A systematic review and meta-analysis of epigenetic clocks in schizophrenia.

INTRODUCTION: Evidence suggests that schizophrenia (SZ) is associated with accelerated biological aging. DNA methylation can be used as an indicator of biological aging by means of epigenetic clock estimates. OBJECTIVE: The aim of this systematic review and meta-analysis was to investigate the association between SZ and different epigenetic clocks. METHODS: Search terms were applied in different databases: Embase, MEDLINE (EBSCO), Cochrane Central Register of Controlled Trials, PubMed, PsychINFO and Web of Science. To assess for risk of bias we utilized an adapted version of the Newcastle-Ottawa Scale. Meta-analyses were conducted using the random effects model and meta-regressions were used to assess factors associated with heterogeneity. RESULTS: Eight studies were included (Controls, n = 3394; SZ subjects, n = 3096), which analyzed five different epigenetic clocks. Overall meta-analysis revealed no significant differences between SZ and controls on epigenetic aging (Standardized Mean Difference - SMD = -0.21; p = 0.13). However, epigenetic clock method was a significant moderator of heterogeneity (p = 0.004). Using Horvath's clock as reference, higher SMD's were found for PhenoAge and Intrinsic epigenetic age acceleration (IEAA) clocks. In a stratified meta-analysis restricted to the two clocks mentioned above, a significant accelerating effect was found in patients with SZ when compared to controls (SMD = 0.29; p = 0.003). CONCLUSION: Our findings suggest that the method of epigenetic clocks is a critical factor associated with estimates of aging acceleration in SZ. However, more studies are needed to confirm these findings and in order to evaluate a possible minor effect in overall analysis.

Aging and rejuvenation - a modular epigenome model.

The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm) at specific CpG sites could be used as a highly accurate biomarker of age defined by an algorithm known as the Horvath clock. It was at this point where epigenetic rejuvenation came into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. Initial evidence suggests that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. In order to explain the results, a bimodular epigenome is proposed, where module A represents the DNAm clock component and module B the remainder of the epigenome. Epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging.

Reproduction, DNA methylation and biological age.

STUDY QUESTION: Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age? SUMMARY ANSWER: Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age. WHAT IS KNOWN ALREADY: A study of 397 young Filipino women (ages 20-22) observed increasing epigenetic age with an increasing number of pregnancies. STUDY DESIGN, SIZE, DURATION: We used data from 2356 non-Hispanic white women (ages 35-74) enrolled in the Sister Study cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina's HumanMethylation450 BeadChip. We estimated association ß-values and 95% CIs using linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: ß = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: ß = 0.12, 95% CI = -0.04, 0.27, P = 0.14; Levine: ß = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (ß = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (ß = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7). LIMITATIONS, REASONS FOR CAUTION: We relied on retrospective recall to ascertain reproductive history and pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls.

Epigenetic age is an indicator of biological aging, capturing the impact of environmental and behavioral influences across time on cellular function. Deviance between epigenetic age and chronological age (AgeAccel) is a predictor of health. Pubertal timing has similarly been associated with cancer risk and mortality rate among females. We examined the association between AgeAccel and pubertal timing and adolescent breast composition in the longitudinal Growth and Obesity Cohort Study. AgeAccel was estimated in whole blood using the Horvath method at breast Tanner 2 (B2) and 4 (B4). Total breast volume, absolute fibro-glandular volume (FGV), and %FGV were evaluated at B4 using dual X-ray absorptiometry. The impact of AgeAccel (mean: 0; SD: 3.78) across puberty on the time to breast development (thelarche), menarche, and pubertal tempo (thelarche to menarche) was estimated using accelerated failure time models; generalized estimating equations were used to evaluate associations with breast density. A five-year increase in average adolescent AgeAccel was associated with a significant decrease in time to menarche [hazard ratio (HR): 1.37; 95% confidence interval (CI): 1.04, 1.80] adjusting for birth weight, maternal pre-pregnancy body mass index, maternal height, maternal education, B2 height, fat percentage, and cell composition. AgeAccel displayed a stronger inverse association with pubertal tempo (HR: 1.48; 95% CI: 1.10, 1.99). A five-year increase in AgeAccel was associated with 5% greater %FGV, adjusting for B4 percent body fat, and maternal traits (95% CI: 1.01, 1.10). Our study provides unique insight into the influence of AgeAccel on pubertal development in girls, which may have implications for adult health.