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<p>Aging is regulated by both genetic and environmental factors, and <i>Caenorhabditis elegans</i> is a key model due to its conserved longevity pathways. The <i>fln-2</i> gene, encoding an ortholog of human filamin A (FLNa) with up to 27 isoforms, is known to modulate pharyngeal infection and lifespan in <i>C. elegans</i>. Still, its isoform-specific roles and mechanisms have not been fully elucidated. Here, we demonstrate that mutations specifically disrupting the longest <i>fln-2</i> isoforms (<i>fln-2a/e/s/t/r/u/v/w</i>) extend healthspan, whereas those disrupting all isoforms shorten it. The FLN-2&#xa0;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 <i>fln-2</i> mutations extend lifespan without reducing food intake. These findings demonstrate the molecular mechanism by which specific <i>fln-2</i> isoforms modulate aging by enhancing pharyngeal function and reducing intestinal bacterial load, providing a new insight into FLNa’s role in aging.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月11日

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  • Ya-Hong Chang,
  • Ai-Qiu Chi,
  • Yu-Chen Ren,
  • Xue-Pan Mu,
  • Bei-Bei Tao,
  • Zhiyong Shao,
  • Yi-Chun Zhu

摘要

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, 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.