Counteracting Damage by Nutrition

This ‘survival’ response suppresses growth and enhances maintenance and defense systems (anti-oxidant defenses, stress resistance, immunological and metabolic parameters) and -interestingly- resembles the anti-aging longevity response induced by dietary restriction (DR). Strikingly, subjecting progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals: 30% DR tripled median and maximal remaining lifespan, and drastically retarded all aspects of accelerated aging investigated, but most impressively neurodegeneration. DR animals retained 50% more neurons, maintained full motoric function, and even lost tremors not only arresting neuronal decline, but even improving neurofunctioning. Repair-deficient progeroid Xpg-/- mice responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1Δ/- animals resembled DR in wt. Importantly, ad libitum Ercc1Δ/- liver showed a progressive dramatic genome-wide decline of overall transcription, preferentially of long genes. This lowered and imbalanced transcriptional output was subsequently also discovered in normal aging in numerous post-mitotic tissues in many species including humans, and appeared even present in C.elegans, demonstrating its universal occurrence and stressing the value of progeroid repair-deficient mutants for normal aging. Moreover, this phenomenon of transcription stress was shown to be the direct consequence of DNA damage blocking elongating RNA polymerase affecting genes proportional to length.

As transcription is essential for all cellular processes, DNA-damage-driven transcription stress impacts numerous cellular processes, found to change with aging, revealing how accumulation of DNA damage causes aging in most of the soma. DR largely prevented this decline of transcriptional output, indicating that DR reduces DNA damage levels and prolongs genome function and revealing how DR delays aging. These findings strengthen the link between DNA damage and aging, provide insight into the molecular mechanism underlying DR, establish Ercc1Δ/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases. Indeed, reducing calorie intake in CS and TTD children, which normally get extra nutrition as they are severely growth-retarded, induced dramatic improvements, most spectacularly in neurological performance, and most likely extends life expectancy, constituting the first therapeutic intervention for these dramatic syndromes. This stresses the clinical importance and the validity of the findings in the corresponding mouse mutants.