Altering RNA helicases in roundworms doubles their lifespan; a related approach could inform human cell research
Most of the lifestyle choices people make—quitting smoking, changing diet, exercising—produce modest effects on longevity. Yet the biology of aging progresses regardless: growth and repair mechanisms that serve us well in youth decline with age. A research team at the Institute for Basic Science (IBS) Center for Plant Aging Research in Korea has identified a molecular regulator that dramatically slows aging in a model organism, offering new insight into pathways that could be relevant to human cells.
The researchers focused on the tiny nematode Caenorhabditis elegans, a well-established model for aging studies because many cellular processes are conserved between worms and humans. They examined the family of RNA helicases—enzymes that control RNA structure, processing and regulation—to determine whether specific helicases influence organismal lifespan. While RNA helicases are commonly thought to play general “housekeeping” roles in RNA metabolism, the team discovered that individual helicases can have distinct, specific effects on longevity.
To systematically assess function, the group tested all 78 RNA helicase genes in C. elegans. Altering more than 30 of those genes shortened lifespan, indicating that many helicases perform essential roles for normal survival. However, one helicase stood out: HEL-1. Inhibiting or modulating HEL-1 activity in certain genetic contexts produced a robust increase in lifespan.
Key to the work was a widely studied longevity model in C. elegans: mutants with reduced activity of the daf-2 gene, which encodes an insulin/insulin-like growth factor 1 (IGF-1) receptor. Reduced insulin/IGF-1 signaling (IIS) via daf-2 produces worms that are more resistant to stress and live roughly twice as long as wild-type worms. The IBS team found that HEL-1 acts specifically within this longevity pathway.
Mechanistically, HEL-1 appears to act as a transcriptional coregulator that enhances activity of the DAF-16/FOXO transcription factor, a master regulator of stress resistance and longevity downstream of IIS. The researchers showed that HEL-1 is required for the lifespan extension driven by reduced IIS and that increasing HEL-1 activity is sufficient to extend lifespan. Expression of HEL-1 in the intestine and in neurons contributes to these effects, and HEL-1 promotes the induction of a substantial subset of DAF-16 target genes.
These findings refine our understanding of how RNA homeostasis and specific RNA helicases influence aging. Rather than serving only broad, nonspecific roles, some helicases like HEL-1 have targeted functions in defined longevity pathways. Because both HEL-1 and the insulin/IGF-1 signaling axis are evolutionarily conserved, the authors suggest a similar RNA helicase–dependent modulation of FOXO signaling might exist in mammals.
Beyond lifespan extension in worms, the work has potential implications for human health. The mammalian ortholog of HEL-1 is DDX39, which has been observed at elevated levels in brain tissue from patients with Alzheimer’s disease. While it is far too early to translate worm lifespan manipulation into human therapies, understanding how DDX39 and related helicases regulate FOXO signaling and stress-response programs could open new avenues for treating neurodegenerative disease or modulating cellular aging in human cells.
The research does not claim to cure disease or confer human immortality. Instead, it provides a clearer molecular picture of how RNA helicases can shape longevity pathways and highlights a specific helicase—HEL-1—as a regulator of DAF-16/FOXO–dependent transcription and lifespan in C. elegans. As work progresses, these mechanistic insights may guide experiments in mammalian systems and inform strategies for preserving cellular function during aging.
Source: Institute for Basic Science (IBS)
Image credit: Public domain image
Abstract
RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans
RNA homeostasis plays an underexplored role in aging. RNA helicases regulate RNA biogenesis and stability, but their functional contributions to aging have been unclear. This study reports that many RNA helicases influence C. elegans lifespan and that the DEAD-box helicase HEL-1 specifically promotes longevity by activating the DAF-16/FOXO transcription factor pathway. HEL-1 is necessary for the increased lifespan seen with reduced insulin/IGF-1 signaling and is sufficient to extend lifespan when modulated. Expression of HEL-1 in the intestine and neurons contributes to longevity, and HEL-1 amplifies the induction of numerous DAF-16 target genes. Given evolutionary conservation of HEL-1 and insulin/IGF-1 signaling, a comparable mechanism linking RNA helicase activity to FOXO signaling and aging may operate in mammals, including humans.
Reference: Seo M., Seo K., Hwang W., Koo H.J., Hahm J.-H., Yang J.-S., Han S.K., Hwang D., Kim S., Jang S.K., Lee Y., Nam H.G., Lee S.-J.V. “RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans.” Proceedings of the National Academy of Sciences, 2015. doi:10.1073/pnas.1505451112