fln-2 isoform-specifically regulates Caenorhabditis elegans health span by affecting pharyngeal function.

Aging is regulated by both genetic and environmental factors, and Caenorhabditis elegans is a key model due to its conserved longevity pathways. The fln-2 gene, encoding an ortholog of human filamin A (FLNa) with up to 27 isoforms, is known to modulate pharyngeal infection and lifespan in C. elegans. Still, its isoform-specific roles and mechanisms have not been fully elucidated. Here, we demonstrate that mutations specifically disrupting the longest fln-2 isoforms (fln-2a/e/s/t/r/u/v/w) extend healthspan(definition), whereas those disrupting all isoforms shorten it. The FLN-2 A/E/S/T/R/U/V/W are enriched in the pharyngeal epical region, and their loss of function results in enhanced pharyngeal grinding efficiency, reduced pharyngeal infections, decreased bacterial colonization in the intestine, and maintenance of intestinal integrity, ultimately extending lifespan. Dietary restriction has been reported to extend lifespan in multiple species, whereas the fln-2 mutations extend lifespan without reducing food intake. These findings demonstrate the molecular mechanism by which specific fln-2 isoforms modulate aging by enhancing pharyngeal function and reducing intestinal bacterial load, providing a new insight into FLNa’s role in aging.