Male-specific features of C. elegans neuronal aging

Aging is a complex biological process, with sexually dimorphic aspects. For example, men and women differ in their vulnerabilities in cognitive decline, suggesting biological sex may contribute to the heterogeneous nature of aging. Although we know a great deal about the cognitive aging of hermaphrodites of the model system C. elegans, less is known about cognitive decline in males. Through behavioral analyses, we found that the cognitive aging process has both sex-shared and sex-dimorphic characteristics. Through neuron-specific sequencing, we identified neuronal age-associated sex-differential targets. In addition to sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age. In addition, the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age, indicating possible X-chromosomal dysregulation that contributes to sexual dimorphism in cognitive aging. Finally, we found that the sex-differentially expressed gene hrg-7, which encodes an aspartic-type endopeptidase, regulates male behavior during cognitive aging but does not affect hermaphrodites behaviors. Overall, these results suggest that males and hermaphrodites exhibit different age-related neuronal changes. This study will strengthen our understanding of sex-specific vulnerability and resilience and help identify new pathways to target with novel treatments that could benefit both sexes.