Abstract
BackgroundDiagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health.ResultsOne hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83–0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is ‘up-regulated’ in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case–control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA ‘disease signature’, the healthy ageing RNA classifier is diagnostic for AD.ConclusionsWe identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0750-x) contains supplementary material, which is available to authorized users.
Highlights
Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age
Identification of a reproducible RNA signature for age of human muscle, brain and skin Our objective was to discover a pattern of RNA expression that could be reliably used as a biomarker for ‘health status’ in older subjects — one that differed substantially in terms of ability to stratify health, and one that was more informative than chronological age
We selected muscle tissue genechip profiles from 15 sedentary young and 15 sedentary older subjects with good aerobic fitness (Gene Expression Omnibus (GEO) accession [GSE59880]) [31, 44] and who were free of diabetes [42, 44]
Summary
Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. It is anticipated that novel genomic diagnostics that predict future health risks will help guide targeted preventative measures and enable the evaluation of individualized treatment strategies for many prevalent diseases of older age. Use of individual molecular biomarkers in healthy populations has offered modest performance [1, 2] compared with traditional, more integrated disease markers (e.g., blood pressure) or chronological age [3]. Sood et al Genome Biology (2015) 16:185 humans, we hypothesized that a molecular profile may be useful at distinguishing people at risk for a variety of age-related diseases. There is a pressing need to stratify the older healthy population, using simple and costeffective methods, to, for example, identify those appropriate to enrich clinical trials of novel AD treatments. The candidate AD marker proteins included cytokines and other markers of metabolic or cardiovascular disease [27] and these will not be clinically specific for AD when applied to older populations [28]
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