Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing

Aging Cell

Lorna W. Harries¹  Dena Hernandez⁶  William Henley³  Andrew R. Wood¹  Alice C. Holly¹  Rachel M. Bradley-Smith¹  Hanieh Yaghootkar¹  Ambarish Dutta⁴  Anna Murray¹  Timothy M. Frayling¹  Jack M. Guralnik²  Stefania Bandinelli⁵  Andrew Singleton⁶  Luigi Ferrucci⁷ 

[1] Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, UK;Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD 20892-9205, USA;Centre for Health and Environmental Statistics, University of Plymouth, Plymouth PL4 8AA, UK;Epidemiology and Public Health, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, UK;Geriatric Unit, Azienda Sanitaria Firenze, Florence 50125, Italy;Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA;National Institute on Aging, Clinical Research Branch, Harbor Hospital, Baltimore, MD 21225, USA

关键词: aging;    cell senescence;    mRNA processing;    gene expression;    predictive model;   

DOI  :  10.1111/j.1474-9726.2011.00726.x

来源: Wiley

【 摘 要 】

Summary

Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30–104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following-up findings in a replication set (n = 240). We confirmed expression of key results by real-time PCR. Of 16 571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P < 0.002, false discovery rate (FDR) q < 0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland