Accelerated DNA Methylation Aging in U.S. Military Veterans: Results From the National Health and Resilience in Veterans Study.

OBJECTIVE: The aim of this study was to identify how a broad range of sociodemographic, military, health, and psychosocial factors relate to accelerated DNA methylation aging (Δage) in a large, contemporary, nationally representative sample of male U.S. veterans. METHODS: Data were analyzed from a sample of U.S. male European-American veterans who participated in the National Health and Resilience in Veterans Study (N = 1,135). RESULTS: Psychosocial factors of lifetime trauma burden, child sexual trauma, and negative beliefs about aging were independently associated with Δage. Three health variables-diabetes, hypertension, and body mass index-emerged as additional correlates of Δage. CONCLUSION: Results of the study build on prior work demonstrating associations between accelerated DNA methylation aging and traumatic stress, highlighting a role for child sexual abuse in particular. They further underscore the importance of targeting negative beliefs about aging, which are modifiable, in prevention efforts designed to forestall accelerated DNA methylation aging.

The Impact of Childhood Mental Health and Substance Use on Methylation Aging Into Adulthood.

OBJECTIVE: To test whether childhood mental health symptoms, substance use, and early adversity accelerate the rate of DNA methylation (DNAm) aging from adolescence to adulthood. METHOD: DNAm was assayed from blood samples in 381 participants in both adolescence (mean [SD] age = 13.9 [1.6] years) and adulthood (mean [SD] age = 25.9 [2.7] years). Structured diagnostic interviews were completed with participants and their parents at multiple childhood observations (1,950 total) to assess symptoms of common mental health disorders (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, anxiety, and depression) and common types of substance use (alcohol, cannabis, nicotine) and early adversities. RESULTS: Neither childhood mental health symptoms nor substance use variables were associated with DNAm aging cross-sectionally. In contrast, the following mental health symptoms and substance variables were associated with accelerated DNAm aging from adolescence to adulthood: depressive symptoms (b = 0.314, SE = 0.127, p = .014), internalizing symptoms (b = 0.108, SE = 0.049, p = .029), weekly cannabis use (b =1.665, SE = 0.591, p = .005), and years of weekly cannabis use (b = 0.718, SE = 0.283, p = .012). In models testing all individual variables simultaneously, the combined effect of the variables was equivalent to a potential difference of 3.17 to 3.76 years in DNAm aging. A final model tested a variable assessing cumulative exposure to mental health symptoms, substance use, and early adversities. This cumulative variable was strongly associated with accelerated aging (b = 0.126, SE = 0.044, p = .005). CONCLUSION: Mental health symptoms and substance use accelerated DNAm aging into adulthood in a manner consistent with a shared risk mechanism. PLAIN LANGUAGE SUMMARY: Using data from 381 participants in the Great Smoky Mountains Study, the authors examined whether childhood mental health symptoms, substance use, and early adversity accelerate biological aging, as measured by DNA methylation age, from adolescence to adulthood. Depressive symptoms and cannabis use were found to significantly accelerate biological aging. Models that tested the combined effect of mental health symptoms, substance use, and early adversity demonstrated that there was a shared effect across these types of childhood problems on accelerated aging.

Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain.

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

The associations of multiple metals mixture with accelerated DNA methylation aging.

Aging is a leading cause of mortality for the elderly and DNA methylation age is reported to be predictive of biological aging. However, few studies have investigated the associations between multiple metals exposure and accelerated aging in the elderly. We performed a pilot study of 288 elderly participants aged 50-115 years and measured genome-wide DNA methylation and 22 blood metals concentrations. Measures of DNA methylation age were estimated using CpGs from Illumina HumanMethylation EPIC BeadChip. Linear mixed regression and Bayesian kernel machine regression (BKMR) models were used to estimate the individual and overall associations between multiple metals and accelerated methylation aging. Single metal models revealed that each 1-standard deviance (SD) increase in log-transformed vanadium, cobalt, nickel, zinc, arsenic, and barium was associated with a -2.256, -1.318, 1.004, -1.926, 1.910 and -1.356 changes in ΔAge, respectively; meanwhile, for aging rate, the change was -0.019, -0.013, 0.010, -0.018, 0.023, and -0.012, respectively (all P < 0.05). The BKMR models showed reverse U-shaped associations of the overall metals mixture with ΔAge and aging rate. Downward trends of ΔAge and aging rate were observed for increasing quantiles of essential metals mixture, but upward trends were observed for non-essential metals mixture. Further individual analysis of the BKMR revealed that the 95% confidence interval of ΔAge and aging rate associated with vanadium, zinc, and arsenic did not cross 0, when other metals concentrations set at 25th, 50th, and 75th percentile. Our findings suggest reverse U-shaped associations of the overall metals mixture with accelerated methylation aging for the first time, and vanadium, zinc, and arsenic may be major contributors driving the associations.