Seven Longevity Compounds Extend Worm Male Lifespan But Only Two Boost Reproductive Health

Sex differences in aging are well-documented across species, yet most longevity research—including studies using C. elegans—focuses almost exclusively on hermaphrodites. This study from Al-Saadi and Phillips (University of Oregon, 2025) is the first systematic effort to test whether compounds validated by the Caenorhabditis Intervention Testing Program (CITP) also extend lifespan and healthspan in C. elegans males, and whether the magnitude of benefit differs by sex.

Seven compounds were tested at two concentrations each on him-8 mutant males (which produce males at higher frequency than wild-type N2): all-trans retinoic acid (a Vitamin A derivative), gold sodium thiomalate (anti-rheumatic), metformin (type 2 diabetes drug), propyl gallate and resveratrol (antioxidants), sulforaphane (cruciferous vegetable-derived), and thioflavin T (amyloid-binding dye). All seven compounds significantly extended male median lifespan. Thioflavin T produced the largest median lifespan extension (76.92%), followed by sulforaphane (43.75%). Notably, lifespan extension was also achieved at half the standard hermaphrodite-effective concentration for all compounds, with gold sodium thiomalate, metformin, and thioflavin T showing similar effect sizes at the reduced dose—suggesting males are more chemically sensitive and could enable more cost-effective screening.

Comparison with published CITP hermaphrodite data revealed sex-dependent differences in compound efficacy. All-trans retinoic acid, sulforaphane, and gold sodium thiomalate produced larger median lifespan increases in hermaphrodites, while thioflavin T produced a larger increase in males. These interaction effects were statistically significant for four of the seven compounds.

Despite universal lifespan extension, reproductive healthspan—measured as mating success at days 1, 5, and 7 of adulthood—improved under only two conditions. Sulforaphane treatment increased day-7 mating success by 201%, and metformin increased day-5 mating success by 215%. The mating assay required a single male to locate, court, and inseminate fog-2 pseudo-female hermaphrodites within 24 hours, integrating chemotaxis, mechanosensation, spicule insertion, and sperm transfer into one functional output. The dissociation between lifespan and healthspan across five of seven compounds underscores that longevity extension does not automatically translate to preserved functional capacity.

The authors argue that male C. elegans offer two practical advantages for pharmacological screening: reproductive success provides a multi-tissue integrative healthspan readout, and males do not require FUdR sterilization (which confounds hermaphrodite experiments). Together, these results establish a new framework for sex-inclusive longevity compound screening and suggest that the mechanistic pathways by which compounds extend life may differ substantially between the sexes.