Loss of Splicing Homeostasis as a Hallmark of Aging.
Loss of Splicing Homeostasis as a Hallmark of Aging.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Baltimore, US · Author affiliation
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.Location evidence
Exeter, GB · Author affiliation
RNA-Mediated Mechanisms of Disease Group, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.Location evidence
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Original abstract
Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.