Key PointsQuestion听
Is systemic oxidative stress-induced damage to RNA and DNA increased in community-dwelling individuals with psychiatric illness and associated with all-cause mortality?
Findings听
In this cohort study, oxidative stress-induced damage to RNA was increased in individuals with psychiatric illness and showed a dose-response association with mortality.
Meaning听
The findings suggest that RNA damage from oxidation may be a mechanism in the accelerated aging observed in psychiatric illness and could have utility as a marker of mortality risk in these common disorders.
Importance听
All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders.
Objective听
To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality.
Design, Setting, and Participants听
This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2鈥�-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography鈥搕andem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years.
Exposures听
History of psychiatric illness.
Main Outcomes and Measures听
Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level.
Results听
A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P鈥�<鈥�.001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P鈥�<鈥�.001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P鈥�<鈥�.001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex.
Conclusions and Relevance听
This study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.