Effects of anticonvulsant drugs on life span.
Aging is characterized by widespread degenerative changes in tissue morphology and function and an increase in the incidence of human diseases such as cancer, stroke, and Alzheimer disease. Findings from recent genetic studies suggest that molecular mechanisms that influence life span are evolutionarily conserved, and interventions that extend the life span of model organisms such as worms and flies are likely to have similar effects on vertebrates such as humans. However, little progress has been made in identifying drugs that delay aging. We identified 3 pharmacologic compounds, ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone, that extend lifespan and delay age-related degenerative changes in the nematode worm Caenorhabditis elegans. All 3 compounds are anticonvulsants that modulate neural activity in vertebrates, and ethosuximide and trimethadione are used to treat absence seizures in humans. We discuss existing evidence that these drugs might also delay vertebrate aging and suggest experiments that could test this hypothesis. Genetic and cell ablation studies conducted with model organisms have demonstrated connections between the nervous system and aging. Our studies provide additional support for the hypothesis that neural activity plays a role in lifespan determination, since ethosuximide and trimethadione regulated neuromuscular activity in nematodes. Our findings suggest that the lifespan extending activity of these compounds is related to the anticonvulsant activity, implicating neural activity in the regulation of aging. We also discuss models that explain how the nervous system influences lifespan.
Kornfeld
Kerry
K
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA. kornfeld@molecool.wustl.edu
Evason
Kimberley
K
D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D017173:Caenorhabditis elegans; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005013:Ethosuximide / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007769:Lactams / Q000494:pharmacology / Q000627:therapeutic use; D008136:Longevity / Q000187:drug effects* / Q000502:physiology; D023421:Models, Animal; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D014293:Trimethadione / Q000494:pharmacology / Q000627:therapeutic use
C113196:3,3-diethyl-2-pyrrolidinone; D000927:Anticonvulsants; D007769:Lactams; D005013:Ethosuximide; D014293:Trimethadione