Unlocking neuronal health: leveraging C. elegans for drug repurposing studies.

Aging affects neuronal function, leading to both structural and functional changes in the human brain. The concomitant cognitive decline and neurodegenerative diseases drive efforts to find pharmaceutical drugs to ameliorate the consequences of neuron-associated deficits during aging. C. elegans is an excellent model to combine studies of the nervous system and drug screening. C. elegans has a well-characterized and relatively simple nervous system that allows for precise mapping of neuronal circuits. Neuronal activity plays a crucial role in regulating lifespan in C. elegans. Various genetic, environmental, and pharmacological factors modulate neuronal signaling, affecting longevity by activating cell non-autonomous mechanisms in other tissues. Drug repurposing through screening approved human drugs in model organisms is an increasingly applied approach to identify off-label therapeutic effects. This review discusses research in C. elegans that applied drugs as neuromodulators with the aim to increase lifespan and healthspan. We focused on drugs with confirmed anticonvulsant, antidepressant, antipsychotic, antihypertensive, or anti-inflammatory properties. This review highlights potential mechanisms of how such drugs can exert a beneficial effect during organismal aging. Future research must intensify efforts to not only demonstrate a beneficial effect of repurposed drugs, but more importantly, to elucidate the underlying cellular responses. This will be essential for advancing selected drugs that have the potential for conserved benefit in humans.