The Role of DNA Damage and Nutritional Interventions in Aging in Progeroid Mice

The global shift toward an aging population brings both opportunities and challenges. Older individuals provide valuable caregiving and experience, yet aging increases vulnerability to diseases such as cancer, neurodegeneration, and sarcopenia, creating economic and healthcare pressures. At the cellular level, aging reflects a decline in fitness driven by accumulated DNA damage, which disrupts essential protein functions. Although cells possess repair mechanisms such as base excision repair (BER), nucleotide excision repair (NER), and double-strand break repair through homologous recombination (HR) or non-homologous end joining (NHEJ), these systems are imperfect and allow damage to accumulate over time.
The causal role of DNA damage in aging is evident in conditions with rapid damage accumulation, such as during chemotherapy or in genetic disorders that impair repair capacity. Human progeroid syndromes, including Hutchinson-Gilford Progeria Syndrome, Werner Syndrome, and Cockayne Syndrome, demonstrate how defective DNA repair triggers premature aging. Researchers use DNA repair-deficient mice, such as Xpg-/- and Ercc1Δ/-, to model these processes. Both exhibit impaired NER function, short lifespans, and age-like pathologies including sarcopenia, osteoporosis, neurodegeneration, and organ dysfunction, underscoring the importance of genomic stability in longevity.
Quantifying DNA damage is crucial for understanding and mitigating aging. Traditional biomarkers like 8-hydroxy-2′-deoxyguanosine, cyclobutane pyrimidine dimers, and γ-H2AX foci are informative but limited. New transcriptomic approaches have revealed the existence of gene length-dependent transcriptional decline (GLTD), where longer genes are more likely to be affected by DNA lesions. This provides a genome-wide indicator of transcriptional stress. Combining such molecular markers with functional assays allows for accurate assessment of cellular health and the impact of anti-aging interventions.
This thesis investigates the relationship between DNA damage, metabolism, and aging through nutritional and molecular interventions. Dietary restriction (DR), which reduces food intake by 10–40% without malnutrition, is identified as the most effective strategy for extending lifespan. DR enhances DNA repair and cellular stress resilience through metabolic reprogramming, while NAD+ precursors such as nicotinamide riboside yield similar but weaker effects. Combining DR with myostatin/activin inhibition (sActRIIB) preserved muscle strength and extended longevity, showing that targeting both catabolic and anabolic pathways can optimize healthspan.
Dietary composition was further found to play a critical role in healthy aging. High-protein diets were found to elevate transcriptional stress and inflammation in both mutant and wild-type mouse models, indicating a link between excessive protein intake, genomic instability, and accelerated aging. Further analyses using ribosome profiling revealed that DR influences translation by enhancing initiation factor expression, modulating codon usage, and improving translational control.
Finally, studies on nonsense-mediated decay (NMD) in the aging brain showed that RNA surveillance remains mostly stable despite DNA damage but is sensitive to proteotoxic stress. Collectively, these findings establish DNA damage as a key driver of aging and highlight DR as the most effective intervention for preserving genomic integrity and promoting healthy longevity.