The splicing axis of aging: mechanisms and therapeutic opportunities.
Abstract
Aging is characterized by progressive loss of molecular fidelity that compromises stem-cell function and tissue homeostasis. Aging transcriptomes show widespread disruption of RNA processing, including increased intron retention, cryptic splice-site usage, and altered RNA quality control. These changes arise from somatic mutations as well as accumulated transcriptional, metabolic, and proteostatic stress. Importantly, similar splicing abnormalities are observed in age-associated diseases such as clonal hematopoiesis and neurodegeneration, overlapping with physiological aging states. Here, we synthesize mechanistic, stem-cell, and longevity studies to define declining RNA-processing fidelity as a unifying contributor to aging across systems. We propose the 'splicing axis of aging' as a framework linking RNA-processing dysfunction to tissue decline and outline emerging therapeutic strategies to restore spliceosome integrity and RNA homeostasis.
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Research summary
The paper proposes that declining RNA-processing fidelity, specifically splicing errors, is a unifying mechanistic driver of aging and tissue decline. This is relevant because it identifies a specific molecular mechanism (the "splicing axis") as a potential root cause of aging rather than just a symptom, offering a framework for therapeutic intervention to restore homeostasis.
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