Actin Cytoskeleton Integrity Directly Drives Healthy Aging Across Species
Disrupting actin or its regulators accelerates aging in worms; mild stabilization extends lifespan—and human ACTB variants link to gait decline.
Summary
Researchers systematically tested how disrupting or stabilizing the actin cytoskeleton affects aging in C. elegans using genetic knockdowns and chemical probes. Knocking down actin or key actin-binding proteins—Arp2/3, cofilin, and tropomyosin—caused premature actin disorganization, shortened lifespan, impaired motility, mitochondrial dysfunction, loss of proteostasis, lipid dysregulation, and gut barrier failure. Transcriptomic analysis showed these perturbations produce an 'aged' gene expression signature even in young animals. Mild actin stabilization with jasplakinolide modestly extended lifespan, while destabilization with latrunculin A mirrored genetic knockdowns. Human genome-wide association data further revealed that common ACTB polymorphisms correlate with age-related gait speed decline, suggesting the actin-aging axis is evolutionarily conserved.
Detailed Summary
The actin cytoskeleton is one of the most ancient and conserved cellular structures in eukaryotic biology, yet its direct causal role in organismal aging has remained poorly defined. This study from the Higuchi-Sanabria lab and collaborators provides the most comprehensive interrogation to date of how actin form and function shape the aging process, using C. elegans as a primary model and extending findings to human genetic data.
The team used RNAi to knock down actin itself (act-1, targeting all five C. elegans isoforms) and three key actin-binding proteins: arx-2 (Arp2/3 complex, which nucleates branched actin networks), unc-60 (cofilin, which severs filaments), and lev-11 (tropomyosin, which stabilizes filaments). Using LifeAct::mRuby transgenic animals, they visualized actin structure in muscle, intestine, and hypodermis across the lifespan. All four knockdowns caused premature actin disorganization in at least one tissue, with tissue-specific patterns: unc-60 knockdown caused early intestinal disorganization at day 1 of adulthood, while arx-2 and lev-11 showed stronger late-life phenotypes. All conditions significantly shortened lifespan, reduced brood size, and impaired locomotor performance at older ages.
Bulk RNA-seq of day-1 adults under these knockdowns revealed that arx-2 and unc-60 knockdowns produced the largest transcriptional changes, including a gene expression signature strongly resembling aged animals. Single-nucleus RNA-sequencing provided tissue-resolved transcriptomic data, revealing cell-type-specific responses to actin dysfunction. Beyond transcriptomics, actin perturbations broadly exacerbated canonical hallmarks of aging: mitochondrial respiration declined (Seahorse assays), lipid homeostasis was dysregulated, proteostasis was compromised, autophagic flux was impaired, and intestinal barrier integrity failed.
Pharmacological approaches complemented the genetic findings. Latrunculin A (LatA), which depolymerizes actin and sequesters monomers, phenocopied genetic knockdowns—accelerating aging phenotypes. Jasplakinolide (Jasp), which promotes filament polymerization and stability, modestly but significantly extended lifespan, underscoring that the direction of perturbation matters and that optimally tuned actin dynamics are essential for longevity.
Critically, the study extended its findings to humans. Genome-wide association analysis of ACTB (cytoplasmic beta-actin) polymorphisms in large human cohorts revealed that common variants correlate with differences in age-related gait speed decline—a well-validated biomarker of biological aging and mortality risk. This cross-species convergence suggests the actin-aging relationship is not a worm-specific phenomenon but reflects a deeply conserved biological principle. The authors frame this work explicitly as a descriptive resource—a publicly accessible, multi-omic, multi-tissue dataset—intended to catalyze future mechanistic studies linking specific actin regulatory nodes to discrete aging pathways.
Key Findings
- RNAi knockdown of actin or actin-binding proteins (Arp2/3, cofilin, tropomyosin) significantly shortens C. elegans lifespan.
- Actin dysfunction in young animals produces a transcriptomic signature indistinguishable from normal aged animals.
- Mild actin stabilization with jasplakinolide modestly extends lifespan; destabilization with latrunculin A accelerates aging.
- Actin perturbations worsen mitochondrial dysfunction, lipid dysregulation, proteostasis failure, impaired autophagy, and gut barrier breakdown.
- Human ACTB polymorphisms associate with age-related gait speed decline, suggesting evolutionary conservation of actin's role in healthy aging.
Methodology
The study used whole-animal and tissue-specific RNAi in C. elegans combined with LifeAct::mRuby imaging, bulk RNA-seq, single-nucleus RNA-seq, Seahorse metabolic assays, and pharmacological probes (latrunculin A, jasplakinolide) to assess lifespan and aging hallmarks. Human GWAS data were analyzed for associations between ACTB variants and gait speed decline as a proxy for biological aging.
Study Limitations
This is a preprint and has not yet undergone formal peer review. The primary model organism is C. elegans, which lacks many mammalian tissue complexities, and translation to vertebrate aging requires validation. Jasplakinolide's modest lifespan extension was observed at specific doses; the therapeutic window between beneficial stabilization and toxicity is likely narrow.
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