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nir barzilai

Leland Perice, Nir Barzilai, Joe Verghese, Erica F Weiss, Roee Holtzer, Pinchas Cohen, Sofiya Milman
Mutations that reduce somatotropic signaling result in improved lifespan and health-span in model organisms and humans. However, whether reduced circulating insulin-like growth factor-I (IGF-I) level is detrimental to cognitive and muscle function in older adults remains understudied. A cross-sectional analysis was performed in Ashkenazi Jews with exceptional longevity (age ≥95 years). Cognition was assessed using the Mini-Mental State Examination and muscle function with the chair rise test, grip-strength, and gait speed...
October 14, 2016: Aging
Avishag Laish-Farkash, Sharon Bruoha, Amos Katz, Ilan Goldenberg, Mahmoud Suleiman, Yoav Michowitz, Nir Shlomo, Michal Einhorn-Cohen, Vladimir Khalameizer
AIMS: Cardiac resynchronization therapy (CRT) with a defibrillator (CRT-D) has downsides of high cost and inappropriate shocks compared to CRT without a defibrillator (CRT-P). Recent data suggest that the survival benefit of implantable cardioverter defibrillator (ICD) therapy is attenuated in the older age group. We hypothesized that, among octogenarians eligible for cardiac resynchronization therapy, CRT-P confers similar morbidity and mortality benefits as CRT-D. METHODS AND RESULTS: We compared morbidity and mortality outcomes between consecutive octogenarian patients eligible for CRT therapy who underwent CRT-P implantation at Barzilai MC (n = 142) vs...
October 12, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
John C Newman, Sofiya Milman, Shahrukh K Hashmi, Steve N Austad, James L Kirkland, Jeffrey B Halter, Nir Barzilai
Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use...
August 16, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Derek M Huffman, Jamie N Justice, Michael B Stout, James L Kirkland, Nir Barzilai, Steven N Austad
Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains...
August 16, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Jamie Justice, Jordan D Miller, John C Newman, Shahrukh K Hashmi, Jeffrey Halter, Steve N Austad, Nir Barzilai, James L Kirkland
Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions-a concept dubbed the "geroscience hypothesis." Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging...
August 16, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Christin E Burd, Matthew S Gill, Laura J Niedernhofer, Paul D Robbins, Steven N Austad, Nir Barzilai, James L Kirkland
Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes...
August 16, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Hye J Heo, Jessica N Tozour, Fabien Delahaye, Yongmei Zhao, Lingguang Cui, Nir Barzilai, Francine Hughes Einstein
Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals...
October 2016: Aging Cell
Christian Fuchsberger, Jason Flannick, Tanya M Teslovich, Anubha Mahajan, Vineeta Agarwala, Kyle J Gaulton, Clement Ma, Pierre Fontanillas, Loukas Moutsianas, Davis J McCarthy, Manuel A Rivas, John R B Perry, Xueling Sim, Thomas W Blackwell, Neil R Robertson, N William Rayner, Pablo Cingolani, Adam E Locke, Juan Fernandez Tajes, Heather M Highland, Josee Dupuis, Peter S Chines, Cecilia M Lindgren, Christopher Hartl, Anne U Jackson, Han Chen, Jeroen R Huyghe, Martijn van de Bunt, Richard D Pearson, Ashish Kumar, Martina Müller-Nurasyid, Niels Grarup, Heather M Stringham, Eric R Gamazon, Jaehoon Lee, Yuhui Chen, Robert A Scott, Jennifer E Below, Peng Chen, Jinyan Huang, Min Jin Go, Michael L Stitzel, Dorota Pasko, Stephen C J Parker, Tibor V Varga, Todd Green, Nicola L Beer, Aaron G Day-Williams, Teresa Ferreira, Tasha Fingerlin, Momoko Horikoshi, Cheng Hu, Iksoo Huh, Mohammad Kamran Ikram, Bong-Jo Kim, Yongkang Kim, Young Jin Kim, Min-Seok Kwon, Juyoung Lee, Selyeong Lee, Keng-Han Lin, Taylor J Maxwell, Yoshihiko Nagai, Xu Wang, Ryan P Welch, Joon Yoon, Weihua Zhang, Nir Barzilai, Benjamin F Voight, Bok-Ghee Han, Christopher P Jenkinson, Teemu Kuulasmaa, Johanna Kuusisto, Alisa Manning, Maggie C Y Ng, Nicholette D Palmer, Beverley Balkau, Alena Stancáková, Hanna E Abboud, Heiner Boeing, Vilmantas Giedraitis, Dorairaj Prabhakaran, Omri Gottesman, James Scott, Jason Carey, Phoenix Kwan, George Grant, Joshua D Smith, Benjamin M Neale, Shaun Purcell, Adam S Butterworth, Joanna M M Howson, Heung Man Lee, Yingchang Lu, Soo-Heon Kwak, Wei Zhao, John Danesh, Vincent K L Lam, Kyong Soo Park, Danish Saleheen, Wing Yee So, Claudia H T Tam, Uzma Afzal, David Aguilar, Rector Arya, Tin Aung, Edmund Chan, Carmen Navarro, Ching-Yu Cheng, Domenico Palli, Adolfo Correa, Joanne E Curran, Denis Rybin, Vidya S Farook, Sharon P Fowler, Barry I Freedman, Michael Griswold, Daniel Esten Hale, Pamela J Hicks, Chiea-Chuen Khor, Satish Kumar, Benjamin Lehne, Dorothée Thuillier, Wei Yen Lim, Jianjun Liu, Yvonne T van der Schouw, Marie Loh, Solomon K Musani, Sobha Puppala, William R Scott, Loïc Yengo, Sian-Tsung Tan, Herman A Taylor, Farook Thameem, Gregory Wilson, Tien Yin Wong, Pål Rasmus Njølstad, Jonathan C Levy, Massimo Mangino, Lori L Bonnycastle, Thomas Schwarzmayr, João Fadista, Gabriela L Surdulescu, Christian Herder, Christopher J Groves, Thomas Wieland, Jette Bork-Jensen, Ivan Brandslund, Cramer Christensen, Heikki A Koistinen, Alex S F Doney, Leena Kinnunen, Tõnu Esko, Andrew J Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E Jørgensen, Torben Jørgensen, Claes Ladenvall, Johanne Marie Justesen, Annemari Käräjämäki, Jennifer Kriebel, Wolfgang Rathmann, Lars Lannfelt, Torsten Lauritzen, Narisu Narisu, Allan Linneberg, Olle Melander, Lili Milani, Matt Neville, Marju Orho-Melander, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Amy Swift, Anders H Rosengren, Kathleen Stirrups, Andrew R Wood, Evelin Mihailov, Christine Blancher, Mauricio O Carneiro, Jared Maguire, Ryan Poplin, Khalid Shakir, Timothy Fennell, Mark DePristo, Martin Hrabé de Angelis, Panos Deloukas, Anette P Gjesing, Goo Jun, Peter Nilsson, Jacquelyn Murphy, Robert Onofrio, Barbara Thorand, Torben Hansen, Christa Meisinger, Frank B Hu, Bo Isomaa, Fredrik Karpe, Liming Liang, Annette Peters, Cornelia Huth, Stephen P O'Rahilly, Colin N A Palmer, Oluf Pedersen, Rainer Rauramaa, Jaakko Tuomilehto, Veikko Salomaa, Richard M Watanabe, Ann-Christine Syvänen, Richard N Bergman, Dwaipayan Bharadwaj, Erwin P Bottinger, Yoon Shin Cho, Giriraj R Chandak, Juliana C N Chan, Kee Seng Chia, Mark J Daly, Shah B Ebrahim, Claudia Langenberg, Paul Elliott, Kathleen A Jablonski, Donna M Lehman, Weiping Jia, Ronald C W Ma, Toni I Pollin, Manjinder Sandhu, Nikhil Tandon, Philippe Froguel, Inês Barroso, Yik Ying Teo, Eleftheria Zeggini, Ruth J F Loos, Kerrin S Small, Janina S Ried, Ralph A DeFronzo, Harald Grallert, Benjamin Glaser, Andres Metspalu, Nicholas J Wareham, Mark Walker, Eric Banks, Christian Gieger, Erik Ingelsson, Hae Kyung Im, Thomas Illig, Paul W Franks, Gemma Buck, Joseph Trakalo, David Buck, Inga Prokopenko, Reedik Mägi, Lars Lind, Yossi Farjoun, Katharine R Owen, Anna L Gloyn, Konstantin Strauch, Tiinamaija Tuomi, Jaspal Singh Kooner, Jong-Young Lee, Taesung Park, Peter Donnelly, Andrew D Morris, Andrew T Hattersley, Donald W Bowden, Francis S Collins, Gil Atzmon, John C Chambers, Timothy D Spector, Markku Laakso, Tim M Strom, Graeme I Bell, John Blangero, Ravindranath Duggirala, E Shyong Tai, Gilean McVean, Craig L Hanis, James G Wilson, Mark Seielstad, Timothy M Frayling, James B Meigs, Nancy J Cox, Rob Sladek, Eric S Lander, Stacey Gabriel, Noël P Burtt, Karen L Mohlke, Thomas Meitinger, Leif Groop, Goncalo Abecasis, Jose C Florez, Laura J Scott, Andrew P Morris, Hyun Min Kang, Michael Boehnke, David Altshuler, Mark I McCarthy
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups...
August 4, 2016: Nature
Ling-Shiang Chuang, Nicole Villaverde, Ken Y Hui, Arthur Mortha, Adeeb Rahman, Adam P Levine, Talin Haritunians, Sok Meng Evelyn Ng, Wei Zhang, Nai-Yun Hsu, Jody-Ann Facey, Tramy Luong, Heriberto Fernandez-Hernandez, Dalin Li, Manuel Rivas, Elena R Schiff, Alexander Gusev, L Phillip Schumm, Beatrice M Bowen, Yashoda Sharma, Kaida Ning, Romain Remark, Sacha Gnjatic, Peter Legnani, James George, Bruce E Sands, Joanne M Stempak, Lisa W Datta, Seth Lipka, Seymour Katz, Adam S Cheifetz, Nir Barzilai, Nikolas Pontikos, Clara Abraham, Marla J Dubinsky, Stephan Targan, Kent Taylor, Jerome I Rotter, Ellen J Scherl, Robert J Desnick, Maria T Abreu, Hongyu Zhao, Gil Atzmon, Itsik Pe'er, Subra Kugathasan, Hakon Hakonarson, Jacob L McCauley, Todd Lencz, Ariel Darvasi, Vincent Plagnol, Mark S Silverberg, Aleixo M Muise, Steven R Brant, Mark J Daly, Anthony W Segal, Richard H Duerr, Miriam Merad, Dermot P B McGovern, Inga Peter, Judy H Cho
BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB)...
October 2016: Gastroenterology
Khadija Ismail, Lisa Nussbaum, Paola Sebastiani, Stacy Andersen, Thomas Perls, Nir Barzilai, Sofiya Milman
OBJECTIVES: To determine, in a sample of Ashkenazi Jewish aged 95 and older, whether there is a compression of morbidity similar to what has been reported in other cohorts with exceptional longevity. DESIGN: Case-control study. SETTING: Longevity Genes Project (LGP) and New England Centenarian Study (NECS). PARTICIPANTS: LGP (n = 439, mean age 97.8 ± 2.8) and NECS (n = 1,498, mean age 101.4 ± 4.0) participants with exceptional longevity and their respective younger referent cohorts (LGP, n = 696; NECS, n = 302)...
August 2016: Journal of the American Geriatrics Society
Michele L Callisaya, Emmeline Ayers, Nir Barzilai, Luigi Ferrucci, Jack M Guralnik, Richard B Lipton, Petr Otahal, Velandai K Srikanth, Joe Verghese
BACKGROUND: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. OBJECTIVES: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. METHODS: Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability...
June 18, 2016: Journal of Alzheimer's Disease: JAD
Nir Barzilai, Jill P Crandall, Stephen B Kritchevsky, Mark A Espeland
Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
June 14, 2016: Cell Metabolism
Sofiya Milman, Derek M Huffman, Nir Barzilai
Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life- and healthspan across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicate that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases...
June 14, 2016: Cell Metabolism
Yun Freudenberg-Hua, Wentian Li, Avinash Abhyankar, Vladimir Vacic, Vanessa Cortes, Danny Ben-Avraham, Jeremy Koppel, Blaine Greenwald, Soren Germer, Robert B Darnell, Nir Barzilai, Jan Freudenberg, Gil Atzmon, Peter Davies
We compared coding region variants of 53 cognitively healthy centenarians and 45 patients with Alzheimer's disease (AD), all of Ashkenazi Jewish (AJ) ancestry. Despite the small sample size, the known AD risk variant APOE4 reached genome-wide significance, indicating the advantage of utilizing "super-controls". We restricted our subsequent analysis to rare variants observed at most once in the 1000 Genomes database and having a minor allele frequency below 2% in our AJ sample. We compared the burden of predicted protein altering variants between cases and controls as normalized by the level of rare synonymous variants...
June 3, 2016: Human Molecular Genetics
Delnaz Roshandel, Ronald Klein, Barbara E K Klein, Bruce H R Wolffenbuttel, Melanie M van der Klauw, Jana V van Vliet-Ostaptchouk, Gil Atzmon, Danny Ben-Avraham, Jill P Crandall, Nir Barzilai, Shelley B Bull, Angelo J Canty, S Mohsen Hosseini, Linda T Hiraki, John Maynard, David R Sell, Vincent M Monnier, Patricia A Cleary, Barbara H Braffett, Andrew D Paterson
Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)...
July 2016: Diabetes
Henry Brodaty, Claudia Woolf, Stacy Andersen, Nir Barzilai, Carol Brayne, Karen Siu-Lan Cheung, Maria M Corrada, John D Crawford, Catriona Daly, Yasuyuki Gondo, Bo Hagberg, Nobuyoshi Hirose, Henne Holstege, Claudia Kawas, Jeffrey Kaye, Nicole A Kochan, Bobo Hi-Po Lau, Ugo Lucca, Gabriella Marcon, Peter Martin, Leonard W Poon, Robyn Richmond, Jean-Marie Robine, Ingmar Skoog, Melissa J Slavin, Jan Szewieczek, Mauro Tettamanti, José Viña, Thomas Perls, Perminder S Sachdev
BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population...
2016: BMC Neurology
Laura J Cobb, Changhan Lee, Jialin Xiao, Kelvin Yen, Richard G Wong, Hiromi K Nakamura, Hemal H Mehta, Qinglei Gao, Carmel Ashur, Derek M Huffman, Junxiang Wan, Radhika Muzumdar, Nir Barzilai, Pinchas Cohen
Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action...
April 2016: Aging
Michal Marzec, Colin P Hawkes, Davide Eletto, Sarah Boyle, Ron Rosenfeld, Vivian Hwa, Jan M Wit, Hermine A van Duyvenvoorde, Wilma Oostdijk, Monique Losekoot, Oluf Pedersen, Bu Beng Yeap, Leon Flicker, Nir Barzilai, Gil Atzmon, Adda Grimberg, Yair Argon
IGFs are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that the production of IGF-1 and IGF-2 requires interaction with the chaperone glucose-regulated protein 94 (GRP94) and that the amount of secreted IGFs is proportional to the GRP94 activity. Therefore, we tested the hypothesis that functional polymorphisms of human GRP94 affect IGF production and thereby human health. We describe a hypomorphic variant of human GRP94, P300L, whose heterozygous carriers have 9% lower circulating IGF-1 concentration...
May 2016: Endocrinology
Seungjin Ryu, Gil Atzmon, Nir Barzilai, Nalini Raghavachari, Yousin Suh
Apolipoprotein E (APOE) gene has been the most replicated longevity-associated gene in humans. Two common APOE alleles are either significantly depleted (ε4 allele) or enriched (ε2 allele) in long-lived individuals as compared to controls. We performed high-throughput sequencing analysis of exons and 2kb proximal promoter of APOE in 450 centenarians and 500 controls of Ashkenazi Jewish decent. We found two common regulatory variants, rs405509 (p=0.006) and rs769449 (p=0.036), that were significantly depleted in centenarians...
April 2016: Mechanisms of Ageing and Development
Kristen Fortney, Edgar Dobriban, Paolo Garagnani, Chiara Pirazzini, Daniela Monti, Daniela Mari, Gil Atzmon, Nir Barzilai, Claudio Franceschi, Art B Owen, Stuart K Kim
We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population...
December 2015: PLoS Genetics
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