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The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesized to represent a measure of biological aging with a positive/negative residual signifying age acceleration (AA)/deceleration, respectively. The present study examines the associations of 4 epigenetic clocks—Horvath, Hannum, PhenoAge, GrimAge—with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA). HorvathAA and HannumAA were not predictive of health; PhenoAgeAA was associated with 4/9 outcomes (walking speed, frailty MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8/9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of walking speed, .polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine. [ABSTRACT FROM AUTHOR]

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker., Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach., Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers., Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results., Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol., Competing Interests: FM, DM, KT, EB, PH, KB, AP, DB, IC, RM, GD, TR, RR No competing interests declared, AL declares that UC Regents filed the patent "DNA METHYLATION BASED BIOMARKERS FOR LIFE EXPECTANCY AND MORBIDITY" (International Application Number PCT/US2019/055444; in pending status) and that the Epigenetic Clock Development Foundation and Foxo Labs hold licenses, CR declares that UC Regents filed the patent "DNA METHYLATION BASED BIOMARKERS FOR LIFE EXPECTANCY AND MORBIDITY" (International Application Number PCT/US2019/055444; in pending status) and that the Epigenetic Clock Development Foundation and Foxo Labs hold licenses. SH receives consulting fees from the Epigenetic Clock Development Foundation and royalties for patents involving epigenetic clocks, SH has received a speaker fee from Illumina and is an advisor to the Epigenetic Clock Development Foundation, RM is employed part time by Novo Nordisk outside of this work, (© 2022, Morales Berstein et al.)

Objective: To detect abnormal corneal thinning in keratoconus using pachymetry maps measured by high-speed anterior segment optical coherence tomography (OCT)., Design: Cross-sectional observational study., Participants: Thirty-seven keratoconic eyes from 21 subjects and 36 eyes from 18 normal subjects., Methods: The OCT system operated at a 1.3 microm wavelength with a scan rate of 2000 axial scans per second. A pachymetry scan pattern (8 radials, 128 axial scans each; 10 mm diameter) centered at the corneal vertex was used to map the corneal thickness. The pachymetry map was divided into zones by octants and annular rings. Five pachymetric parameters were calculated from the region inside the 5 mm diameter: minimum, minimum-median, inferior-superior (I-S), inferotemporal-superonasal (IT-SN), and the vertical location of the thinnest cornea. The 1-percentile value of the normal group was used to define the diagnostic cutoff. Placido-ring-based corneal topography was obtained for comparison., Main Outcome Measures: The OCT pachymetric parameters and a quantitative topographic keratoconus index (keratometry, I-S, astigmatism, and skew percentage [KISA%]) were used for keratoconus diagnosis. Diagnostic performance was assessed by the area under the receiver operating characteristic (AROC) curve., Results: Keratoconic corneas were thinner. The pachymetric minimum averaged 452.6+/-60.9 microm in keratoconic eyes versus 546+/-23.7 microm in normal eyes. The 1-percentile cutoff was 491.6 microm. The thinnest location was inferiorly displaced in keratoconus (-805+/-749 microm vs -118+/-260 microm; cutoff, -716 microm). The thinning was focal (minimum-median: -95.2+/-41.1 microm vs -45+/-7.7 microm; cutoff, -62.6 microm). Keratoconic maps were more asymmetric (I-S, -44.8+/-28.7 microm vs -9.9+/-9.3 microm; cutoff, -31.3 microm; and IT-SN, -63+/-35.7 microm vs -22+/-11.4 microm; cutoff, -48.2 microm). Keratoconic eyes had a higher KISA% index (2641+/-5024 vs 21+/-19). All differences were statistically significant (t test, P<0.0001). Applying the diagnostic criteria of any 1 OCT pachymetric parameter below the keratoconus cutoff yielded an AROC of 0.99, which was marginally better (P = .09) than the KISA% topographic index (AROC, 0.91)., Conclusions: Optical coherence tomography pachymetry maps accurately detected the characteristic abnormal corneal thinning in keratoconic eyes. This method was at least as sensitive and specific as the topographic KISA., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

This prospective longitudinal study examines patterns of psychiatric symptomatology among men admitted to treatment for cocaine dependence in 1988-1989. Study participants were interviewed at treatment intake, and at 1 year, 2 years and 12 years after treatment. The Hopkins Symptom Checklist-58 (SCL) and Natural History Interview were administered at the 4 time points. Of the 266 study participants interviewed at the 12-year follow-up, 138 (52%) had been cocaine abstinent for 5 years or more. Repeated measures ANOVA assessed changes in SCL scores over time for cocaine-abstinent and non-abstinent men. Both groups had similarly high mean SCL scores at treatment intake, and reductions in symptom severity 1 year after treatment. By 12-year follow-up, the abstinent group reported significantly lower SCL scores than the non-abstinent group on 4 of the 5 symptom measures. Additionally, cocaine-abstinent men reported lower rates of depressive and psychotic disorders, and lower use of psychopharmacologic and inpatient treatment than non-abstinent men. These findings suggest that severe psychiatric symptomatology persists among individuals unable to achieve a stable recovery from cocaine dependence.