Ageing-associated changes in transcriptional elongation influence longevity

Area of Science:

• Molecular Biology
• Genetics
• Aging Research

Background:

• Physiological homeostasis declines with age due to impaired cellular processes like transcription and RNA splicing.
• The molecular basis of age-related loss in transcriptional fidelity and prevention strategies remain unclear.

Purpose of the Study:

• To investigate genome-wide, age-related changes in transcriptional processes across multiple species.
• To identify molecular mechanisms underlying aging and lifespan extension.

Main Methods:

• Genome-wide profiling and analysis of transcriptional processes in nematodes, fruit flies, mice, rats, and humans.
• Assessing the impact of lifespan-extending interventions (dietary restriction, reduced insulin-IGF signaling) on aging-related transcriptional changes.
• Investigating the effects of modulating RNA polymerase II speed and histone components on lifespan and cellular division potential.

Main Results:

• Transcriptional elongation speed (RNA polymerase II speed) increased with age across all studied species.
• Age-related changes in splicing, including reduced unspliced transcripts and increased circular RNAs, were observed.
• Dietary restriction and reduced insulin-IGF signaling reversed most age-related transcriptional alterations.
• Genetic variants and interventions that decreased RNA polymerase II speed extended lifespan in model organisms and improved human cell division potential.

Conclusions:

• Increased RNA polymerase II speed is a fundamental mechanism contributing to animal aging.
• Slowing RNA polymerase II speed represents a viable strategy for lifespan extension and potentially preventing age-related decline.
• Findings provide molecular insights into aging and interventions, suggesting new preventive measures.