2,406 results on '"Horvath, Steve"'
Search Results
2. Reversal of biological age in multiple rat organs by young porcine plasma fraction
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Horvath, Steve, Singh, Kavita, Raj, Ken, Khairnar, Shraddha I, Sanghavi, Akshay, Shrivastava, Agnivesh, Zoller, Joseph A, Li, Caesar Z, Herenu, Claudia B, Canatelli-Mallat, Martina, Lehmann, Marianne, Habazin, Siniša, Novokmet, Mislav, Vučković, Frano, Solberg Woods, Leah C, Martinez, Angel Garcia, Wang, Tengfei, Chiavellini, Priscila, Levine, Andrew J, Chen, Hao, Brooke, Robert T, Gordevicius, Juozas, Lauc, Gordan, Goya, Rodolfo G, and Katcher, Harold L
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Aging ,Inflammatory and immune system ,Humans ,Rats ,Mice ,Animals ,Swine ,Epigenesis ,Genetic ,Biomarkers ,Plasma ,Immunoglobulin G ,Rejuvenation ,Plasma fraction ,Epigenetic clock ,DNA methylation ,Glycans ,Rat ,Clinical sciences - Abstract
Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young adult pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n = 613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain, liver, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n = 1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers, behavioral responses encompassing cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.
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- 2024
3. A methylation risk score for chronic kidney disease: a HyperGEN study
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Jones, Alana C, Patki, Amit, Srinivasasainagendra, Vinodh, Hidalgo, Bertha A, Tiwari, Hemant K, Limdi, Nita A, Armstrong, Nicole D, Chaudhary, Ninad S, Minniefield, Bré, Absher, Devin, Arnett, Donna K, Lange, Leslie A, Lange, Ethan M, Young, Bessie A, Diamantidis, Clarissa J, Rich, Stephen S, Mychaleckyj, Josyf C, Rotter, Jerome I, Taylor, Kent D, Kramer, Holly J, Tracy, Russell P, Durda, Peter, Kasela, Silva, Lappalinen, Tuuli, Liu, Yongmei, Johnson, W Craig, Van Den Berg, David J, Franceschini, Nora, Liu, Simin, Mouton, Charles P, Bhatti, Parveen, Horvath, Steve, Whitsel, Eric A, and Irvin, Marguerite R
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Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Prevention ,Clinical Research ,Human Genome ,Health Disparities ,Kidney Disease ,Minority Health ,Women's Health ,2.1 Biological and endogenous factors ,4.1 Discovery and preclinical testing of markers and technologies ,Renal and urogenital ,Humans ,Renal Insufficiency ,Chronic ,DNA Methylation ,Male ,Female ,Middle Aged ,Glomerular Filtration Rate ,CpG Islands ,Risk Factors ,Black or African American ,Aged ,Genome-Wide Association Study ,Epigenesis ,Genetic ,Adult ,Genetic Predisposition to Disease ,Chronic kidney disease ,eGFR ,Methylation risk score ,Epigenetics - Abstract
Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.
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- 2024
4. Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications
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Haefliger, Simon, Chervova, Olga, Davies, Christopher, Loh, Chet, Tirabosco, Roberto, Amary, Fernanda, Pillay, Nischalan, Horvath, Steve, Beck, Stephan, Flanagan, Adrienne M., and Lyskjær, Iben
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- 2024
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5. A case-control study: epigenetic age acceleration in psoriasis
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Macit, Betul, Ragi, Sara D, Moseley, Isabelle, Molino, Janine, McGeary, John E, Horvath, Steve, Qureshi, Abrar, Reginato, Anthony M., and Cho, Eunyoung
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- 2024
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6. Bloom syndrome patients and mice display accelerated epigenetic aging.
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Lee, Jamie, Zhang, Joshua, Flanagan, Maeve, Martinez, Julian, Cunniff, Christopher, Kucine, Nicole, Lu, Ake, Haghani, Amin, Gordevičius, Juozas, Horvath, Steve, and Chang, Vivian
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Bloom syndrome ,DNA repair ,cancer ,epigenetic aging ,Humans ,Animals ,Mice ,Bloom Syndrome ,Epigenesis ,Genetic ,Aging ,Aging ,Premature ,Methylation ,DNA Methylation - Abstract
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
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- 2023
7. Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.
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Bobba-Alves, Natalia, Sturm, Gabriel, Lin, Jue, Ware, Sarah, Karan, Kalpita, Monzel, Anna, Bris, Céline, Procaccio, Vincent, Lenaers, Guy, Higgins-Chen, Albert, Levine, Morgan, Horvath, Steve, Santhanam, Balaji, Kaufman, Brett, Hirano, Michio, Picard, Martin, and Epel, Elissa
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Aging ,Allostatic load ,Chronic stress ,Epigenetic aging ,Glucocorticoid ,Hypermetabolism ,Mitochondria ,Telomere ,Humans ,Allostasis ,Aging ,Adaptation ,Physiological ,Cellular Senescence ,Energy Metabolism - Abstract
Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.
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- 2023
8. Accelerated aging with HIV begins at the time of initial HIV infection
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Breen, Elizabeth Crabb, Sehl, Mary E, Shih, Roger, Langfelder, Peter, Wang, Ruibin, Horvath, Steve, Bream, Jay H, Duggal, Priya, Martinson, Jeremy, Wolinsky, Steven M, Martínez-Maza, Otoniel, Ramirez, Christina M, and Jamieson, Beth D
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Good Health and Well Being - Abstract
[This corrects the article DOI: 10.1016/j.isci.2022.104488.].
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- 2023
9. Epigenetic aging studies of pair bonding in prairie voles
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Sailer, Lindsay L., Haghani, Amin, Zoller, Joseph A., Li, Caesar Z., Ophir, Alexander G., and Horvath, Steve
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- 2024
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10. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation
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Moqri, Mahdi, Cipriano, Andrea, Simpson, Daniel J., Rasouli, Sajede, Murty, Tara, de Jong, Tineke Anna, Nachun, Daniel, de Sena Brandine, Guilherme, Ying, Kejun, Tarkhov, Andrei, Aberg, Karolina A., van den Oord, Edwin, Zhou, Wanding, Smith, Andrew, Mackall, Crystal, Gladyshev, Vadim N., Horvath, Steve, Snyder, Michael P., and Sebastiano, Vittorio
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- 2024
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11. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk
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Ori, Anil P. S., Olde Loohuis, Loes M., Guintivano, Jerry, Hannon, Eilis, Dempster, Emma, St. Clair, David, Bass, Nick J., McQuillin, Andrew, Mill, Jonathan, Sullivan, Patrick F., Kahn, Rene S., Horvath, Steve, and Ophoff, Roel A.
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- 2024
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12. Causality-enriched epigenetic age uncouples damage and adaptation
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Ying, Kejun, Liu, Hanna, Tarkhov, Andrei E., Sadler, Marie C., Lu, Ake T., Moqri, Mahdi, Horvath, Steve, Kutalik, Zoltán, Shen, Xia, and Gladyshev, Vadim N.
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- 2024
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13. Validation of biomarkers of aging
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Moqri, Mahdi, Herzog, Chiara, Poganik, Jesse R., Ying, Kejun, Justice, Jamie N., Belsky, Daniel W., Higgins-Chen, Albert T., Chen, Brian H., Cohen, Alan A., Fuellen, Georg, Hägg, Sara, Marioni, Riccardo E., Widschwendter, Martin, Fortney, Kristen, Fedichev, Peter O., Zhavoronkov, Alex, Barzilai, Nir, Lasky-Su, Jessica, Kiel, Douglas P., Kennedy, Brian K., Cummings, Steven, Slagboom, P. Eline, Verdin, Eric, Maier, Andrea B., Sebastiano, Vittorio, Snyder, Michael P., Gladyshev, Vadim N., Horvath, Steve, and Ferrucci, Luigi
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- 2024
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14. Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and DNA-methylation based PAI1
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Kusters, Cynthia D. J., Paul, Kimberly C., Lu, Ake T., Ferruci, Luigi, Ritz, Beate R., Binder, Alexandra M., and Horvath, Steve
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- 2024
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15. DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging
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Zoller, Joseph A., Parasyraki, Eleftheria, Lu, Ake T., Haghani, Amin, Niehrs, Christof, and Horvath, Steve
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- 2024
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16. Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity
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Dec, Eric, Clement, James, Cheng, Kaiyang, Church, George M, Fossel, Michael B, Rehkopf, David H, Rosero-Bixby, Luis, Kobor, Michael S, Lin, David TS, Lu, Ake T, Fei, Zhe, Guo, Wei, Chew, Yap Ching, Yang, Xiaojing, Putra, Sulistyo E Dwi, Reiner, Alex P, Correa, Adolfo, Vilalta, Adrian, Pirazzini, Chiara, Passarino, Giuseppe, Monti, Daniela, Arosio, Beatrice, Garagnani, Paolo, Franceschi, Claudio, and Horvath, Steve
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Biological Sciences ,Genetics ,Aging ,Clinical Research ,Human Genome ,Aged ,80 and over ,Humans ,Longevity ,Centenarians ,DNA Methylation ,Epigenesis ,Genetic ,Centenarian clocks ,Epigenetic clocks ,Clinical sciences - Abstract
Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.
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- 2023
17. Persistent accelerated epigenetic ageing in a longitudinal cohort of vertically infected HIV-positive adolescents.
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Heany, Sarah, Levine, Andrew, Lesosky, Maia, Phillips, Nicole, Fouche, Jean-Paul, Myer, Landon, Zar, Heather, Stein, Dan, Horvath, Steve, and Hoare, Jacqueline
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Accelerated ageing ,DNA methylation ,Epigenetic clock ,Perinatal HIV ,Humans ,Adolescent ,Child ,Diffusion Tensor Imaging ,Cohort Studies ,HIV Infections ,South Africa ,Aging ,Epigenesis ,Genetic - Abstract
We have previously shown accelerated ageing in adolescents perinatally infected with HIV (PHIV +), based on discrepancies between epigenetic and chronological age. The current study examines follow-up longitudinal patterns of epigenetic ageing and the association of epigenetic ageing with cognition as well as whole brain structure changes in PHIV + and healthy controls enrolled in the Cape Town Adolescent Antiretroviral Cohort Study (CTAAC). The Illumina EPIC array was used to generate blood DNA methylation data from 60 PHIV + adolescents and 36 age-matched controls aged 9-12 years old at baseline and again at a 36-month follow-up. Epigenetic clock software estimated two measures of epigenetic age acceleration: extrinsic epigenetic accelerated ageing (EEAA) and age acceleration difference (AAD) at both time points. At follow-up, each participant completed neuropsychological testing, structural magnetic resonance imaging, and diffusion tensor imaging. At follow-up, PHIV infection remains associated with increased EEAA and AAD. Accelerated epigenetic ageing remained positively associated with viral load and negatively associated with CD4 ratio. EEAA was positively associated with whole brain grey matter volume and alterations in whole brain white matter integrity. AAD and EEAA were not associated with cognitive function within the PHIV + group. Measures of epigenetic ageing, as detected in DNA methylation patterns, remain increased in PHIV + adolescents across a 36-month period. Associations between epigenetic ageing measures, viral biomarkers, and alterations in brain micro- and macrostructure also persist at 36-month follow-up. Further study should determine if epigenetic age acceleration is associated with cognitive functional changes due to brain alterations in later life.
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- 2023
18. Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function
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Zhang, Yuankai, Liu, Xue, Wiggins, Kerri L, Kurniansyah, Nuzulul, Guo, Xiuqing, Rodrigue, Amanda L, Zhao, Wei, Yanek, Lisa R, Ratliff, Scott M, Pitsillides, Achilleas, Aguirre Patiño, Juan Sebastian, Sofer, Tamar, Arking, Dan E, Austin, Thomas R, Beiser, Alexa S, Blangero, John, Boerwinkle, Eric, Bressler, Jan, Curran, Joanne E, Hou, Lifang, Hughes, Timothy M, Kardia, Sharon LR, Launer, Lenore J, Levy, Daniel, Mosley, Thomas H, Nasrallah, Ilya M, Rich, Stephen S, Rotter, Jerome I, Seshadri, Sudha, Tarraf, Wassim, González, Kevin A, Ramachandran, Vasan, Yaffe, Kristine, Nyquist, Paul A, Psaty, Bruce M, DeCarli, Charles S, Smith, Jennifer A, Glahn, David C, González, Hector M, Bis, Joshua C, Fornage, Myriam, Heckbert, Susan R, Fitzpatrick, Annette L, Liu, Chunyu, Satizabal, Claudia L, Aguilera, Norma, Ament, Seth, Ammous, Farah, Arnett, Donna K, Becker, Diane, Bis, Joshua, Blue, Elizabeth, Breaux, Camille, Chaar, Dima, MHI, Clarkson-Townsend, Danielle, Cooper, Brigidann, Coresh, Josef, Correa, Adolfo, DeStefano, Anita, Ding, Jingzhong, Fardo, David, Fitzpatrick, Annette, French, Jennifer, Glahn, David, Gonzalez, Hector, Granot-Hershkovitz, Einat, Hanly, Patrick, Hayden, Kathleen, Heckbert, Susan, Heemann, Scott, Horvath, Steve, Hoth, Karin, Hughes, Timothy, Jaiswal, Sidd, Jian, Xueqiu, Katsumata, Yuriko, Kho, Minjung, Kooperberg, Charles, Launer, Lenore, Lin, Honghuang, Litkowski, Elizabeth, Longstreth, Will, Martin, Alexandra, Mayeux, Richard, Mikulla, Julie, Miller, Amy, Misra, Biswapriya, Mosley, Thomas, Nyquist, Paul, O'Connell, Jeff, Olivier, Michael, Peloso, Gina, Perry, James, Psaty, Bruce, Purcell, Shaun, and Raffield, Laura
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Alzheimer's Disease ,Neurodegenerative ,Dementia ,Aging ,Biomedical Imaging ,Acquired Cognitive Impairment ,Behavioral and Social Science ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Precision Medicine ,Genetics ,4.1 Discovery and preclinical testing of markers and technologies ,2.1 Biological and endogenous factors ,Mental health ,Neurological ,Good Health and Well Being ,Middle Aged ,Humans ,Female ,Aged ,Male ,DNA ,Mitochondrial ,DNA Copy Number Variations ,Prospective Studies ,Cross-Sectional Studies ,Alzheimer Disease ,Magnetic Resonance Imaging ,Cognition ,Brain ,NHLBI Trans-Omics for Precision Medicine (TOPMed) program ,Mitochondrial and Neurocognitive Working Groups ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
Background and objectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (
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- 2023
19. Multi-tissue DNA methylation aging clocks for sea lions, walruses and seals.
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Robeck, Todd, Haghani, Amin, Fei, Zhe, Lindemann, Dana, Russell, Jennifer, Herrick, Kelsey, Montano, Gisele, Steinman, Karen, Katsumata, Etsuko, Zoller, Joseph, and Horvath, Steve
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Animals ,Sea Lions ,Walruses ,DNA Methylation ,Phylogeny ,Caniformia ,Seals ,Earless ,Aging - Abstract
Age determination of wild animals, including pinnipeds, is critical for accurate population assessment and management. For most pinnipeds, current age estimation methodologies utilize tooth or bone sectioning which makes antemortem estimations problematic. We leveraged recent advances in the development of epigenetic age estimators (epigenetic clocks) to develop highly accurate pinniped epigenetic clocks. For clock development, we applied the mammalian methylation array to profile 37,492 cytosine-guanine sites (CpGs) across highly conserved stretches of DNA in blood and skin samples (n = 171) from primarily three pinniped species representing the three phylogenetic families: Otariidae, Phocidae and Odobenidae. We built an elastic net model with Leave-One-Out-Cross Validation (LOOCV) and one with a Leave-One-Species-Out-Cross-Validation (LOSOCV). After identifying the top 30 CpGs, the LOOCV produced a highly correlated (r = 0.95) and accurate (median absolute error = 1.7 years) age estimation clock. The LOSOCV elastic net results indicated that blood and skin clock (r = 0.84) and blood (r = 0.88) pinniped clocks could predict age of animals from pinniped species not used for clock development to within 3.6 and 4.4 years, respectively. These epigenetic clocks provide an improved and relatively non-invasive tool to determine age in skin or blood samples from all pinniped species.
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- 2023
20. Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.
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Do, Whitney, Sun, Dianjianyi, Meeks, Karlijn, Dugué, Pierre-Antoine, Demerath, Ellen, Guan, Weihua, Li, Shengxu, Chen, Wei, Milne, Roger, Adeyemo, Abedowale, Agyemang, Charles, Nassir, Rami, Manson, JoAnn, Hou, Lifang, Horvath, Steve, Assimes, Themistocles, Bhatti, Parveen, Jordahl, Kristina, Baccarelli, Andrea, Smith, Alicia, Staimez, Lisa, Stein, Aryeh, Whitsel, Eric, Narayan, K, Conneely, Karen, and Shadyab, Aladdin
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BMI ,DNA methylation ,adiposity ,epigenome-wide association study ,epigenomics ,metabolic disease ,obesity ,prediction ,Humans ,Female ,Body Mass Index ,Epigenome ,Epigenesis ,Genetic ,Obesity ,Cholesterol ,HDL ,Genome-Wide Association Study ,DNA Methylation ,Epigenomics ,Triglycerides ,CpG Islands - Abstract
This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Womens Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p
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- 2023
21. Alcohol consumption and epigenetic age acceleration in young adults
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Nannini, Drew R, Joyce, Brian T, Zheng, Yinan, Gao, Tao, Wang, Jun, Liu, Lei, Jacobs, David R, Schreiner, Pamela J, Liu, Chunyu, Dai, Qi, Horvath, Steve, Lu, Ake T, Yaffe, Kristine, Greenland, Philip, Lloyd-Jones, Donald M, and Hou, Lifang
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Pediatric ,Clinical Research ,Genetics ,Underage Drinking ,Alcoholism ,Alcohol Use and Health ,Aging ,Substance Misuse ,2.3 Psychological ,social and economic factors ,Aetiology ,Oral and gastrointestinal ,Cardiovascular ,Stroke ,Cancer ,Good Health and Well Being ,Aged ,Humans ,Alcohol Drinking ,Alcoholic Beverages ,Beer ,Binge Drinking ,United States ,Wine ,Epigenomics ,alcohol ,epigenetic age ,DNA methylation ,lifetime alcohol consumption ,binge drinking ,Biochemistry and Cell Biology ,Physiology ,Oncology and Carcinogenesis ,Developmental Biology - Abstract
Alcohol is a widely consumed substance in the United States, however its effect on aging remains understudied. In this study of young adults, we examined whether cumulative alcohol consumption, i.e., alcohol years of beer, liquor, wine, and total alcohol, and recent binge drinking, were associated with four measures of age-related epigenetic changes via blood DNA methylation. A random subset of study participants in the Coronary Artery Risk Development in Young Adults Study underwent DNA methylation profiling using the Illumina MethylationEPIC Beadchip. Participants with alcohol consumption and methylation data at examination years 15 (n = 1,030) and 20 (n = 945) were included. Liquor and total alcohol consumption were associated with a 0.31-year (P = 0.002) and a 0.12-year (P = 0.013) greater GrimAge acceleration (GAA) per additional five alcohol years, while beer and wine consumption observed marginal (P = 0.075) and no associations (P = 0.359) with GAA, respectively. Any recent binge drinking and the number of days of binge drinking were associated with a 1.38-year (P < 0.001) and a 0.15-year (P < 0.001) higher GAA, respectively. We observed statistical interactions between cumulative beer (P < 0.001) and total alcohol (P = 0.004) consumption with chronological age, with younger participants exhibiting a higher average in GAA compared to older participants. No associations were observed with the other measures of epigenetic aging. These results suggest cumulative liquor and total alcohol consumption and recent binge drinking may alter age-related epigenetic changes as captured by GAA. With the increasing aging population and widespread consumption of alcohol, these findings may have potential implications for lifestyle modification to promote healthy aging.
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- 2023
22. An epigenetic DNA methylation clock for age estimates in Indo-Pacific bottlenose dolphins (Tursiops aduncus).
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Peters, Katharina, Gerber, Livia, Scheu, Luca, Cicciarella, Riccardo, Zoller, Joseph, Fei, Zhe, Horvath, Steve, Allen, Simon, King, Stephanie, Connor, Richard, Rollins, Lee, and Krützen, Michael
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aging ,bottlenose dolphin ,epigenetic clock - Abstract
Knowledge of an animals chronological age is crucial for understanding and predicting population demographics, survival and reproduction, but accurate age determination for many wild animals remains challenging. Previous methods to estimate age require invasive procedures, such as tooth extraction to analyse growth layers, which are difficult to carry out with large, mobile animals such as cetaceans. However, recent advances in epigenetic methods have opened new avenues for precise age determination. These epigenetic clocks present a less invasive alternative and can provide age estimates with unprecedented accuracy. Here, we present a species-specific epigenetic clock based on skin tissue samples for a population of Indo-Pacific bottlenose dolphins (Tursiops aduncus) in Shark Bay, Western Australia. We measured methylation levels at 37,492 cytosine-guanine sites (CpG sites) in 165 samples using the mammalian methylation array. Chronological age estimates with an accuracy of ±1 year were available for 68 animals as part of a long-term behavioral study of this population. Using these samples with known age, we built an elastic net model with Leave-One-Out-Cross-Validation, which retained 43 CpG sites, providing an r = 0.86 and median absolute age error (MAE) = 2.1 years (5% of maximum age). This model was more accurate for our data than the previously published methylation clock based on skin samples of common bottlenose dolphins (T. truncatus: r = 0.83, MAE = 2.2) and the multi-species odontocete methylation clock (r = 0.68, MAE = 6.8), highlighting that species-specific clocks can have superior performance over those of multi-species assemblages. We further developed an epigenetic sex estimator, predicting sex with 100% accuracy. As age and sex are critical parameters for the study of animal populations, this clock and sex estimator will provide a useful tool for extracting life history information from skin samples rather than long-term observational data for free-ranging Indo-Pacific bottlenose dolphins worldwide.
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- 2023
23. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases
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Sturm, Gabriel, Karan, Kalpita R, Monzel, Anna S, Santhanam, Balaji, Taivassalo, Tanja, Bris, Céline, Ware, Sarah A, Cross, Marissa, Towheed, Atif, Higgins-Chen, Albert, McManus, Meagan J, Cardenas, Andres, Lin, Jue, Epel, Elissa S, Rahman, Shamima, Vissing, John, Grassi, Bruno, Levine, Morgan, Horvath, Steve, Haller, Ronald G, Lenaers, Guy, Wallace, Douglas C, St-Onge, Marie-Pierre, Tavazoie, Saeed, Procaccio, Vincent, Kaufman, Brett A, Seifert, Erin L, Hirano, Michio, and Picard, Martin
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Genetics ,Biological Sciences ,Aging ,Clinical Research ,Human Genome ,Underpinning research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Generic health relevance ,Humans ,Oxidative Phosphorylation ,Longevity ,Mitochondrial Diseases ,Mitochondria ,DNA ,Mitochondrial ,Biological sciences ,Biomedical and clinical sciences - Abstract
Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.
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- 2023
24. Correction to: Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno‑/GrimAge and DNA‑methylation based PAI1
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Kusters, Cynthia D. J., Paul, Kimberly C., Lu, Ake T., Ferrucci, Luigi, Ritz, Beate R., Binder, Alexandra M., and Horvath, Steve
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- 2024
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25. In vivo reprogramming leads to premature death linked to hepatic and intestinal failure
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Parras, Alberto, Vílchez-Acosta, Alba, Desdín-Micó, Gabriela, Picó, Sara, Mrabti, Calida, Montenegro-Borbolla, Elena, Maroun, Céline Yacoub, Haghani, Amin, Brooke, Robert, del Carmen Maza, María, Rechsteiner, Cheyenne, Battiston, Fabrice, Branchina, Clémence, Perez, Kevin, Horvath, Steve, Bertelli, Claire, Sempoux, Christine, and Ocampo, Alejandro
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- 2023
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26. Pan-primate studies of age and sex
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Horvath, Steve, Haghani, Amin, Zoller, Joseph A., Lu, Ake T., Ernst, Jason, Pellegrini, Matteo, Jasinska, Anna J., Mattison, Julie A., Salmon, Adam B., Raj, Ken, Horvath, Markus, Paul, Kimberly C., Ritz, Beate R., Robeck, Todd R., Spriggs, Maria, Ehmke, Erin E., Jenkins, Susan, Li, Cun, and Nathanielsz, Peter W.
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- 2023
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27. DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation
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Jokai, Matyas, Torma, Ferenc, McGreevy, Kristen M., Koltai, Erika, Bori, Zoltan, Babszki, Gergely, Bakonyi, Peter, Gombos, Zoltan, Gyorgy, Bernadett, Aczel, Dora, Toth, Laszlo, Osvath, Peter, Fridvalszky, Marcell, Teglas, Timea, Posa, Aniko, Kujach, Sylwester, Olek, Robert, Kawamura, Takuji, Seki, Yasuhiro, Suzuki, Katsuhiko, Tanisawa, Kumpei, Goto, Sataro, Kerepesi, Csaba, Boldogh, Istvan, Ba, Xueqing, Davies, Kelvin J. A., Horvath, Steve, and Radak, Zsolt
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- 2023
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28. Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans
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Benavente, Ernest Diez, Hartman, Robin J.G., Sakkers, Tim R., Wesseling, Marian, Sloots, Yannicke, Slenders, Lotte, Boltjes, Arjan, Mol, Barend M., de Borst, Gert J., de Kleijn, Dominique P.V., Prange, Koen H.M., de Winther, Menno P.J., Kuiper, Johan, Civelek, Mete, van der Laan, Sander W., Horvath, Steve, Onland-Moret, Charlotte, Mokry, Michal, Pasterkamp, Gerard, and den Ruijter, Hester M.
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- 2024
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29. DNA methylation GrimAge version 2
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Lu, Ake T, Binder, Alexandra M, Zhang, Joshua, Yan, Qi, Reiner, Alex P, Cox, Simon R, Corley, Janie, Harris, Sarah E, Kuo, Pei-Lun, Moore, Ann Z, Bandinelli, Stefania, Stewart, James D, Wang, Cuicui, Hamlat, Elissa J, Epel, Elissa S, Schwartz, Joel D, Whitsel, Eric A, Correa, Adolfo, Ferrucci, Luigi, Marioni, Riccardo E, and Horvath, Steve
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Good Health and Well Being ,Humans ,Aged ,Aged ,80 and over ,DNA Methylation ,Aging ,Diabetes Mellitus ,Type 2 ,Metabolic Syndrome ,Biomarkers ,Epigenesis ,Genetic ,DNA methylation ,epigenetic clock ,mortality ,healthspan ,Biochemistry and cell biology ,Clinical sciences - Abstract
We previously described a DNA methylation (DNAm) based biomarker of human mortality risk DNAm GrimAge. Here we describe version 2 of GrimAge (trained on individuals aged between 40 and 92) which leverages two new DNAm based estimators of (log transformed) plasma proteins: high sensitivity C-reactive protein (logCRP) and hemoglobin A1C (logA1C). We evaluate GrimAge2 in 13,399 blood samples across nine study cohorts. After adjustment for age and sex, GrimAge2 outperforms GrimAge in predicting mortality across multiple racial/ethnic groups (meta P=3.6x10-167 versus P=2.6x10-144) and in terms of associations with age related conditions such as coronary heart disease, lung function measurement FEV1 (correlation= -0.31, P=1.1x10-136), computed tomography based measurements of fatty liver disease. We present evidence that GrimAge version 2 also applies to younger individuals and to saliva samples where it tracks markers of metabolic syndrome. DNAm logCRP is positively correlated with morbidity count (P=1.3x10-54). DNAm logA1C is highly associated with type 2 diabetes (P=5.8x10-155). DNAm PAI-1 outperforms the other age-adjusted DNAm biomarkers including GrimAge2 in correlating with triglyceride (cor=0.34, P=9.6x10-267) and visceral fat (cor=0.41, P=4.7x10-41). Overall, we demonstrate that GrimAge version 2 is an attractive epigenetic biomarker of human mortality and morbidity risk.
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- 2022
30. A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.
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Sturm, Gabriel, Monzel, Anna, Karan, Kalpita, Michelson, Jeremy, Ware, Sarah, Cardenas, Andres, Lin, Jue, Bris, Céline, Santhanam, Balaji, Murphy, Michael, Levine, Morgan, Horvath, Steve, Belsky, Daniel, Wang, Shuang, Procaccio, Vincent, Kaufman, Brett, Hirano, Michio, and Picard, Martin
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Humans ,Aging ,Fibroblasts ,Longevity ,Cellular Senescence ,Glycolysis - Abstract
Aging is a process of progressive change. To develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omics longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n = 6) and individuals with lifespan-shortening mitochondrial disease (n = 3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the hallmarks of aging, with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/.
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- 2022
31. Marijuana use and DNA methylation-based biological age in young adults
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Nannini, Drew R, Zheng, Yinan, Joyce, Brian T, Gao, Tao, Liu, Lei, Jacobs, David R, Schreiner, Pamela, Liu, Chunyu, Horvath, Steve, Lu, Ake T, Yaffe, Kristine, Sidney, Stephen, Greenland, Philip, Lloyd-Jones, Donald M, and Hou, Lifang
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Biological Sciences ,Genetics ,Clinical Research ,Human Genome ,Alcoholism ,Alcohol Use and Health ,Cannabinoid Research ,Aging ,Substance Misuse ,Cancer ,Cardiovascular ,Good Health and Well Being ,Humans ,Young Adult ,DNA Methylation ,Marijuana Use ,Epigenesis ,Genetic ,Epigenomics ,Marijuana ,Epigenetic age acceleration ,Alcohol ,CARDIA ,Clinical Sciences ,Paediatrics and Reproductive Medicine - Abstract
BackgroundMarijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana's effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation.ResultsA random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P
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- 2022
32. Stress induced aging in mouse eye
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Xu, Qianlan, Rydz, Cezary, Huu, Viet Anh Nguyen, Rocha, Lorena, La Torre, Claudia Palomino, Lee, Irene, Cho, William, Jabari, Mary, Donello, John, Lyon, David C, Brooke, Robert T, Horvath, Steve, Weinreb, Robert N, Ju, Won‐Kyu, Foik, Andrzej, and Skowronska‐Krawczyk, Dorota
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Neurosciences ,Human Genome ,Aging ,Prevention ,Neurodegenerative ,Genetics ,Eye Disease and Disorders of Vision ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Eye ,Mice ,Animals ,Intraocular Pressure ,Retinal Ganglion Cells ,Glaucoma ,Disease Models ,Animal ,Chromatin ,aging ,IOP ,retinal ganglion cells ,senescence ,stress response ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited; therefore, we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on chromatin level. We demonstrate that ocular hypertension activates a stress response that is similar to natural aging and involves activation of inflammation and senescence. We show that multiple instances of pressure elevation cause aging of young retina as measured on transcriptional and DNA methylation level and are accompanied by local histone modification changes. Our data show that repeated stress accelerates appearance of aging features in tissues and suggest chromatin modifications as the key molecular components of aging. Lastly, our work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related diseases, including glaucoma.
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- 2022
33. Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients
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Paul, Kimberly C, Kusters, Cynthia, Furlong, Melissa, Zhang, Keren, Yu, Yu, Folle, Aline Duarte, Del Rosario, Irish, Keener, Adrienne, Bronstein, Jeff, Sinsheimer, Janet S, Horvath, Steve, and Ritz, Beate
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Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Genetics ,Human Genome ,Neurosciences ,Biotechnology ,Behavioral and Social Science ,Brain Disorders ,Aging ,Neurodegenerative ,Mental Health ,Parkinson's Disease ,Depression ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Neurological ,DNA methylation ,Inflammation ,Methylation QTLs ,Neutrophil-to-lymphocyte ratio ,Parkinson's disease ,Clinical sciences - Abstract
Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS
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- 2022
34. Mapping brain gene coexpression in daytime transcriptomes unveils diurnal molecular networks and deciphers perturbation gene signatures.
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Richman, Jeffrey, Vaca, Raymond, Plascencia, Mary, Gu, Xiaofeng, Zhang, Shasha, Tamai, T, Zhang, Liguo, Gao, Fuying, Ouk, Koliane, Lu, Xiang, Ivanov, Leonid, Vogt, Thomas, Lu, Qing, Morton, A, Stricos, Matthew, Aaronson, Jeffrey, Rosinski, Jim, Horvath, Steve, Yang, Xiangdong, Colwell, Christopher, Ramanathan, Lalini, Wang, Nan, and Langfelder, Peter
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Huntington’s disease ,Parkinson’s disease ,Trank1 ,WGCNA ,bipolar disorder ,coexpression ,cortex ,diurnal ,gene ,striatum ,Animals ,Mice ,Transcriptome ,Protein Kinase C-theta ,Gene Regulatory Networks ,Huntington Disease ,Brain - Abstract
Brain tissue transcriptomes may be organized into gene coexpression networks, but their underlying biological drivers remain incompletely understood. Here, we undertook a large-scale transcriptomic study using 508 wild-type mouse striatal tissue samples dissected exclusively in the afternoons to define 38 highly reproducible gene coexpression modules. We found that 13 and 11 modules are enriched in cell-type and molecular complex markers, respectively. Importantly, 18 modules are highly enriched in daily rhythmically expressed genes that peak or trough with distinct temporal kinetics, revealing the underlying biology of striatal diurnal gene networks. Moreover, the diurnal coexpression networks are a dominant feature of daytime transcriptomes in the mouse cortex. We next employed the striatal coexpression modules to decipher the striatal transcriptomic signatures from Huntingtons disease models and heterozygous null mice for 52 genes, uncovering novel functions for Prkcq and Kdm4b in oligodendrocyte differentiation and bipolar disorder-associated Trank1 in regulating anxiety-like behaviors and nocturnal locomotion.
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- 2022
35. Premature aging is associated with higher levels of 8‐oxoguanine and increased DNA damage in the Polg mutator mouse
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Yu, Tenghui, Slone, Jesse, Liu, Wensheng, Barnes, Ryan, Opresko, Patricia L, Wark, Landon, Mai, Sabine, Horvath, Steve, and Huang, Taosheng
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Biological Sciences ,Genetics ,Aging ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Aging ,Premature ,Animals ,DNA Damage ,DNA Polymerase gamma ,DNA ,Mitochondrial ,DNA-Directed DNA Polymerase ,Guanine ,Mice ,Mutation ,8-oxoguanine ,aging ,mitochondria ,oxidative stress ,telomeres ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut ). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.
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- 2022
36. Association of subjective social status with epigenetic aging among Black and White women
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Hamlat, Elissa J, Adler, Nancy E, Laraia, Barbara, Surachman, Agus, Lu, Ake T, Zhang, Joshua, Horvath, Steve, and Epel, Elissa S
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Biomedical and Clinical Sciences ,Psychology ,Genetics ,Health Disparities ,Aging ,Clinical Research ,Adult ,Black People ,Child ,Epigenesis ,Genetic ,Female ,Humans ,Social Class ,Social Status ,Socioeconomic status ,Subjective social status ,Epigenetic clock ,Epigenetic age acceleration ,Race ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biomedical and clinical sciences - Abstract
ObjectiveSubjective social status (SSS), an individual's assessment of their own social status in relation to others, is associated with health and mortality independently of objective SES; however, no studies have tested whether SSS influences epigenetic aging. The current study examines if SSS is associated with epigenetic age acceleration in both Black and White women, independently of objective SES measured during both childhood and adulthood.MethodFor 9- and 10-year-old Black and White girls, parental education and annual household income was obtained. At ages 39-42, 361 participants (175 Black, 186 White) reported their current education, household income, and SSS, and provided saliva to assess age acceleration using the GrimAge epigenetic clock. Linear regression estimated the association of SSS with epigenetic age acceleration, controlling for objective SES (current education, current income, parents' education, income during childhood), smoking, and counts of cell types.ResultsWhen all objective SES variables were included in the model, SSS remained significantly associated with epigenetic age acceleration, b = - 0.31, p = .003, ß = - 0.15. Black women had significantly greater age acceleration than White women, (t(359) = 5.20, p > .001, d = 0.55) but race did not moderate the association between SSS and epigenetic age acceleration.ConclusionsWomen who rated themselves lower in SSS had greater epigenetic age acceleration, regardless of income and education. There was no difference by race for this association.
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- 2022
37. Accelerated epigenetic aging in newborns with Down syndrome
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Xu, Keren, Li, Shaobo, Muskens, Ivo S, Elliott, Natalina, Myint, Swe Swe, Pandey, Priyatama, Hansen, Helen M, Morimoto, Libby M, Kang, Alice Y, Ma, Xiaomei, Metayer, Catherine, Mueller, Beth A, Roberts, Irene, Walsh, Kyle M, Horvath, Steve, Wiemels, Joseph L, and de Smith, Adam J
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Intellectual and Developmental Disabilities (IDD) ,Aging ,Brain Disorders ,Down Syndrome ,Congenital ,Good Health and Well Being ,Adult ,Aging ,Premature ,DNA Methylation ,Epigenesis ,Genetic ,Epigenomics ,Humans ,Infant ,Newborn ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p
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- 2022
38. Accelerated aging with HIV begins at the time of initial HIV infection
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Breen, Elizabeth Crabb, Sehl, Mary E, Shih, Roger, Langfelder, Peter, Wang, Ruibin, Horvath, Steve, Bream, Jay H, Duggal, Priya, Martinson, Jeremy, Wolinsky, Steven M, Martínez-Maza, Otoniel, Ramirez, Christina M, and Jamieson, Beth D
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Genetics ,Prevention ,Clinical Research ,Infectious Diseases ,HIV/AIDS ,Aging ,Infection ,Good Health and Well Being ,Epigenetics ,Human physiology ,Immunology ,Virology - Abstract
Living with HIV infection is associated with early onset of aging-related chronic conditions, sometimes described as accelerated aging. Epigenetic DNA methylation patterns can evaluate acceleration of biological age relative to chronological age. The impact of initial HIV infection on five epigenetic measures of aging was examined before and approximately 3 years after HIV infection in the same individuals (n=102). Significant epigenetic age acceleration (median 1.9-4.8 years) and estimated telomere length shortening (all p≤ 0.001) were observed from pre-to post-HIV infection, and remained significant in three epigenetic measures after controlling for T cell changes. No acceleration was seen in age- and time interval-matched HIV-uninfected controls. Changes in genome-wide co-methylation clusters were also significantly associated with initial HIV infection (p≤ 2.0 × 10-4). These longitudinal observations clearly demonstrate an early and substantial impact of HIV infection on the epigenetic aging process, and suggest a role for HIV itself in the earlier onset of clinical aging.
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- 2022
39. Grandparents' educational attainment is associated with grandchildren's epigenetic-based age acceleration in the National Growth and Health Study
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Surachman, Agus, Hamlat, Elissa, Zannas, Anthony S., Horvath, Steve, Laraia, Barbara, and Epel, Elissa
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- 2024
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40. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice
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Zhang, Zhihui, Tian, Xiao, Lu, J. Yuyang, Boit, Kathryn, Ablaeva, Julia, Zakusilo, Frances Tolibzoda, Emmrich, Stephan, Firsanov, Denis, Rydkina, Elena, Biashad, Seyed Ali, Lu, Quan, Tyshkovskiy, Alexander, Gladyshev, Vadim N., Horvath, Steve, Seluanov, Andrei, and Gorbunova, Vera
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- 2023
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41. Multi-omic rejuvenation and lifespan extension on exposure to youthful circulation
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Zhang, Bohan, Lee, David E., Trapp, Alexandre, Tyshkovskiy, Alexander, Lu, Ake T., Bareja, Akshay, Kerepesi, Csaba, McKay, Lauren K., Shindyapina, Anastasia V., Dmitriev, Sergey E., Baht, Gurpreet S., Horvath, Steve, Gladyshev, Vadim N., and White, James P.
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- 2023
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42. Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging
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Rosoff, Daniel B., Mavromatis, Lucas A., Bell, Andrew S., Wagner, Josephin, Jung, Jeesun, Marioni, Riccardo E., Davey Smith, George, Horvath, Steve, and Lohoff, Falk W.
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- 2023
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43. Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans
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Diez Benavente, Ernest, Hartman, Robin J.G., Sakkers, Tim R., Wesseling, Marian, Sloots, Yannicke, Slenders, Lotte, Boltjes, Arjan, Mol, Barend M., de Borst, Gert J., de Kleijn, Dominique P.V., Prange, Koen H.M., de Winther, Menno P.J., Kuiper, Johan, Civelek, Mete, van der Laan, Sander W., Horvath, Steve, Onland-Moret, N. Charlotte, Mokry, Michal, Pasterkamp, Gerard, and den Ruijter, Hester M.
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- 2024
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44. Association of Epigenetic Age Acceleration with Incident Mild Cognitive Impairment and Dementia Among Older Women
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Shadyab, Aladdin H, McEvoy, Linda K, Horvath, Steve, Whitsel, Eric A, Rapp, Stephen R, Espeland, Mark A, Resnick, Susan M, Manson, JoAnn E, Chen, Jiu-Chiuan, Chen, Brian H, Li, Wenjun, Hayden, Kathleen M, Bao, Wei, Kusters, Cynthia DJ, and LaCroix, Andrea Z
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Alzheimer's Disease ,Heart Disease ,Dementia ,Prevention ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Cardiovascular ,Aging ,Clinical Research ,Neurodegenerative ,Brain Disorders ,Acquired Cognitive Impairment ,Neurological ,Acceleration ,Aged ,Cognitive Dysfunction ,Cohort Studies ,Epigenesis ,Genetic ,Female ,Humans ,Prospective Studies ,Alzheimer's disease ,Biomarker ,Cognitive aging ,Alzheimer’s disease ,Clinical Sciences ,Gerontology - Abstract
BackgroundEpigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia.MethodsThis prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated.ResultsIEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99-1.53), dementia (HR, 1.10; 95% CI, 0.88-1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia.ConclusionsIEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.
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- 2022
45. HIV, pathology and epigenetic age acceleration in different human tissues
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Horvath, Steve, Lin, David TS, Kobor, Michael S, Zoller, Joseph A, Said, Jonathan W, Morgello, Susan, Singer, Elyse, Yong, William H, Jamieson, Beth D, and Levine, Andrew J
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,HIV/AIDS ,Infectious Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Acceleration ,Epigenesis ,Genetic ,HIV Infections ,HIV-1 ,Humans ,Hypertension ,Male ,Epigenetic clock ,DNA methylation ,Cross tissue analysis ,HIV ,Clinical sciences - Abstract
Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.
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- 2022
46. Epigenetic clock and methylation studies in marsupials: opossums, Tasmanian devils, kangaroos, and wallabies.
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Horvath, Steve, Haghani, Amin, Zoller, Joseph A, Raj, Ken, Sinha, Ishani, Robeck, Todd R, Black, Pete, Couzens, Aidan, Lau, Clive, Manoyan, Meghety, Ruiz, Yadiamaris Aviles, Talbott, Annais, Belov, Katherine, Hogg, Carolyn J, and Sears, Karen E
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Animals ,Mice ,Inbred C57BL ,Macropodidae ,Mice ,DNA Methylation ,Epigenesis ,Genetic ,Epigenomics ,Aging ,DNA methylation ,Development ,Epigenetic clock ,Opossum ,Genetics ,Human Genome - Abstract
The opossum (Monodelphis domestica), with its sequenced genome, ease of laboratory care and experimental manipulation, and unique biology, is the most used laboratory marsupial. Using the mammalian methylation array, we generated DNA methylation data from n = 100 opossum samples from the ear, liver, and tail. We contrasted postnatal development and later aging effects in the opossum methylome with those in mouse (Mus musculus, C57BL/6 J strain) and other marsupial species such as Tasmanian devil, kangaroos, and wallabies. While the opossum methylome is similar to that of mouse during postnatal development, it is distinct from that shared by other mammals when it comes to the age-related gain of methylation at target sites of polycomb repressive complex 2. Our immunohistochemical staining results provide additional support for the hypothesis that PRC2 activity increases with later aging in mouse tissues but remains constant in opossum tissues. We present several epigenetic clocks for opossums that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (opossum and human). Two dual-species human-opossum pan-tissue clocks accurately measure chronological age and relative age, respectively. The human-opossum epigenetic clocks are expected to provide a significant boost to the attractiveness of opossum as a biological model. Additional epigenetic clocks for Tasmanian devil, red kangaroos and other species of the genus Macropus may aid species conservation efforts.
- Published
- 2022
47. Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice.
- Author
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Gu, Xiaofeng, Richman, Jeffrey, Langfelder, Peter, Wang, Nan, Zhang, Shasha, Bañez-Coronel, Monica, Wang, Huei-Bin, Yang, Lucia, Ramanathan, Lalini, Deng, Linna, Park, Chang Sin, Choi, Christopher R, Cantle, Jeffrey P, Gao, Fuying, Gray, Michelle, Coppola, Giovanni, Bates, Gillian P, Ranum, Laura PW, Horvath, Steve, Colwell, Christopher S, and Yang, X William
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Neurons ,Chromosomes ,Artificial ,Bacterial ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Huntington Disease ,Disease Models ,Animal ,Nerve Tissue Proteins ,Nuclear Proteins ,Trinucleotide Repeat Expansion ,Huntingtin Protein ,BAC transgenic ,BAC-CAG ,BACHD ,CAG repeat ,HD ,Huntingtin ,Huntington’s disease ,RAN translation ,RNA foci ,RNA-seq ,aggregation ,instability ,knockin ,motor deficits ,muscleblind ,mutant huntingtin ,nuclear inclusions ,polyglutamine ,striatum ,transcriptional dysregulation ,transcriptionopathy ,Rare Diseases ,Genetics ,Neurosciences ,Neurodegenerative ,Biotechnology ,Huntington's Disease ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively.
- Published
- 2022
48. Accelerated epigenetic aging in adolescents living with HIV is associated with altered development of brain structures
- Author
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Hoare, Jacqueline, Stein, Dan J, Heany, Sarah J, Fouche, Jean-Paul, Phillips, Nicole, Er, Sebnem, Myer, Landon, Zar, Heather J, Horvath, Steve, and Levine, Andrew J
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Paediatrics ,Biomedical and Clinical Sciences ,HIV/AIDS ,Biomedical Imaging ,Aging ,Pediatric ,Clinical Research ,Neurosciences ,Behavioral and Social Science ,Brain Disorders ,Neurological ,Good Health and Well Being ,Adolescent ,Brain ,Cross-Sectional Studies ,Diffusion Tensor Imaging ,Epigenesis ,Genetic ,HIV Infections ,Humans ,South Africa ,HIV ,DNA methylation ,Perinatal HIV ,Epigenetic clock ,MRI ,DTI ,Brain imaging ,Clinical Sciences ,Medical Microbiology ,Virology ,Clinical sciences ,Medical microbiology - Abstract
We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12 years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01 years) of the participants was higher than their mean chronological age (10.77 years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ .
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- 2022
49. Epigenetic clock and methylation studies in vervet monkeys.
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Jasinska, Anna J, Haghani, Amin, Zoller, Joseph A, Li, Caesar Z, Arneson, Adriana, Ernst, Jason, Kavanagh, Kylie, Jorgensen, Matthew J, Mattison, Julie A, Wojta, Kevin, Choi, Oi-Wa, DeYoung, Joseph, Li, Xinmin, Rao, Andrew W, Coppola, Giovanni, Freimer, Nelson B, Woods, Roger P, and Horvath, Steve
- Subjects
Animals ,Mammals ,Macaca mulatta ,DNA Methylation ,Epigenesis ,Genetic ,Longevity ,Epigenomics ,Chlorocebus aethiops ,Aging ,DNA methylation ,Development ,Epigenetic clock ,Monkey ,Vervet ,Genetics ,Biotechnology ,Digestive Diseases ,Underpinning research ,1.1 Normal biological development and functioning - Abstract
DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.
- Published
- 2022
50. Hibernation slows epigenetic ageing in yellow-bellied marmots
- Author
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Pinho, Gabriela M, Martin, Julien GA, Farrell, Colin, Haghani, Amin, Zoller, Joseph A, Zhang, Joshua, Snir, Sagi, Pellegrini, Matteo, Wayne, Robert K, Blumstein, Daniel T, and Horvath, Steve
- Subjects
Aging ,Animals ,Epigenesis ,Genetic ,Female ,Hibernation ,Longevity ,Marmota ,Seasons - Abstract
Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor-arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the 'hibernation-ageing hypothesis' whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7-8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation-ageing hypothesis and may explain the enhanced longevity in hibernators.
- Published
- 2022
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