Age-Dependent Effects of UV Exposure and Xeroderma Pigmentosum Group A on DNA Damage, Repair Mechanisms, Genomic Instability, Cancer Risk, and Neurological Disorders

Abstract

Background: Xeroderma pigmentosum, complementation group A (XPA), is a rare genetic disorder characterized by marked sensitivity to ultraviolet (UV) radiation, leading to increased risks of skin cancer, accelerated aging, and significant neurologic disorders. XPA prominently impacts DNA repair mechanisms, specifically nucleotide excision repair (NER), which is crucial for correcting UV-induced DNA damage. Methods: This study utilized an advanced aiHumanoids platform to simulate the disease progression in individuals with XPA from birth to age 20 years. The virtual longitudinal study assessed the impacts of moderate and severe XPA under various UV exposure scenarios. The research included 25 age-matched wild-type controls to elucidate the comparative effects of XPA on DNA damage, genomic instability, cancer risk, and neurological outcomes. Results: Using Wilcoxon sign rank p values and Cliffs delta estimates of true effect size, the aiHumanoid simulations revealed significant differences in DNA repair efficiency between XPA affected and control groups, with pronounced deficits in XPA cohorts under UV exposure. Genomic instability and skin cancer risks were consistently elevated across all XPA simulations, particularly under UV stress. Neurological assessments indicated greater susceptibility to disorders in younger XPA subjects, with effects moderating somewhat with age. Conclusion: The aiHumanoid platform provided novel insights into the progression of XPA, highlighting the severe impact of UV exposure on individuals with this condition. These findings advocate for early intervention strategies and underscore the necessity for rigorous protective measures against UV radiation, especially in younger populations. This research contributes to our further understanding of XPA, potentially guiding future therapeutic developments including early stage virtual drug trials and preventive approaches personalized to individual risk profiles.