scholarly journals SCHIZOPHRENIA EPIGENETIC AGING PATTERNS REFLECT ALTERED MORTALITY AND CANCER RISKS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S893-S893
Author(s):  
Albert T Higgins-Chen ◽  
Christiaan Vinkers ◽  
Marco P Boks ◽  
Morgan E Levine
Keyword(s):  
Accelerated Aging ◽  
Principal Component ◽  
Epidemiological Studies ◽  
Mitotic Rate ◽  
Biological Aging ◽  
Data Sets ◽  
Epigenetic Clock ◽  
Medication Effects ◽  
Age Related ◽  
Associated Proteins

Abstract Schizophrenia (SZ) is associated with large increases in all-cause mortality, high smoking rates, and elevated levels of age-associated proteins—suggesting individuals with SZ may experience accelerated rates of biological aging. Yet surprisingly, multiple previous studies found no association between SZ and biological age using Horvath’s epigenetic clock, a well-recognized and validated biomarker of aging based on DNA methylation (DNAm) levels. However, numerous epigenetic clocks have been developed to date, many of which are better indicators of differential lifespan and healthspan than the original Horvath clock. Thus, we hypothesize that these epigenetic clocks may be better proxies for the presumed accelerated aging rate in SZ. Here we investigate 14 epigenetic clocks using three publicly available DNAm datasets from whole blood, comparing SZ to non-psychiatric controls (NPC). In all data sets, we find SZ age acceleration in three clocks previously shown to be most predictive of age-related morbidity and mortality risk. In contrast, two clocks developed to capture mitotic rate are decelerated in SZ, consistent with low cancer rates despite smoking observed in epidemiological studies of SZ. We use these clocks to investigate the determinants of altered aging in SZ, such as smoking, alcohol, BMI, age-associated proteins, blood cell composition, and psychotropic medications. Principal component analysis suggests mortality clock acceleration, mitotic clock deceleration, and medication effects are independent phenomena in SZ. Our study demonstrates the importance of studying the various epigenetic clocks in tandem and highlights their potential utility for understanding how mental illness influences long-term outcomes including cancer and early mortality.

scholarly journals Epigenetic Clocks and Allostatic Load Reveal Potential Sex-Specific Drivers of Biological Aging

2019 ◽  
Author(s):  
Cathal McCrory ◽  
Giovanni Fiorito ◽  
Sinead McLoughlin ◽  
Silvia Polidoro ◽  
Cliona Ni Cheallaigh ◽  
...  
Keyword(s):  
Allostatic Load ◽  
Accelerated Aging ◽  
Community Dwelling ◽  
Biological Aging ◽  
Cross Sectional ◽  
Metabolic Dysregulation ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Dna Methylation Age

Abstract Allostatic load (AL) and epigenetic clocks both attempt to characterize the accelerated aging of biological systems, but at present it is unclear whether these measures are complementary or distinct. This study examines the cross-sectional association of AL with epigenetic age acceleration (EAA) in a subsample of 490 community-dwelling older adults participating in The Irish Longitudinal study on Aging (TILDA). A battery of 14 biomarkers representing the activity of four different physiological systems: immunological, cardiovascular, metabolic, renal, was used to construct the AL score. DNA methylation age was computed according to the algorithms described by Horvath, Hannum, and Levine allowing for estimation of whether an individual is experiencing accelerated or decelerated aging. Horvath, Hannum, and Levine EAA correlated 0.05, 0.03, and 0.21 with AL, respectively. Disaggregation by sex revealed that AL was more strongly associated with EAA in men compared with women as assessed using Horvath’s clock. Metabolic dysregulation was a strong driver of EAA in men as assessed using Horvath and Levine’s clock, while metabolic and cardiovascular dysregulation were associated with EAA in women using Levine’s clock. Results indicate that AL and the epigenetic clocks are measuring different age-related variance and implicate sex-specific drivers of biological aging.

scholarly journals Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age

2019 ◽  
Vol 16 (17) ◽  
pp. 3074 ◽  
Author(s):  
Pavanello ◽  
Campisi ◽  
Tona ◽  
Lin ◽  
Iliceto
Keyword(s):  
Myocardial Infarction ◽  
Age Estimation ◽  
Healthy Subjects ◽  
Molecular Mechanisms ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Age Related ◽  
Epigenetic Age

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined “epigenetic clock”, with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

scholarly journals Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging

2020 ◽  
Author(s):  
Line Jee Hartmann Rasmussen ◽  
Avshalom Caspi ◽  
Antony Ambler ◽  
Andrea Danese ◽  
Maxwell Elliott ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Functional Decline ◽  
Accelerated Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Blood Levels ◽  
Urokinase Plasminogen Activator Receptor ◽  
Reactive Protein ◽  
Age Related ◽  
Organ Systems

Abstract Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

scholarly journals Schizophrenia is characterized by age- and sex-specific effects on epigenetic aging

2019 ◽  
Author(s):  
Anil P.S. Ori ◽  
Loes M. Olde Loohuis ◽  
Jerry Guintivano ◽  
Eilis Hannon ◽  
Emma Dempster ◽  
...  
Keyword(s):  
Accelerated Aging ◽  
Disease Status ◽  
Risk Scores ◽  
Chronological Age ◽  
Biological Aging ◽  
Disease Trajectory ◽  
Clinical Biomarkers ◽  
Age Related ◽  
Epigenetic Aging ◽  
Increased Risk

AbstractSchizophrenia (SCZ) is a severe mental illness that is associated with an increased prevalence of age-related disability and morbidity compared to the general population. An accelerated aging process has therefore been hypothesized as a component of the SCZ disease trajectory. Here, we investigated differential aging using three DNA methylation (DNAm) clocks (i.e. Hannum, Horvath, Levine) in a multi-cohort SCZ whole blood sample consisting of 1,100 SCZ cases and 1,200 controls. It is known that all three DNAm clocks are highly predictive of chronological age and capture different features of biological aging. We found that blood-based DNAm aging is significantly altered in SCZ with age- and sexspecific effects that differ between clocks and map to distinct chronological age windows. Most notably, the predicted phenotypic age (Levine clock) in female cases, starting at age 36 and beyond, is 3.21 years older compared to matching control subjects (95% CI: 1.92-4.50, P=1.3e-06) explaining 7.7% of the variance in disease status. Female cases with high SCZ polygenic risk scores present the highest age acceleration in this age group with +7.03 years (95% CI: 3.87-10.18, P=1.7E-05). Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings suggests that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age- and sexspecific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.

scholarly journals COVID-19 severity is predicted by earlier evidence of accelerated aging

2020 ◽  
Author(s):  
Chia-Ling Kuo ◽  
Luke C. Pilling ◽  
Janice L Atkins ◽  
Jane AH Masoli ◽  
João Delgado ◽  
...  
Keyword(s):  
Clinical Chemistry ◽  
Accelerated Aging ◽  
Biological Age ◽  
Chronological Age ◽  
Biological Aging ◽  
Severe Illness ◽  
Mortality Data ◽  
Age Related ◽  
Underlying Mechanisms ◽  
The Uk

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.

scholarly journals A Computational Solution to Bolster Epigenetic Clock Reliability for Clinical Trials and Longitudinal Tracking

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 5-5
Author(s):  
Albert Higgins-Chen ◽  
Kyra Thrush ◽  
Tina Hu-Seliger ◽  
Yunzhang Wang ◽  
Sara Hagg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Reliability ◽  
Principal Component ◽  
Epigenetic Clock ◽  
Age Related ◽  
Longitudinal Tracking ◽  
Short And Long Term ◽  
Epigenetic Biomarker ◽  
Computational Solution

Abstract Epigenetic clocks are widely used aging biomarkers, but they are calculated from methylation data for individual CpGs that can be surprisingly unreliable. We report that technical noise causes six major epigenetic clocks to deviate by 3 to 9 years between replicates. We present a novel computational solution: we perform principal component analysis followed by biological age prediction using principal components, extracting shared age-related changes across CpGs while ignoring noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 1 year, and increased stability in short- and long-term longitudinal studies. This requires only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The extremely high reliability of principal component epigenetic clocks makes them particularly useful for personalized medicine and clinical trials evaluating novel aging interventions.

scholarly journals AltumAge: A Pan-Tissue DNA-Methylation Epigenetic Clock Based on Deep Learning

2021 ◽  
Author(s):  
Lucas Paulo de Lima ◽  
Louis R Lapierre ◽  
Ritambhara Singh
Keyword(s):  
Dna Methylation ◽  
Deep Learning ◽  
Placental Tissue ◽  
Training Data ◽  
Data Sets ◽  
Epigenetic Clock ◽  
Neural Network Approach ◽  
Cpg Sites ◽  
Age Related ◽  
Model Predictions

Several age predictors based on DNA methylation, dubbed epigenetic clocks, have been created in recent years. Their accuracy and potential for generalization vary widely based on the training data. Here, we gathered 143 publicly available data sets from several human tissues to develop AltumAge, a highly accurate and precise age predictor based on deep learning. Compared to Horvath's 2013 model, AltumAge performs better across both normal and malignant tissues and is more generalizable to new data sets. Interestingly, it can predict gestational week from placental tissue with low error. Lastly, we used deep learning interpretation methods to learn which methylation sites contributed to the final model predictions. We observed that while most important CpG sites are linearly related to age, some highly-interacting CpG sites can influence the relevance of such relationships. We studied the associated genes of these CpG sites and found literary evidence of their involvement in age-related gene regulation. Using chromatin annotations, we observed that the CpG sites with the highest contribution to the model predictions were related to heterochromatin and gene regulatory regions in the genome. We also found age-related KEGG pathways for genes containing these CpG sites. In general, neural networks are better predictors due to their ability to capture complex feature interactions compared to the typically used regularized linear regression. Altogether, our neural network approach provides significant improvement and flexibility to current epigenetic clocks without sacrificing model interpretability.

scholarly journals Associations Between a New Biomarker of Elevated Chronic Inflammation and Accelerated Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 141-142
Author(s):  
Line Rasmussen ◽  
Avshalom Caspi ◽  
Terrie Moffitt
Keyword(s):  
Chronic Inflammation ◽  
Functional Capacity ◽  
Functional Decline ◽  
Accelerated Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Blood Levels ◽  
Urokinase Plasminogen Activator Receptor ◽  
Age Related ◽  
Organ Systems

Abstract To further understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. We used data from the population-representative longitudinal Dunedin Study (N=875). Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, and C-reactive protein. suPAR levels increased from 2.39 ng/mL (SD 0.89) at age 38 to 3.01 (SD 1.03) at age 45 years. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems (β 0.28, 95% CI 0.21–0.35), older facial appearance (β 0.16, 95% CI 0.10–0.22), and with structural signs of older brain age (β 0.06, 95% CI -0.00–0.13). Moreover, participants with higher suPAR levels had lower functional capacity (more physical limitations [β 0.24, 95% CI 0.18–0.30]; slower gait speed [β -0.14, 95% CI -0.20; -0.08]) and greater decline in cognitive function (β -0.07, 95% CI -0.13; -0.01) from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between age 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

scholarly journals BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for BMI

2021 ◽  
Author(s):  
Sara Lundgren ◽  
Sara Kuitunen ◽  
Kirsi H. Pietiläinen ◽  
Mikko Hurme ◽  
Mika Kähönen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Meta Analysis ◽  
Accelerated Aging ◽  
Positive Association ◽  
Shared Environment ◽  
Epigenetic Clock ◽  
450K Array ◽  
Cross Sectional ◽  
Age Related ◽  
Epigenetic Age

ABSTRACTBackgroundObesity is a heritable complex phenotype which can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various “epigenetic clocks.” Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely relates with mortality.ObjectivesWe aimed to assess the cross-sectional association of BMI with age acceleration in twins to limit confounding by genetics and shared environment.Methods and ResultsParticipants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twins, and DNAm was measured using the Illumina 450k array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10−12) per 1-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI > 3 kg/m2) had an epigenetic age 5.2 months older than their lighter co-twin (p-value = 0.0074). We also found a positive association between log(HOMA-IR) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 0.0025) from adjusted models.ConclusionWe identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.

scholarly journals Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop

2020 ◽  
Vol 5 (1) ◽  
pp. 143 ◽  
Author(s):  
Dana Gabuzda ◽  
Beth D. Jamieson ◽  
Ronald G. Collman ◽  
Michael M. Lederman ◽  
Tricia H. Burdo ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Science Research ◽  
Review Article ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Research Gaps ◽  
Markers Of Inflammation ◽  
Age Related ◽  
Research Working Group ◽  
Key Questions

People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH.

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