Dataset Information

Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration.

ABSTRACT: Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as applies to tissues that do not participate directly in training activity. The establishment of exercise protocols for short-lived genetic models will be critical for deciphering fundamental mechanisms of transtissue exercise benefits to healthy aging. Here we document optimization of a long-term swim exercise protocol for Caenorhabditis elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase of adulthood. We found that multiple daily swim sessions are essential for exercise adaptation, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters, such as mitochondrial respiration and midlife survival, increases functional healthspan of the pharynx and intestine, and enhances nervous system health by increasing learning ability and protecting against neurodegeneration in models of tauopathy, Alzheimer's disease, and Huntington's disease. Remarkably, swim training only during early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into midlife. Our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health, and establish the foundation for exploiting the powerful advantages of this genetic model for the dissection of the exercise-dependent molecular circuitry that confers system-wide health benefits to aging adults.

SUBMITTER: Laranjeiro R

PROVIDER: S-EPMC6876156 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Swim exercise in <i>Caenorhabditis elegans</i> extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration.

Laranjeiro Ricardo R Harinath Girish G Hewitt Jennifer E JE Hartman Jessica H JH Royal Mary Anne MA Meyer Joel N JN Vanapalli Siva A SA Driscoll Monica M

Proceedings of the National Academy of Sciences of the United States of America 20191104 47

Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as applies to tissues that do not participate directly in training activity. The establishment of exercise protocols for short-lived genetic models will be critical for deciphering fundamental mechanisms of transtissue exercise benefits to healthy aging. ...[more]

PMID: 31685639

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Project description:BackgroundThe longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend life span by targeting pathways with a defined role in the aging process. On the environmental side, the molecular mechanisms responsible for the positive influence of interventions such as dietary restriction are being explored. The environment experienced by humans in modern societies already contains countless compounds that may influence longevity. Understanding the role played by common compounds that substantially affect the aging process will be critical for predicting and interpreting the outcome of introducing new interventions. Caffeine is the most widely used psychoactive drug worldwide. Prior studies in flies, worms, and mice indicate that caffeine may positively impact age-associated neurodegenerative pathology, such as that observed in Alzheimer's disease.ResultsHere we report that caffeine is capable of extending life span and improving healthspan in Caenorhabditis elegans, a finding that is in agreement with a recently published screen looking for FDA-approved compounds capable of extending worm life span. Life span extension using caffeine displays epistatic interaction with two known longevity interventions: dietary restriction and reduced insulin signaling. Caffeine treatment also delays pathology in a nematode model of polyglutamine disease.ConclusionsThe identification of caffeine as a relevant factor in aging and healthspan in worms, combined with prior work in both humans and rodents linking caffeine consumption to reduced risk of age-associated disease, suggests that caffeine may target conserved longevity pathways. Further, it may be important to consider caffeine consumption when developing clinical interventions, particularly those designed to mimic dietary restriction or modulate insulin/IGF-1-like signaling. The positive impact of caffeine on a worm model of polyglutamine disease suggests that chronic caffeine consumption may generally enhance resistance to proteotoxic stress and may be relevant to assessing risk and developing treatments for human diseases like Alzheimer's and Huntington's disease. Future work addressing the relevant targets of caffeine in models of aging and healthspan will help to clarify the underlying mechanisms and potentially identify new molecular targets for disease intervention.

Project description:Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Dataset Information

Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration.

Publications

Swim exercise in <i>Caenorhabditis elegans</i> extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration.

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