DAF-2 depletion extends male worm lifespan while exposing sex-specific trade-offs

A genetic experiment in male roundworms produced an unusually large lifespan effect while revealing a less headline-friendly lesson: the outcome depended on the animals’ sex, the tissues targeted and the health measure examined.

In a paper published August 24 in *Aging*, University of Oregon researchers reported that whole-body depletion of DAF-2, the insulin/IGF-1-like receptor in *Caenorhabditis elegans*, increased male median lifespan by 446% relative to controls. Ten percent of the treated population remained alive at 106 days, compared with 15 days for controls. The same manipulation increased median lifespan by 109% in hermaphrodites.

These are laboratory-worm results, not evidence that suppressing insulin or IGF-1 signaling would safely extend human life. The study instead offers a striking demonstration that biological sex can alter the response to a well-established longevity pathway.

A controlled genetic intervention, not a supplement

The researchers used an auxin-inducible degron system: DAF-2 was genetically tagged so that exposure to the plant hormone auxin triggered its destruction. Worms were housed separately by sex, generally with 40 animals per plate in triplicate. The principal survival comparison included at least two biological replicates and 183 to 235 animals per experimental group.

Because the whole-body strain sometimes entered the dauer developmental state without auxin—evidence of unintended or “leaky” DAF-2 depletion—the researchers used a TIR1-only strain exposed to auxin as the negative control. That design choice addresses the leak but also makes the experiment more complicated than a simple treated-versus-untreated comparison.

Male crowding and pheromones can shorten worm lifespan, so the team also tested individually housed animals. Whole-body DAF-2 depletion still increased their median lifespan by about 243%, suggesting that group housing alone did not explain the result. However, the smaller effect in individually housed worms illustrates how experimental conditions can influence lifespan estimates.

Tissue and sex changed the outcome

The tissue-specific experiments were particularly informative. Depleting DAF-2 in the male intestine increased median lifespan by 69.2%. Depleting it in the male germline instead reduced median lifespan by 18.8%, the opposite direction from earlier findings in hermaphrodites. Targeting neurons or the hypodermis did not significantly alter male survival, although those tissues have affected lifespan in hermaphrodite studies.

This pattern argues against treating “reduced insulin signaling” as a single, uniform intervention. The same receptor can have different effects depending on where it is altered and whether the animal is male or hermaphroditic.

Longer life was only partly matched by healthspan

The investigators also evaluated reproductive performance as a functional healthspan measure. Male mating requires coordinated activity across neurons, muscles and reproductive structures and normally deteriorates with age.

Whole-body DAF-2 depletion sustained mating success at later ages and roughly doubled the maximum age at which males could reproduce. The researchers associated this preservation with reduced age-related immobility of the male tail. Intestine-only depletion, however, lengthened life without preserving late-life reproductive success, showing that lifespan and functional health can separate even within this model.

The study did not evaluate mammals, clinical outcomes or a practicable therapy. Its engineered receptor-degradation system also differs fundamentally from changing diet, using a supplement or administering an approved metabolic drug. The useful conclusion is narrower: sex and tissue context can materially reshape a longevity pathway, and future preclinical studies should measure function alongside survival before drawing translational conclusions.