be explained solely by reduced feeding during exercise.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of early life adversity. In humans, ELS has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021). Strategies that enhance stress resilience, particularly non-pharmacological ones, may offer broad benefits for mental and physical health (Nishimi et al., 2021). In this study, we showed that swimming exercise during early developmental stages increases stress resistance in adult C. elegans, including animals not exposed to starvation, suggesting a general benefit of early-life physical activity. While this model does not represent the full complexity of human psychological or physiological stress, many cellular and molecular stress response pathways are conserved. Our results, therefore, provide a foundation for investigating how early behavioral interventions, such as physical activity, may promote long-term resilience to environmental challenges. Future studies should explore the mechanisms underlying these effects and examine whether similar benefits extend across different stressors and developmental stages.
","references":[{"reference":"Birnie MT, Baram TZ. 2025. The evolving neurobiology of early-life stress. Neuron 113: 1474-1490.
","pubmedId":"","doi":"10.1016/j.neuron.2025.02.016"},{"reference":"Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. 2007. An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17: 1646-1656.
","pubmedId":"","doi":"10.1016/j.cub.2007.08.047"},{"reference":"Heim C, Nemeroff CB. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49: 1023-1039.
","pubmedId":"","doi":"10.1016/s0006-3223(01)01157-x"},{"reference":"Jobson MA, Jordan JM, Sandrof MA, Hibshman JD, Lennox AL, Baugh LR. 2015. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 201: 201-212.
","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M. 2017. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol 15(1): 30.
","pubmedId":"28395669","doi":""},{"reference":"Levin RY, Liu RT. 2021. Life stress, early maltreatment, and prospective associations with depression and anxiety in preadolescent children: A six-year, multi-wave study. Journal of Affective Disorders 278: 276-279.
","pubmedId":"","doi":"10.1016/j.jad.2020.09.072"},{"reference":"Naß J, Kampf CJ, Efferth T. 2021. Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs. Molecules 26: 1827.
","pubmedId":"","doi":"10.3390/molecules26071827"},{"reference":"Nishimi KM, Koenen KC, Coull BA, Chen R, Kubzansky LD. 2021. Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study. Proceedings of the National Academy of Sciences 118: 10.1073/pnas.2102619118.
","pubmedId":"","doi":"10.1073/pnas.2102619118"},{"reference":"Peña CJ. 2025. Early-life stress sensitizes response to future stress: Evidence and mechanisms. Neurobiology of Stress 35: 100716.
","pubmedId":"","doi":"10.1016/j.ynstr.2025.100716"},{"reference":"Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al., De Volder. 2022. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. Journal of Affective Disorders 301: 145-153.
","pubmedId":"","doi":"10.1016/j.jad.2022.01.011"},{"reference":"Porta-de-la-Riva M, Fontrodona L, Villanueva A, Cerón Jn. 2012. Basic Caenorhabditis elegans Methods: Synchronization and Observation. Journal of Visualized Experiments : 10.3791/4019.
","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson's disease. MicroPubl Biol 2021: 10.17912/micropub.biology.000413.
","pubmedId":"34222835","doi":""}],"title":"Swimming exercise during early-life starvation enhances adult stress resistance in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"3ac65eef-0f28-4425-94b8-54de2ca9b624","decision":"accept","abstract":"Early-life exposure to adverse conditions, like starvation, can lead to long-term vulnerability to stress. In this study, we used Caenorhabditis elegans to evaluate whether swimming exercise during early-life starvation could counteract this detrimental effect. Larvae subjected to swimming while starving showed enhanced resistance to osmotic and heat stress in adulthood. These findings suggest that this type of physical activity during early life stress can promote long-term resistance to environmental challenges. Given that many cellular stress response pathways are conserved across species, this study provides an insight into how early behavioral interventions might enhance stress resilience later in life.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, PR"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":null,"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/e95d43d20b2d7bb64ee59f24da89e5e4.png"},"imageCaption":"(A) Timeline of experiments for starved animals. Synchronized L1 larvae were transferred to unseeded NGM plates to induce starvation. After 72 hours on starvation, a subset of animals underwent a 15-min swimming session per day for four consecutive days (Starved + Swimming group), while another subset remained on unseeded NGM plates (Starved group). One day after the final swimming session, all animals were transferred to seeded NGM plates to resume normal development at 20 °C. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(B) Timeline of experiments for control (Unstarved) animals. Synchronized L1 larvae were either transferred directly to seeded NGM plates with Escherichia coli OP50 (Control group) or subjected to four 15-min swimming sessions on a single day before transfer to seeded plates. All animals were maintained at 20 °C and allowed to develop normally. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(C) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Kruskal Wallis test, H (3) = 45.23, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that Starved + Swimming animals took significantly longer to paralyze in comparison to Control (p < 0.0001****), Control + Swimming (p = 0.0006***) and Starved animals (p < 0.0001****). No significant differences were found between Control and Control + Swimming (p = 0.1117), Control and Starved (p > 0.9999) or Control + Swimming and Starved (p = 0.4175).
(D) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference was observed between groups, (Kruskal-Wallis test, H (3) = 22.41, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that a significantly higher percentage of Starved + Swimming animals survived the heat shock in comparison to Starved (p = 0.0005***) and Control animals (p = 0.0153*). A significantly higher percentage of Control + Swimming animals also survived in comparison to Control (p = 0.0472*) and Starved animals (p = 0.0041**). No significant differences were observed between Control and Starved animals (p > 0.9999) or Control + Swimming and Starved + Swimming animals (p > 0.9999).
","imageTitle":"Effects of swimming on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20 °C on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20 °C unless otherwise specified.
Starvation: Synchronized L1 larvae were maintained at 20 °C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20 °C.
Two distinct groups were subjected to the swimming protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily swimming session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + Swimming group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four swimming sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, between 100-150 worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naβ et al. (2021). A stopwatch was started immediately to record the time required for all animals to completely paralyze. We performed six independent trials, with 6-9 plates per group per trial.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 °C for 6 hours, following the protocol described by Naβ et al. (2021). After the heat shock, worms returned to 20 °C. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead. Heat stress resistance was assessed in five independent trials with 3-6 plates per group per trial. In some trials, plates with overcrowded animals were excluded from the analysis. An average of 740 animals per group was analyzed across the trials. Where feasible, experimenters were blinded to treatment during scoring of both stress resistance assays.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress resistance experiments, several groups violated normality assumptions. To account for this, the non-parametric tests Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons test.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early-life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the individual is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can lead to cognitive deficits and an increased lifetime risk of psychiatric disorders, including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Physical activity is a non-pharmacological intervention known to improve stress resilience and reduce symptoms of anxiety and depression (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). While these benefits have been documented, less is known about how physical activity influences long-term outcomes when it occurs in the context of early-life adversity. To address this, we used Caenorhabditis elegans as a model system in which swimming has been characterized as an exercise paradigm that shares central features of mammalian exercise, including elevated muscle metabolic activity and post-exercise fatigue, as well as altered carbohydrate and lipid metabolism (Laranjeiro et al. 2017). We, therefore, decided to test whether swimming during early-life starvation affects stress resistance in adulthood.
To induce early-life starvation, synchronized C. elegans L1 larvae were transferred to unseeded NGM plates. Maintaining animals under these conditions leads to developmental arrest at the L1 larval stage (Jobson et al. 2015), ensuring that animals remain in an early-life developmental state. Three days after the onset of starvation, animals were subjected to a daily 15-minute swimming exercise session for four consecutive days (Figure 1A). After each session, they were returned to unseeded NGM plates to maintain starvation conditions. The day after the last swimming session, animals were transferred to seeded NGM plates to resume development. Once they reached adulthood, we assessed osmotic and heat stress resistance.
Animals that were not subjected to starvation (unstarved controls) were maintained on seeded NGM plates throughout the experiment. A subset of these animals underwent four 15-minute swimming exercise sessions, administered at two-hour intervals on the first day after synchronization at the L1 stage. Once they reached adulthood, osmotic and heat stress resistance assays were performed (Figure 1B). Although we recognize that the swimming schedules of starved and unstarved control animals may elicit distinct physiological responses, we wanted to ensure that all animals were at the same developmental stage during exercise. Applying the same swimming schedule to both groups would have resulted in unstarved animals undergoing exercise across different developmental stages, introducing greater variability in physiological and behavioral responses.
Our results showed that starved animals that underwent swimming sessions exhibited significantly higher osmotic stress resistance compared to starved animals that did not swim and unstarved controls (Figure 1C). In the heat stress assay, animals that underwent swimming sessions showed increased heat stress resistance regardless of whether they had experienced starvation or not (Figure 1D). These findings suggest that swimming exercise during early life can enhance stress resistance in adulthood. Although swimming may transiently reduce feeding, resembling a form of dietary restriction, which can enhance stress resistance in C. elegans (Greer et al., 2007), our results suggest that this alone does not account for the observed effects. Unstarved animals that underwent swimming and had normal access to food showed an increase in heat stress resistance consistent with the idea that reduced feeding during exercise may partially contribute to this effect. These animals, however, did not exhibit increased resistance to osmotic stress, suggesting that reduced feeding alone may not be sufficient to induce general stress resilience. In contrast, starved animals that underwent swimming exhibited enhanced resistance to both osmotic and heat stress, while starved animals that did not swim showed a significantly lower resistance. These results indicate that swimming during early-live adversity enhances stress resistance possibly through mechanisms that cannot be explained solely by reduced feeding during exercise.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of early life adversity. In humans, ELS has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021). Strategies that enhance stress resilience, particularly non-pharmacological ones, may offer broad benefits for mental and physical health (Nishimi et al., 2021). In this study, we showed that swimming exercise during early developmental stages increases stress resistance in adult C. elegans, including animals not exposed to starvation, suggesting a general benefit of early-life physical activity. While this model does not represent the full complexity of human psychological or physiological stress, many cellular and molecular stress response pathways are conserved. Our results, therefore, provide a foundation for investigating how early behavioral interventions, such as physical activity, may promote long-term resilience to environmental challenges. Future studies should explore the mechanisms underlying these effects and examine whether similar benefits extend across different stressors and developmental stages.
","references":[{"reference":"Birnie MT, Baram TZ. 2025. The evolving neurobiology of early-life stress. Neuron 113: 1474-1490.
","pubmedId":"","doi":"10.1016/j.neuron.2025.02.016"},{"reference":"Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. 2007. An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17: 1646-1656.
","pubmedId":"","doi":"10.1016/j.cub.2007.08.047"},{"reference":"Heim C, Nemeroff CB. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49: 1023-1039.
","pubmedId":"","doi":"10.1016/s0006-3223(01)01157-x"},{"reference":"Jobson MA, Jordan JM, Sandrof MA, Hibshman JD, Lennox AL, Baugh LR. 2015. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 201: 201-212.
","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M. 2017. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol 15(1): 30.
","pubmedId":"28395669","doi":""},{"reference":"Levin RY, Liu RT. 2021. Life stress, early maltreatment, and prospective associations with depression and anxiety in preadolescent children: A six-year, multi-wave study. Journal of Affective Disorders 278: 276-279.
","pubmedId":"","doi":"10.1016/j.jad.2020.09.072"},{"reference":"Naß J, Kampf CJ, Efferth T. 2021. Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs. Molecules 26: 1827.
","pubmedId":"","doi":"10.3390/molecules26071827"},{"reference":"Nishimi KM, Koenen KC, Coull BA, Chen R, Kubzansky LD. 2021. Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study. Proceedings of the National Academy of Sciences 118: 10.1073/pnas.2102619118.
","pubmedId":"","doi":"10.1073/pnas.2102619118"},{"reference":"Peña CJ. 2025. Early-life stress sensitizes response to future stress: Evidence and mechanisms. Neurobiology of Stress 35: 100716.
","pubmedId":"","doi":"10.1016/j.ynstr.2025.100716"},{"reference":"Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al., De Volder. 2022. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. Journal of Affective Disorders 301: 145-153.
","pubmedId":"","doi":"10.1016/j.jad.2022.01.011"},{"reference":"Porta-de-la-Riva M, Fontrodona L, Villanueva A, Cerón Jn. 2012. Basic Caenorhabditis elegans Methods: Synchronization and Observation. Journal of Visualized Experiments : 10.3791/4019.
","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson's disease. MicroPubl Biol 2021: 10.17912/micropub.biology.000413.
","pubmedId":"34222835","doi":""}],"title":"Swimming exercise during early-life starvation enhances adult stress resistance in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1774630520744"}]},{"id":"7f50c56c-c3f6-4413-aa08-e537fe9521ca","decision":"accept","abstract":"Early-life exposure to adverse conditions, like starvation, can lead to long-term vulnerability to stress. In this study, we used Caenorhabditis elegans to evaluate whether swimming exercise during early-life starvation could counteract this detrimental effect. Larvae subjected to swimming while starving showed enhanced resistance to osmotic and heat stress in adulthood. These findings suggest that this type of physical activity during early life stress can promote long-term resistance to environmental challenges. Given that many cellular stress response pathways are conserved across species, this study provides an insight into how early behavioral interventions might enhance stress resilience later in life.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, PR"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/24c916fb168e1b5241cbffd0ca8b10e7.png"},"imageCaption":"(A) Timeline of experiments for starved animals. Synchronized L1 larvae were transferred to unseeded NGM plates to induce starvation. After 72 hours on starvation, a subset of animals underwent a 15-min swimming session per day for four consecutive days (Starved + Swimming group), while another subset remained on unseeded NGM plates (Starved group). One day after the final swimming session, all animals were transferred to seeded NGM plates to resume normal development at 20 °C. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(B) Timeline of experiments for control (Unstarved) animals. Synchronized L1 larvae were either transferred directly to seeded NGM plates with Escherichia coli OP50 (Control group) or subjected to four 15-min swimming sessions on a single day before transfer to seeded plates. All animals were maintained at 20 °C and allowed to develop normally. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(C) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Kruskal Wallis test, H (3) = 45.23, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that Starved + Swimming animals took significantly longer to paralyze in comparison to Control (p < 0.0001****), Control + Swimming (p = 0.0006***) and Starved animals (p < 0.0001****). No significant differences were found between Control and Control + Swimming (p = 0.1117), Control and Starved (p > 0.9999) or Control + Swimming and Starved (p = 0.4175).
(D) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference was observed between groups, (Kruskal-Wallis test, H (3) = 22.41, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that a significantly higher percentage of Starved + Swimming animals survived the heat shock in comparison to Starved (p = 0.0005***) and Control animals (p = 0.0153*). A significantly higher percentage of Control + Swimming animals also survived in comparison to Control (p = 0.0472*) and Starved animals (p = 0.0041**). No significant differences were observed between Control and Starved animals (p > 0.9999) or Control + Swimming and Starved + Swimming animals (p > 0.9999).
","imageTitle":"Effects of swimming on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20 °C on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20 °C unless otherwise specified.
Starvation: Synchronized L1 larvae were maintained at 20 °C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20 °C.
Two distinct groups were subjected to the swimming protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily swimming session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + Swimming group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four swimming sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, between 100-150 worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naβ et al. (2021). A stopwatch was started immediately to record the time required for all animals to completely paralyze. We performed six independent trials, with 6-9 plates per group per trial.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 °C for 6 hours, following the protocol described by Naβ et al. (2021). After the heat shock, worms returned to 20 °C. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead. Heat stress resistance was assessed in five independent trials with 3-6 plates per group per trial. In some trials, plates with overcrowded animals were excluded from the analysis. An average of 740 animals per group was analyzed across the trials. Where feasible, experimenters were blinded to treatment during scoring of both stress resistance assays.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress resistance experiments, several groups violated normality assumptions. To account for this, the non-parametric tests Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons test.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early-life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the individual is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can lead to cognitive deficits and an increased lifetime risk of psychiatric disorders, including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Physical activity is a non-pharmacological intervention known to improve stress resilience and reduce symptoms of anxiety and depression (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). While these benefits have been documented, less is known about how physical activity influences long-term outcomes when it occurs in the context of early-life adversity. To address this, we used Caenorhabditis elegans as a model system in which swimming has been characterized as an exercise paradigm that shares central features of mammalian exercise, including elevated muscle metabolic activity and post-exercise fatigue, as well as altered carbohydrate and lipid metabolism (Laranjeiro et al. 2017). We, therefore, decided to test whether swimming during early-life starvation affects stress resistance in adulthood.
To induce early-life starvation, synchronized C. elegans L1 larvae were transferred to unseeded NGM plates. Maintaining animals under these conditions leads to developmental arrest at the L1 larval stage (Jobson et al. 2015), ensuring that animals remain in an early-life developmental state. Three days after the onset of starvation, animals were subjected to a daily 15-minute swimming exercise session for four consecutive days (Figure 1A). After each session, they were returned to unseeded NGM plates to maintain starvation conditions. The day after the last swimming session, animals were transferred to seeded NGM plates to resume development. Once they reached adulthood, we assessed osmotic and heat stress resistance.
Animals that were not subjected to starvation (unstarved controls) were maintained on seeded NGM plates throughout the experiment. A subset of these animals underwent four 15-minute swimming exercise sessions, administered at two-hour intervals on the first day after synchronization at the L1 stage. Once they reached adulthood, osmotic and heat stress resistance assays were performed (Figure 1B). Although we recognize that the swimming schedules of starved and unstarved control animals may elicit distinct physiological responses, we wanted to ensure that all animals were at the same developmental stage during exercise. Applying the same swimming schedule to both groups would have resulted in unstarved animals undergoing exercise across different developmental stages, introducing greater variability in physiological and behavioral responses.
Our results showed that starved animals that underwent swimming sessions exhibited significantly higher osmotic stress resistance compared to starved animals that did not swim and unstarved controls (Figure 1C). In the heat stress assay, animals that underwent swimming sessions showed increased heat stress resistance regardless of whether they had experienced starvation or not (Figure 1D). These findings suggest that swimming exercise during early life can enhance stress resistance in adulthood. Although swimming may transiently reduce feeding, resembling a form of dietary restriction, which can enhance stress resistance in C. elegans (Greer et al., 2007), our results suggest that this alone does not account for the observed effects. Unstarved animals that underwent swimming and had normal access to food showed an increase in heat stress resistance consistent with the idea that reduced feeding during exercise may partially contribute to this effect. These animals, however, did not exhibit increased resistance to osmotic stress, suggesting that reduced feeding alone may not be sufficient to induce general stress resilience. In contrast, starved animals that underwent swimming exhibited enhanced resistance to both osmotic and heat stress, while starved animals that did not swim showed a significantly lower resistance. These results indicate that swimming during early-live adversity enhances stress resistance possibly through mechanisms that cannot be explained solely by reduced feeding during exercise.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of early life adversity. In humans, ELS has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021). Strategies that enhance stress resilience, particularly non-pharmacological ones, may offer broad benefits for mental and physical health (Nishimi et al., 2021). In this study, we showed that swimming exercise during early developmental stages increases stress resistance in adult C. elegans, including animals not exposed to starvation, suggesting a general benefit of early-life physical activity. While this model does not represent the full complexity of human psychological or physiological stress, many cellular and molecular stress response pathways are conserved. Our results, therefore, provide a foundation for investigating how early behavioral interventions, such as physical activity, may promote long-term resilience to environmental challenges. Future studies should explore the mechanisms underlying these effects and examine whether similar benefits extend across different stressors and developmental stages.
","references":[{"reference":"Birnie MT, Baram TZ. 2025. The evolving neurobiology of early-life stress. Neuron 113: 1474-1490.
","pubmedId":"","doi":"10.1016/j.neuron.2025.02.016"},{"reference":"Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. 2007. An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17: 1646-1656.
","pubmedId":"","doi":"10.1016/j.cub.2007.08.047"},{"reference":"Heim C, Nemeroff CB. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49: 1023-1039.
","pubmedId":"","doi":"10.1016/s0006-3223(01)01157-x"},{"reference":"Jobson MA, Jordan JM, Sandrof MA, Hibshman JD, Lennox AL, Baugh LR. 2015. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 201: 201-212.
","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M. 2017. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol 15(1): 30.
","pubmedId":"28395669","doi":""},{"reference":"Levin RY, Liu RT. 2021. Life stress, early maltreatment, and prospective associations with depression and anxiety in preadolescent children: A six-year, multi-wave study. Journal of Affective Disorders 278: 276-279.
","pubmedId":"","doi":"10.1016/j.jad.2020.09.072"},{"reference":"Naß J, Kampf CJ, Efferth T. 2021. Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs. Molecules 26: 1827.
","pubmedId":"","doi":"10.3390/molecules26071827"},{"reference":"Nishimi KM, Koenen KC, Coull BA, Chen R, Kubzansky LD. 2021. Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study. Proceedings of the National Academy of Sciences 118: 10.1073/pnas.2102619118.
","pubmedId":"","doi":"10.1073/pnas.2102619118"},{"reference":"Peña CJ. 2025. Early-life stress sensitizes response to future stress: Evidence and mechanisms. Neurobiology of Stress 35: 100716.
","pubmedId":"","doi":"10.1016/j.ynstr.2025.100716"},{"reference":"Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al., De Volder. 2022. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. Journal of Affective Disorders 301: 145-153.
","pubmedId":"","doi":"10.1016/j.jad.2022.01.011"},{"reference":"Porta-de-la-Riva M, Fontrodona L, Villanueva A, Cerón Jn. 2012. Basic Caenorhabditis elegans Methods: Synchronization and Observation. Journal of Visualized Experiments : 10.3791/4019.
","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson's disease. MicroPubl Biol 2021: 10.17912/micropub.biology.000413.
","pubmedId":"34222835","doi":""}],"title":"Swimming exercise during early-life starvation enhances adult stress resistance in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"c688d4ad-7dd7-419b-b8dd-b04741f2871e","decision":"publish","abstract":"Early-life exposure to adverse conditions, like starvation, can lead to long-term vulnerability to stress. In this study, we used Caenorhabditis elegans to evaluate whether swimming exercise during early-life starvation could counteract this detrimental effect. Larvae subjected to swimming while starving showed enhanced resistance to osmotic and heat stress in adulthood. These findings suggest that this type of physical activity during early life stress can promote long-term resistance to environmental challenges. Given that many cellular stress response pathways are conserved across species, this study provides an insight into how early behavioral interventions might enhance stress resilience later in life.
","acknowledgements":"Ricardo Rodríguez-Arriaga and Keishla M. González Pérez for helping with the experiments.
Strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico"],"departments":["Department of Biomedical Sciences"],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"nzayasfeliciano@pucpr.edu","firstName":"Natacha S.","lastName":"Zayas-Feliciano","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico"],"departments":["Department of Natural Sciences"],"credit":["conceptualization","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","supervision","validation","writing_reviewEditing"],"email":"dinah_ramos@pucpr.edu","firstName":"Dinah L.","lastName":"Ramos-Ortolaza","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0003-4450-0800"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Funds provided by the Pontifical Catholic University of Puerto Rico
","image":{"url":"https://portal.micropublication.org/uploads/6f79a45674997d009e23772a27e012d5.png"},"imageCaption":"(A) Timeline of experiments for starved animals. Synchronized L1 larvae were transferred to unseeded NGM plates to induce starvation. After 72 hours on starvation, a subset of animals underwent a 15-min swimming session per day for four consecutive days (Starved + Swimming group), while another subset remained on unseeded NGM plates (Starved group). One day after the final swimming session, all animals were transferred to seeded NGM plates to resume normal development at 20 °C. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(B) Timeline of experiments for control (Unstarved) animals. Synchronized L1 larvae were either transferred directly to seeded NGM plates with Escherichia coli OP50 (Control group) or subjected to four 15-min swimming sessions on a single day before transfer to seeded plates. All animals were maintained at 20 °C and allowed to develop normally. Upon reaching adulthood, they were tested for osmotic and heat stress resistance.
(C) Time to paralysis following exposure to 500 mM NaCl was used as a measure of osmotic stress resistance. A significant overall difference was observed between groups, (Kruskal Wallis test, H (3) = 45.23, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that Starved + Swimming animals took significantly longer to paralyze in comparison to Control (p < 0.0001****), Control + Swimming (p = 0.0006***) and Starved animals (p < 0.0001****). No significant differences were found between Control and Control + Swimming (p = 0.1117), Control and Starved (p > 0.9999) or Control + Swimming and Starved (p = 0.4175).
(D) Percentage of worms that survived a 6-hour heat shock as a measure of heat stress resistance. A significant difference was observed between groups, (Kruskal-Wallis test, H (3) = 22.41, p < 0.0001). Post hoc Dunn's multiple comparisons test showed that a significantly higher percentage of Starved + Swimming animals survived the heat shock in comparison to Starved (p = 0.0005***) and Control animals (p = 0.0153*). A significantly higher percentage of Control + Swimming animals also survived in comparison to Control (p = 0.0472*) and Starved animals (p = 0.0041**). No significant differences were observed between Control and Starved animals (p > 0.9999) or Control + Swimming and Starved + Swimming animals (p > 0.9999).
","imageTitle":"Effects of swimming on stress resistance in Caenorhabditis elegans
","methods":"Strains: Caenorhabditis elegans N2 strain was obtained from the Caenorhabditis Genetics Center at the University of Minnesota. Worms were cultured at 20 °C on Nematode Growth Medium (NGM) seeded with a streptomycin resistant strain of Escherichia coli (OP50), as a food source.
Synchronization: To obtain a homogeneous population of worms, we performed a synchronization protocol based on that from Porta-de-la-Riva et al. (2012). Briefly, gravid adults were transferred to 2.0 ml tubes and washed three times with M9 buffer. They were then treated with a 4% Sodium hypochlorite solution. Obtained eggs were washed three times with M9 buffer and kept rotating overnight at room temperature for hatching. L1 larvae were then transferred to NGM plates and kept at 20 °C unless otherwise specified.
Starvation: Synchronized L1 larvae were maintained at 20 °C in unseeded NGM plates for 7 days to induce L1 arrest and starvation as an early life stressor (Jobson et al. 2015).
Physical activity: Worms underwent swimming exercise following a protocol adapted from Schmidt et al (2021). In each session, worms were transferred to 35 mm unseeded NGM plates containing 1 ml of M9 buffer and allowed to swim for 15 minutes. During this time, plates were left undisturbed on the benchtop and covered with a cardboard box to minimize external stimuli that could affect movement, and to block light exposure. After each session, worms were collected, returned to their respective NGM plates, and maintained at 20 °C.
Two distinct groups were subjected to the swimming protocol. The first group experienced early-life stress as previously described. Worms from this group, which were developmentally arrested at the L1 stage, underwent one daily swimming session for four consecutive days, starting two days after synchronization. The second group, referred to as the Control + Swimming group, was not subjected to starvation, therefore progressed through normal development. To ensure that these worms were still in the larval stage during the swimming sessions, they underwent four swimming sessions spaced two hours apart, conducted one day after synchronization.
Osmotic Stress Resistance Assay: Upon reaching adulthood, between 100-150 worms were collected and placed at the center of a 35 mm NGM plate containing 500 mM NaCl, according to the protocol described by Naβ et al. (2021). A stopwatch was started immediately to record the time required for all animals to completely paralyze. We performed six independent trials, with 6-9 plates per group per trial.
Heat Stress Resistance Assay: Upon reaching adulthood, worms were collected and subjected to heat shock by incubating at 37 °C for 6 hours, following the protocol described by Naβ et al. (2021). After the heat shock, worms returned to 20 °C. After 20 hours, survival was assessed by gently prodding the worms with a platinum wire. Worms that failed to respond were scored as dead. Heat stress resistance was assessed in five independent trials with 3-6 plates per group per trial. In some trials, plates with overcrowded animals were excluded from the analysis. An average of 740 animals per group was analyzed across the trials. Where feasible, experimenters were blinded to treatment during scoring of both stress resistance assays.
Statistical Analysis: All statistical analysis were performed using GraphPad Prism (Version 10.6.1). Data were first assessed for normality using the Shapiro-Wilk test. In both the heat and osmotic stress resistance experiments, several groups violated normality assumptions. To account for this, the non-parametric tests Kruskal-Wallis test was performed, followed by Dunn's multiple comparisons test.
","reagents":"Strain | Genotype | Available from |
C. elegans wild isolate | CGC | |
OP50-1 – Streptomycin resistant | CGC |
Early-life stress (ELS) refers to exposure during childhood to adverse physical and/or psychological stimuli to the extent that the individual is unable to adequately cope. It involves a wide range of stressful or traumatic experiences including, but not limited to, malnutrition, abuse, parental loss, and violence. Unfortunately, ELS can induce long-lasting alterations in the developing brain, which can lead to cognitive deficits and an increased lifetime risk of psychiatric disorders, including depression, anxiety and substance abuse (Birnie & Baram, 2025). Although the mechanisms underlying the long-term effects of ELS are not yet fully understood, studies suggest that sustained neurobiological changes may result in altered cognitive function, disrupted reward-processing, and increased sensitivity to stressors (Peña, 2025) further highlighting the potential impact of ELS on brain development and behavior.
Physical activity is a non-pharmacological intervention known to improve stress resilience and reduce symptoms of anxiety and depression (Philippot et al., 2022; Saeed, Cunningham and Bloch, 2019). While these benefits have been documented, less is known about how physical activity influences long-term outcomes when it occurs in the context of early-life adversity. To address this, we used Caenorhabditis elegans as a model system in which swimming has been characterized as an exercise paradigm that shares central features of mammalian exercise, including elevated muscle metabolic activity and post-exercise fatigue, as well as altered carbohydrate and lipid metabolism (Laranjeiro et al. 2017). We, therefore, decided to test whether swimming during early-life starvation affects stress resistance in adulthood.
To induce early-life starvation, synchronized C. elegans L1 larvae were transferred to unseeded NGM plates. Maintaining animals under these conditions leads to developmental arrest at the L1 larval stage (Jobson et al. 2015), ensuring that animals remain in an early-life developmental state. Three days after the onset of starvation, animals were subjected to a daily 15-minute swimming exercise session for four consecutive days (Figure 1A). After each session, they were returned to unseeded NGM plates to maintain starvation conditions. The day after the last swimming session, animals were transferred to seeded NGM plates to resume development. Once they reached adulthood, we assessed osmotic and heat stress resistance.
Animals that were not subjected to starvation (unstarved controls) were maintained on seeded NGM plates throughout the experiment. A subset of these animals underwent four 15-minute swimming exercise sessions, administered at two-hour intervals on the first day after synchronization at the L1 stage. Once they reached adulthood, osmotic and heat stress resistance assays were performed (Figure 1B). Although we recognize that the swimming schedules of starved and unstarved control animals may elicit distinct physiological responses, we wanted to ensure that all animals were at the same developmental stage during exercise. Applying the same swimming schedule to both groups would have resulted in unstarved animals undergoing exercise across different developmental stages, introducing greater variability in physiological and behavioral responses.
Our results showed that starved animals that underwent swimming sessions exhibited significantly higher osmotic stress resistance compared to starved animals that did not swim and unstarved controls (Figure 1C). In the heat stress assay, animals that underwent swimming sessions showed increased heat stress resistance regardless of whether they had experienced starvation or not (Figure 1D). These findings suggest that swimming exercise during early life can enhance stress resistance in adulthood. Although swimming may transiently reduce feeding, resembling a form of dietary restriction, which can enhance stress resistance in C. elegans (Greer et al., 2007), our results suggest that this alone does not account for the observed effects. Unstarved animals that underwent swimming and had normal access to food showed an increase in heat stress resistance consistent with the idea that reduced feeding during exercise may partially contribute to this effect. These animals, however, did not exhibit increased resistance to osmotic stress, suggesting that reduced feeding alone may not be sufficient to induce general stress resilience. In contrast, starved animals that underwent swimming exhibited enhanced resistance to both osmotic and heat stress, while starved animals that did not swim showed a significantly lower resistance. These results indicate that swimming during early-live adversity enhances stress resistance possibly through mechanisms that cannot be explained solely by reduced feeding during exercise.
Our findings highlight the potential of physical activity as a protective intervention against the long-term effects of early life adversity. In humans, ELS has been consistently associated with altered stress responsivity, increased vulnerability to psychiatric disorders, and poorer physical health across the lifespan (Heim & Nemeroff, 2001; Levin & Liu, 2021). Strategies that enhance stress resilience, particularly non-pharmacological ones, may offer broad benefits for mental and physical health (Nishimi et al., 2021). In this study, we showed that swimming exercise during early developmental stages increases stress resistance in adult C. elegans, including animals not exposed to starvation, suggesting a general benefit of early-life physical activity. While this model does not represent the full complexity of human psychological or physiological stress, many cellular and molecular stress response pathways are conserved. Our results, therefore, provide a foundation for investigating how early behavioral interventions, such as physical activity, may promote long-term resilience to environmental challenges. Future studies should explore the mechanisms underlying these effects and examine whether similar benefits extend across different stressors and developmental stages.
","references":[{"reference":"Birnie MT, Baram TZ. 2025. The evolving neurobiology of early-life stress. Neuron 113: 1474-1490.
","pubmedId":"","doi":"10.1016/j.neuron.2025.02.016"},{"reference":"Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. 2007. An AMPK-FOXO Pathway Mediates Longevity Induced by a Novel Method of Dietary Restriction in C. elegans. Current Biology 17: 1646-1656.
","pubmedId":"","doi":"10.1016/j.cub.2007.08.047"},{"reference":"Heim C, Nemeroff CB. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 49: 1023-1039.
","pubmedId":"","doi":"10.1016/s0006-3223(01)01157-x"},{"reference":"Jobson MA, Jordan JM, Sandrof MA, Hibshman JD, Lennox AL, Baugh LR. 2015. Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans. Genetics 201: 201-212.
","pubmedId":"","doi":"10.1534/genetics.115.178699"},{"reference":"Laranjeiro R, Harinath G, Burke D, Braeckman BP, Driscoll M. 2017. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol 15(1): 30.
","pubmedId":"28395669","doi":""},{"reference":"Levin RY, Liu RT. 2021. Life stress, early maltreatment, and prospective associations with depression and anxiety in preadolescent children: A six-year, multi-wave study. Journal of Affective Disorders 278: 276-279.
","pubmedId":"","doi":"10.1016/j.jad.2020.09.072"},{"reference":"Naß J, Kampf CJ, Efferth T. 2021. Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants—Implications for Depression Treatment by Medicinal Herbs. Molecules 26: 1827.
","pubmedId":"","doi":"10.3390/molecules26071827"},{"reference":"Nishimi KM, Koenen KC, Coull BA, Chen R, Kubzansky LD. 2021. Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study. Proceedings of the National Academy of Sciences 118: 10.1073/pnas.2102619118.
","pubmedId":"","doi":"10.1073/pnas.2102619118"},{"reference":"Peña CJ. 2025. Early-life stress sensitizes response to future stress: Evidence and mechanisms. Neurobiology of Stress 35: 100716.
","pubmedId":"","doi":"10.1016/j.ynstr.2025.100716"},{"reference":"Philippot A, Dubois V, Lambrechts K, Grogna D, Robert A, Jonckheer U, et al., De Volder. 2022. Impact of physical exercise on depression and anxiety in adolescent inpatients: A randomized controlled trial. Journal of Affective Disorders 301: 145-153.
","pubmedId":"","doi":"10.1016/j.jad.2022.01.011"},{"reference":"Porta-de-la-Riva M, Fontrodona L, Villanueva A, Cerón Jn. 2012. Basic Caenorhabditis elegans Methods: Synchronization and Observation. Journal of Visualized Experiments : 10.3791/4019.
","pubmedId":"","doi":"10.3791/4019"},{"reference":"Saeed SA, Cunningham K, Bloch RM. 2019. Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation. Am Fam Physician 99(10): 620-627.
","pubmedId":"31083878","doi":""},{"reference":"Schmidt MY, Chamoli M, Lithgow GJ, Andersen JK. 2021. Swimming exercise reduces native ⍺-synuclein protein species in a transgenic C. elegans model of Parkinson's disease. MicroPubl Biol 2021: 10.17912/micropub.biology.000413.
","pubmedId":"34222835","doi":""}],"title":"Swimming exercise during early-life starvation enhances adult stress resistance in Caenorhabditis elegans
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