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Steve Horvath

Anna K Knight, Jeffrey M Craig, Christiane Theda, Marie Bækvad-Hansen, Jonas Bybjerg-Grauholm, Christine S Hansen, Mads V Hollegaard, David M Hougaard, Preben B Mortensen, Shantel M Weinsheimer, Thomas M Werge, Patricia A Brennan, Joseph F Cubells, D Jeffrey Newport, Zachary N Stowe, Jeanie L Y Cheong, Philippa Dalach, Lex W Doyle, Yuk J Loke, Andrea A Baccarelli, Allan C Just, Robert O Wright, Mara M Téllez-Rojo, Katherine Svensson, Letizia Trevisi, Elizabeth M Kennedy, Elisabeth B Binder, Stella Iurato, Darina Czamara, Katri Räikkönen, Jari M T Lahti, Anu-Katriina Pesonen, Eero Kajantie, Pia M Villa, Hannele Laivuori, Esa Hämäläinen, Hea Jin Park, Lynn B Bailey, Sasha E Parets, Varun Kilaru, Ramkumar Menon, Steve Horvath, Nicole R Bush, Kaja Z LeWinn, Frances A Tylavsky, Karen N Conneely, Alicia K Smith
BACKGROUND: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. RESULTS: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples...
October 7, 2016: Genome Biology
Judith E Carroll, Michael R Irwin, Morgan Levine, Teresa E Seeman, Devin Absher, Themistocles Assimes, Steve Horvath
BACKGROUND: Insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. Cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. A novel method for determining age acceleration using epigenetic methylation to DNA has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality. METHODS: We examined the association of epigenetic age and immune cell aging with sleep in the Women's Health Initiative study (N = 2078; mean 64...
July 26, 2016: Biological Psychiatry
Brian H Chen, Riccardo E Marioni, Elena Colicino, Marjolein J Peters, Cavin K Ward-Caviness, Pei-Chien Tsai, Nicholas S Roetker, Allan C Just, Ellen W Demerath, Weihua Guan, Jan Bressler, Myriam Fornage, Stephanie Studenski, Amy R Vandiver, Ann Zenobia Moore, Toshiko Tanaka, Douglas P Kiel, Liming Liang, Pantel Vokonas, Joel Schwartz, Kathryn L Lunetta, Joanne M Murabito, Stefania Bandinelli, Dena G Hernandez, David Melzer, Michael Nalls, Luke C Pilling, Timothy R Price, Andrew B Singleton, Christian Gieger, Rolf Holle, Anja Kretschmer, Florian Kronenberg, Sonja Kunze, Jakob Linseisen, Christine Meisinger, Wolfgang Rathmann, Melanie Waldenberger, Peter M Visscher, Sonia Shah, Naomi R Wray, Allan F McRae, Oscar H Franco, Albert Hofman, André G Uitterlinden, Devin Absher, Themistocles Assimes, Morgan E Levine, Ake T Lu, Philip S Tsao, Lifang Hou, JoAnn E Manson, Cara L Carty, Andrea Z LaCroix, Alexander P Reiner, Tim D Spector, Andrew P Feinberg, Daniel Levy, Andrea Baccarelli, Joyce van Meurs, Jordana T Bell, Annette Peters, Ian J Deary, James S Pankow, Luigi Ferrucci, Steve Horvath
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality...
September 28, 2016: Aging
Laura Vidal-Bralo, Yolanda Lopez-Golan, Antonio Mera-Varela, Ignacio Rego-Perez, Steve Horvath, Yuhua Zhang, Álvaro Del Real, Guangju Zhai, Francisco J Blanco, Jose A Riancho, Juan J Gomez-Reino, Antonio Gonzalez
Osteoarthritis (OA) is a disease affecting multiple tissues of the joints in the elderly, but most notably articular cartilage. Premature biological aging has been described in this tissue and in blood cells, suggesting a systemic component of premature aging in the pathogenesis of OA. Here, we have explored epigenetic aging in OA at the local (cartilage and bone) and systemic (blood) levels. Two DNA methylation age-measures (DmAM) were used: the multi-tissue age estimator for cartilage and bone; and a blood-specific biomarker for blood...
September 28, 2016: Aging
Christine J Huh, Bo Zhang, Matheus B Victor, Sonika Dahiya, Luis Fz Batista, Steve Horvath, Andrew S Yoo
Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures...
September 20, 2016: ELife
Steve Horvath, Michael Gurven, Morgan E Levine, Benjamin C Trumble, Hillard Kaplan, Hooman Allayee, Beate R Ritz, Brian Chen, Ake T Lu, Tammy M Rickabaugh, Beth D Jamieson, Dianjianyi Sun, Shengxu Li, Wei Chen, Lluis Quintana-Murci, Maud Fagny, Michael S Kobor, Philip S Tsao, Alexander P Reiner, Kerstin L Edlefsen, Devin Absher, Themistocles L Assimes
BACKGROUND: Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors...
August 11, 2016: Genome Biology
Steve Horvath, Peter Langfelder, Seung Kwak, Jeff Aaronson, Jim Rosinski, Thomas F Vogt, Marika Eszes, Richard L M Faull, Maurice A Curtis, Henry J Waldvogel, Oi-Wa Choi, Spencer Tung, Harry V Vinters, Giovanni Coppola, X William Yang
Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls...
July 2016: Aging
Dongcui Li, Raymond Hsu, Brian Figura, Robert Jacobs, Sinan Li, Steve Horvath, Ted Clifford, Krishnan Chari
Nonionic surfactant-activated microgels (SAMs), composed of hydrophobic alkyl acrylates and hydrophilic hydroxyalkyl esters that utilize the effects of surfactant mediated swelling and interaction to provide pH-independent rheological properties, were previously reported as a new pathway to the rheology modification of surfactant solutions. Crosslinking was shown to play an important role in the properties of these soft microgel systems. To understand the impact of crosslinking chemistry on SAM polymers, we have compared two types of SAM polymers: a conventionally crosslinked SAM polymer via allyl pentaerythritol and a novel SAM polymer, where the surface is self-crosslinked via a reactive surfactant...
September 14, 2016: Soft Matter
Morgan E Levine, Ake T Lu, Brian H Chen, Dena G Hernandez, Andrew B Singleton, Luigi Ferrucci, Stefania Bandinelli, Elias Salfati, JoAnn E Manson, Austin Quach, Cynthia D J Kusters, Diana Kuh, Andrew Wong, Andrew E Teschendorff, Martin Widschwendter, Beate R Ritz, Devin Absher, Themistocles L Assimes, Steve Horvath
Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790)...
August 16, 2016: Proceedings of the National Academy of Sciences of the United States of America
Peter Langfelder, Jeffrey P Cantle, Doxa Chatzopoulou, Nan Wang, Fuying Gao, Ismael Al-Ramahi, Xiao-Hong Lu, Eliana Marisa Ramos, Karla El-Zein, Yining Zhao, Sandeep Deverasetty, Andreas Tebbe, Christoph Schaab, Daniel J Lavery, David Howland, Seung Kwak, Juan Botas, Jeffrey S Aaronson, Jim Rosinski, Giovanni Coppola, Steve Horvath, X William Yang
To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients...
April 2016: Nature Neuroscience
Vijayendran Chandran, Giovanni Coppola, Homaira Nawabi, Takao Omura, Revital Versano, Eric A Huebner, Alice Zhang, Michael Costigan, Ajay Yekkirala, Lee Barrett, Armin Blesch, Izhak Michaelevski, Jeremy Davis-Turak, Fuying Gao, Peter Langfelder, Steve Horvath, Zhigang He, Larry Benowitz, Mike Fainzilber, Mark Tuszynski, Clifford J Woolf, Daniel H Geschwind
The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions...
March 2, 2016: Neuron
Donna Lowe, Steve Horvath, Kenneth Raj
A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific DNA methylation changes that occur in function of age...
February 23, 2016: Oncotarget
Candice Sun Hong, Nicholas A Graham, Wen Gu, Carolina Espindola Camacho, Vei Mah, Erin L Maresh, Mohammed Alavi, Lora Bagryanova, Pascal A L Krotee, Brian K Gardner, Iman Saramipoor Behbahan, Steve Horvath, David Chia, Ingo K Mellinghoff, Sara A Hurvitz, Steven M Dubinett, Susan E Critchlow, Siavash K Kurdistani, Lee Goodglick, Daniel Braas, Thomas G Graeber, Heather R Christofk
Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients. Acute MCT1 inhibition reduces pyruvate export but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that co-express MCT1 and MCT4...
February 23, 2016: Cell Reports
Ake T Lu, Eilis Hannon, Morgan E Levine, Ke Hao, Eileen M Crimmins, Katie Lunnon, Alexey Kozlenkov, Jonathan Mill, Stella Dracheva, Steve Horvath
DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the 'epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 × 10(-8)) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). We find that the SNP in 16p13.3 has a cis-acting effect on the expression levels of MLST8 (P=6.9 × 10(-18)) in most brain regions. In cerebellar samples, the SNP in 2p22...
2016: Nature Communications
Andrew J Levine, Austin Quach, David J Moore, Cristian L Achim, Virawudh Soontornniyomkij, Eliezer Masliah, Elyse J Singer, Benjamin Gelman, Natasha Nemanim, Steve Horvath
HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out...
June 2016: Journal of Neurovirology
Morgan E Levine, Ake T Lu, David A Bennett, Steve Horvath
There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer's disease (AD) related cognitive decline, and AD related neuropathological markers...
December 2015: Aging
Steve Horvath, Chiara Pirazzini, Maria Giulia Bacalini, Davide Gentilini, Anna Maria Di Blasio, Massimo Delledonne, Daniela Mari, Beatrice Arosio, Daniela Monti, Giuseppe Passarino, Francesco De Rango, Patrizia D'Aquila, Cristina Giuliani, Elena Marasco, Sebastiano Collino, Patrick Descombes, Paolo Garagnani, Claudio Franceschi
Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock"...
December 2015: Aging
Steve Horvath, Beate R Ritz
It has been a long standing hypothesis that blood tissue of PD Parkinson's disease (PD) patients may exhibit signs of accelerated aging. Here we use DNA methylation based biomarkers of aging ("epigenetic clock") to assess the aging rate of blood in two ethnically distinct case-control data sets. Using n=508 Caucasian and n=84 Hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (IEAA), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (EEAA) which is associated with age dependent changes in blood cell counts...
December 2015: Aging
Andrew J Simpkin, Gibran Hemani, Matthew Suderman, Tom R Gaunt, Oliver Lyttleton, Wendy L Mcardle, Susan M Ring, Gemma C Sharp, Kate Tilling, Steve Horvath, Sonja Kunze, Annette Peters, Melanie Waldenberger, Cavin Ward-Caviness, Ellen A Nohr, Thorkild I A Sørensen, Caroline L Relton, George Davey Smith
DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children...
January 1, 2016: Human Molecular Genetics
Hongmei Duan, Weihong Ge, Aifeng Zhang, Yue Xi, Zhihua Chen, Dandan Luo, Yin Cheng, Kevin S Fan, Steve Horvath, Michael V Sofroniew, Liming Cheng, Zhaoyang Yang, Yi E Sun, Xiaoguang Li
Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI...
October 27, 2015: Proceedings of the National Academy of Sciences of the United States of America
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