Temporary suppression of the gene regulator NuA4 during early development extended lifespan in worms

Temporary suppression of the gene regulator NuA4 during early development extended lifespan in worms

In a paper published on 16 July, researchers temporarily reduced the activity of the NuA4 complex in the nematode C. elegans. As adults, the animals lived longer, developed paralysis less often in amyloid and α-synuclein models, and accumulated fewer toxic protein aggregates.

In the study, the outcome depended on the age at which the intervention occurred. The researchers used a chemically controlled method to remove MYS-1, a component of NuA4, from embryos and first-stage larvae. By the second larval stage, MYS-1 levels had largely recovered. This brief suppression protected adult worms from amyloid toxicity. When MYS-1 was suppressed later, paralysis became more severe and lifespan decreased. The age at intervention determined the outcome.

NuA4 modifies histones, the proteins around which DNA is packaged, and thereby affects gene activity. Temporary NuA4 suppression in embryos reduced the activity of some genes associated with the endoplasmic reticulum, the membrane network where proteins acquire their functional form. The authors propose that this disruption caused endoplasmic reticulum stress. At the next developmental stage, XBP-1 became active. This protein switches on genes that expand the endoplasmic reticulum and help process improperly folded proteins.

Through the regulatory proteins SBP-1 and MDT-15, XBP-1 increased the activity of FAT-7, an enzyme involved in oleic acid synthesis. Oleic acid accumulated during development, became incorporated into membranes and lipid droplets, and was released from these stores in adulthood. Blocking XBP-1 or FAT-7 eliminated the protection against protein aggregates. Suppressing the lipases that release fats substantially weakened this protection. Oleic acid supplementation reproduced part of the protective effect, but only when the worms received it from the first larval stage. Starting supplementation at the L4 stage did not change the outcome.

Early NuA4 suppression also slowed development and reduced fertility in the worms. TIP60, the human counterpart of MYS-1, contributes to development, DNA repair, and cell division. Separate experiments are needed to determine the age, intensity, and duration at which targeting TIP60 could be safe in humans.