TY - JOUR
T1 - Oxidative Stress-Induced Damage to RNA and DNA and Mortality in Individuals with Psychiatric Illness
AU - Jorgensen, Anders
AU - Brandslund, Ivan
AU - Ellervik, Christina
AU - Henriksen, Trine
AU - Weimann, Allan
AU - Andersen, Mikkel Porsborg
AU - Torp-Pedersen, Christian
AU - Andersen, Per Kragh
AU - Jorgensen, Martin Balslev
AU - Poulsen, Henrik Enghusen
PY - 2024/5/1
Y1 - 2024/5/1
N2 - IMPORTANCE: 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: 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: 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'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem 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: History of psychiatric illness.MAIN OUTCOMES AND MEASURES: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level.RESULTS: 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 < .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 < .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 < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex.CONCLUSIONS AND RELEVANCE: 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.
AB - IMPORTANCE: 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: 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: 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'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem 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: History of psychiatric illness.MAIN OUTCOMES AND MEASURES: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level.RESULTS: 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 < .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 < .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 < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex.CONCLUSIONS AND RELEVANCE: 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.
KW - 8-Hydroxy-2'-Deoxyguanosine/urine
KW - Adult
KW - Aged
KW - Biomarkers
KW - Cohort Studies
KW - DNA Damage
KW - Denmark/epidemiology
KW - Deoxyguanosine/analogs & derivatives
KW - Female
KW - Guanosine/analogs & derivatives
KW - Humans
KW - Male
KW - Mental Disorders/epidemiology
KW - Middle Aged
KW - Mortality
KW - Oxidative Stress/physiology
KW - Prospective Studies
KW - RNA/genetics
UR - http://www.scopus.com/inward/record.url?scp=85187495902&partnerID=8YFLogxK
U2 - 10.1001/jamapsychiatry.2024.0052
DO - 10.1001/jamapsychiatry.2024.0052
M3 - Journal article
C2 - 38446448
SN - 2168-622X
VL - 81
SP - 516
EP - 520
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 5
ER -