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Article: Stochastic Epigenetic Mutations: Reliable Detection and Associations with Cardiovascular Aging.

Markov, Yaroslav / Levine, Morgan / Higgins-Chen, Albert T

bioRxiv : the preprint server for biology

2023

Abstract: Stochastic Epigenetic Mutations (SEMs) have been proposed as novel aging biomarkers that have the potential to capture heterogeneity in age-related DNA methylation (DNAme) changes. SEMs are defined as outlier methylation patterns at cytosine-guanine ... ...

Abstract	Stochastic Epigenetic Mutations (SEMs) have been proposed as novel aging biomarkers that have the potential to capture heterogeneity in age-related DNA methylation (DNAme) changes. SEMs are defined as outlier methylation patterns at cytosine-guanine dinucleotide (CpG) sites, categorized as hypermethylated (hyperSEM) or hypomethylated (hypoSEM) relative to a reference. While individual SEMs are rarely consistent across subjects, the SEM load - the total number of SEMs - increases with age. However, given poor technical reliability of measurement for many DNA methylation sites, we posited that many outliers might represent technical noise. Our study of whole blood samples from 36 individuals, each measured twice, found that 23.3% of hypoSEM and 45.6% hyperSEM are not shared between replicates. This diminishes the reliability of SEM loads, where intraclass correlation coefficients are 0.96 for hypoSEM and 0.90 for hyperSEM. We linked SEM reliability to multiple factors, including blood cell type composition, probe beta-value statistics, and presence of SNPs. A machine learning approach, leveraging these factors, filtered unreliable SEMs, enhancing reliability in a separate dataset of technical replicates from 128 individuals. Analysis of the Framingham Heart Study confirmed previously reported SEM association with mortality and revealed novel connections to cardiovascular disease. We discover that associations with aging outcomes are primarily driven by hypoSEMs at baseline methylated probes and hyperSEMs at baseline unmethylated probes, which are the same subsets that demonstrate highest technical reliability. These aging associations are preserved after filtering out unreliable SEMs and are enhanced after adjusting for blood cell composition. Finally, we utilize these insights to formulate best practices for SEM detection and introduce a novel R package,
Language	English
Publishing date	2023-12-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.12.571149
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Article: Age-Invariant Genes: Multi-Tissue Identification and Characterization of Murine Reference Genes.

González, John T / Thrush, Kyra / Meer, Margarita / Levine, Morgan E / Higgins-Chen, Albert T

bioRxiv : the preprint server for biology

2024

Abstract: Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes ( ...

Abstract	Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes (often called housekeeping genes) in expression studies. Reference genes have mostly been identified and validated in young organisms, and no systematic investigation has been done across the lifespan. Here, we build upon a common pipeline for identifying reference genes in RNA-seq datasets to identify age-invariant genes across seventeen C57BL/6 mouse tissues (brain, lung, bone marrow, muscle, white blood cells, heart, small intestine, kidney, liver, pancreas, skin, brown, gonadal, marrow, and subcutaneous adipose tissue) spanning 1 to 21+ months of age. We identify 9 pan-tissue age-invariant genes and many tissue-specific age-invariant genes. These genes are stable across the lifespan and are validated in independent bulk RNA-seq datasets and RT-qPCR. We find age-invariant genes have shorter transcripts on average and are enriched for CpG islands. Interestingly, pathway enrichment analysis for age-invariant genes identifies an overrepresentation of molecular functions associated with some, but not all, hallmarks of aging. Thus, though hallmarks of aging typically involve changes in cell maintenance mechanisms, select genes associated with these hallmarks resist fluctuations in expression with age. Finally, our analysis concludes no classical reference gene is appropriate for aging studies in all tissues. Instead, we provide tissue-specific and pan-tissue genes for assays utilizing reference gene normalization (i.e., RT-qPCR) that can be applied to animals across the lifespan.
Language	English
Publishing date	2024-04-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.09.588721
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Article ; Online: The Cutting Edge of Epigenetic Clocks: In Search of Mechanisms Linking Aging and Mental Health.

Harvanek, Zachary M / Boks, Marco P / Vinkers, Christiaan H / Higgins-Chen, Albert T

Biological psychiatry

2023 Volume 94, Issue 9, Page(s) 694–705

Abstract: Individuals with psychiatric disorders are at increased risk of age-related diseases and early mortality. Recent studies demonstrate that this link between mental health and aging is reflected in epigenetic clocks, aging biomarkers based on DNA ... ...

Abstract	Individuals with psychiatric disorders are at increased risk of age-related diseases and early mortality. Recent studies demonstrate that this link between mental health and aging is reflected in epigenetic clocks, aging biomarkers based on DNA methylation. The reported relationships between epigenetic clocks and mental health are mostly correlational, and the mechanisms are poorly understood. Here, we review recent progress concerning the molecular and cellular processes underlying epigenetic clocks as well as novel technologies enabling further studies of the causes and consequences of epigenetic aging. We then review the current literature on how epigenetic clocks relate to specific aspects of mental health, such as stress, medications, substance use, health behaviors, and symptom clusters. We propose an integrated framework where mental health and epigenetic aging are each broken down into multiple distinct processes, which are then linked to each other, using stress and schizophrenia as examples. This framework incorporates the heterogeneity and complexity of both mental health conditions and aging, may help reconcile conflicting results, and provides a basis for further hypothesis-driven research in humans and model systems to investigate potentially causal mechanisms linking aging and mental health.
MeSH term(s)	Humans ; Mental Health ; Epigenesis, Genetic ; Aging/genetics ; DNA Methylation ; Schizophrenia/genetics ; Epigenomics
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2023.02.001
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Article ; Online: Aging biomarkers and the brain.

Higgins-Chen, Albert T / Thrush, Kyra L / Levine, Morgan E

Seminars in cell & developmental biology

2021 Volume 116, Page(s) 180–193

Abstract: Quantifying biological aging is critical for understanding why aging is the primary driver of morbidity and mortality and for assessing novel therapies to counter pathological aging. In the past decade, many biomarkers relevant to brain aging have been ... ...

Abstract	Quantifying biological aging is critical for understanding why aging is the primary driver of morbidity and mortality and for assessing novel therapies to counter pathological aging. In the past decade, many biomarkers relevant to brain aging have been developed using various data types and modeling techniques. Aging involves numerous interconnected processes, and thus many complementary biomarkers are needed, each capturing a different slice of aging biology. Here we present a hierarchical framework highlighting how these biomarkers are related to each other and the underlying biological processes. We review those measures most studied in the context of brain aging: epigenetic clocks, proteomic clocks, and neuroimaging age predictors. Many studies have linked these biomarkers to cognition, mental health, brain structure, and pathology during aging. We also delve into the challenges and complexities in interpreting these biomarkers and suggest areas for further innovation. Ultimately, a robust mechanistic understanding of these biomarkers will be needed to effectively intervene in the aging process to prevent and treat age-related disease.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/physiology ; Biomarkers/metabolism ; Brain/physiopathology ; Humans
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2021.01.003
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Article ; Online: Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research.

Diniz, Breno S / Seitz-Holland, Johanna / Sehgal, Raghav / Kasamoto, Jessica / Higgins-Chen, Albert T / Lenze, Eric

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry

2023 Volume 32, Issue 1, Page(s) 1–16

Abstract: The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the ... ...

Abstract	The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the biological aging processes is still in its infancy. In this review, we aim to provide a critical appraisal of the emerging literature focusing on how we measure biological aging systematically, and in the brain and how SMIs affect biological aging measures in older adults. We will also review recent developments in the field of cellular senescence and potential targets for interventions for SMIs in older adults, based on the geroscience hypothesis.
MeSH term(s)	Humans ; Aged ; Geroscience ; Mental Health ; Geriatric Psychiatry ; Aging/physiology ; Biology
Language	English
Publishing date	2023-09-23
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1278145-9
ISSN	1545-7214 ; 1064-7481
ISSN (online)	1545-7214
ISSN	1064-7481
DOI	10.1016/j.jagp.2023.09.014
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Zs.A 4443: Show issues

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Article ; Online: Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer's disease.

Thrush, Kyra L / Bennett, David A / Gaiteri, Christopher / Horvath, Steve / Dyck, Christopher H van / Higgins-Chen, Albert T / Levine, Morgan E

Aging

2022 Volume 14, Issue 14, Page(s) 5641–5668

Abstract: Alzheimer's disease (AD) risk increases exponentially with age and is associated with multiple molecular hallmarks of aging, one of which is epigenetic alterations. Epigenetic age predictors based on 5' cytosine methylation (DNAm), or epigenetic clocks, ... ...

Abstract	Alzheimer's disease (AD) risk increases exponentially with age and is associated with multiple molecular hallmarks of aging, one of which is epigenetic alterations. Epigenetic age predictors based on 5' cytosine methylation (DNAm), or epigenetic clocks, have previously suggested that epigenetic age acceleration may occur in AD brain tissue. Epigenetic clocks are promising tools for the quantification of biological aging, yet we hypothesize that investigation of brain aging in AD will be assisted by the development of brain-specific epigenetic clocks. Therefore, we generated a novel age predictor termed PCBrainAge that was trained solely in cortical samples. This predictor utilizes a combination of principal components analysis and regularized regression, which reduces technical noise and greatly improves test-retest reliability. To characterize the scope of PCBrainAge's utility, we generated DNAm data from multiple brain regions in a sample from the Religious Orders Study and Rush Memory and Aging Project. PCBrainAge captures meaningful heterogeneity of aging: Its acceleration demonstrates stronger associations with clinical AD dementia, pathologic AD, and APOE ε4 carrier status compared to extant epigenetic age predictors. It further does so across multiple cortical and subcortical regions. Overall, PCBrainAge's increased reliability and specificity makes it a particularly promising tool for investigating heterogeneity in brain aging, as well as epigenetic alterations underlying AD risk and resilience.
MeSH term(s)	Aging/genetics ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Brain/pathology ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Reproducibility of Results
Language	English
Publishing date	2022-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.204196
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Article ; Online: Schizophrenia and Epigenetic Aging Biomarkers: Increased Mortality, Reduced Cancer Risk, and Unique Clozapine Effects.

Higgins-Chen, Albert T / Boks, Marco P / Vinkers, Christiaan H / Kahn, René S / Levine, Morgan E

Biological psychiatry

2020 Volume 88, Issue 3, Page(s) 224–235

Abstract: Background: Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath's epigenetic clock, a well-established ... ...

Abstract	Background: Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath's epigenetic clock, a well-established aging biomarker based on DNA methylation. However, numerous epigenetic clocks that may capture distinct aspects of aging have been developed. This study tested the hypothesis that altered aging in SZ manifests in these other clocks. Methods: We performed a comprehensive analysis of 14 epigenetic clocks categorized according to what they were trained to predict: chronological age, mortality, mitotic divisions, or telomere length. To understand the etiology of biological age differences, we also examined DNA methylation predictors of smoking, alcohol, body mass index, serum proteins, and cell proportions. We independently analyzed 3 publicly available multiethnic DNA methylation data sets from whole blood, a total of 567 SZ cases and 594 nonpsychiatric controls. Results: All data sets showed accelerations in SZ for the 3 mortality clocks up to 5 years, driven by smoking and elevated levels of 6 age-associated proteins. The 2 mitotic clocks were decelerated in SZ related to antitumor natural killer and CD8T cells, which may help explain conflicting reports about low cancer rates in epidemiological studies of SZ. One cohort with available medication data showed that clozapine is associated with male-specific decelerations up to 7 years in multiple chronological age clocks. Conclusions: Our study demonstrates the utility of studying the various epigenetic clocks in tandem and highlights potential mechanisms by which mental illness influences long-term outcomes, including cancer and early mortality.
MeSH term(s)	Aging ; Biomarkers ; Clozapine ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Male ; Neoplasms/genetics ; Schizophrenia/genetics
Chemical Substances	Biomarkers ; Clozapine (J60AR2IKIC)
Language	English
Publishing date	2020-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2020.01.025
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Article: Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems.

Sehgal, Raghav / Meer, Margarita / Shadyab, Aladdin H / Casanova, Ramon / Manson, JoAnn E / Bhatti, Parveen / Crimmins, Eileen M / Assimes, Themistocles L / Whitsel, Eric A / Higgins-Chen, Albert T / Levine, Morgan

bioRxiv : the preprint server for biology

2023

Abstract: Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person ... ...

Abstract	Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person heterogeneity. Our aim was to develop novel systems-based methylation clocks that, when assessed in blood, capture aging in distinct physiological systems. We combined supervised and unsupervised machine learning methods to link DNA methylation, system-specific clinical chemistry and functional measures, and mortality risk. This yielded a panel of 11 system-specific scores- Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone, and Metabolic. Each system score predicted a wide variety of outcomes, aging phenotypes, and conditions specific to the respective system, and often did so more strongly than existing epigenetic clocks that report single global measures. We also combined the system scores into a composite Systems Age clock that is predictive of aging across physiological systems in an unbiased manner. Finally, we showed that the system scores clustered individuals into unique aging subtypes that had different patterns of age-related disease and decline. Overall, our biological systems based epigenetic framework captures aging in multiple physiological systems using a single blood draw and assay and may inform the development of more personalized clinical approaches for improving age-related quality of life.
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.13.548904
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Article ; Online: A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration.

Oblak, Lara / van der Zaag, Jeroen / Higgins-Chen, Albert T / Levine, Morgan E / Boks, Marco P

Ageing research reviews

2021 Volume 69, Page(s) 101348

Abstract: Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the ... ...

Abstract	Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. Numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. The aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. We conducted a systematic review of all available literature and included 156 publications across 4 resource databases. We compiled a list of all presently existing blood-based epigenetic clocks. Subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. Statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (Hannum, Horvath, Levine and GrimAge). We found that the Horvath, Hannum, Levine and GrimAge epigenetic clocks tend to agree in direction of effects, but vary in size. Body mass index, HIV infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. Acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. Our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.
MeSH term(s)	Acceleration ; Aging/genetics ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics ; HIV Infections ; Humans ; Male
Language	English
Publishing date	2021-04-28
Publishing country	England
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2021.101348
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Zs.A 5579: Show issues

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Article ; Online: More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome.

Minteer, Christopher J / Thrush, Kyra / Gonzalez, John / Niimi, Peter / Rozenblit, Mariya / Rozowsky, Joel / Liu, Jason / Frank, Mor / McCabe, Thomas / Higgins-Chen, Albert T / Hofstatter, Erin / Pusztai, Lajos / Beckman, Kenneth / Gerstein, Mark / Levine, Morgan E

Science advances

2023 Volume 9, Issue 29, Page(s) eadf4163

Abstract: Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, ... ...

Abstract	Aging is a leading risk factor for cancer. While it is proposed that age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. We show that aging and cancer share a common epigenetic replication signature, which we modeled using DNA methylation from extensively passaged immortalized human cells in vitro and tested on clinical tissues. This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.
MeSH term(s)	Humans ; Epigenome ; Neoplasms/genetics ; Neoplasms/pathology ; Epigenesis, Genetic ; Aging/genetics ; Risk Factors
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adf4163
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