A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

Crossland, Hannah; Sood, Sanjana; PHILLIPS, BETH; Gallagher, Iain J.; ATHERTON, PHILIP; Lunnon, Katie; Rullman, Eric; Keohane, Aoife; Cederholm, Tommy; Jensen, Thomas; JC van Loon, Luc; Lannfelt, Lars; Kraus, William E.; Howard, Robert; Gustafsson, Thomas; Timmons, Angela Hodges and James A.

Abstract

Background
Diagnostics 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.

Results
One 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.

Conclusions
We 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.

Citation

Crossland, H., Sood, S., PHILLIPS, B., Gallagher, I. J., ATHERTON, P., Lunnon, K., Rullman, E., Keohane, A., Cederholm, T., Jensen, T., JC van Loon, L., Lannfelt, L., Kraus, W. E., Howard, R., Gustafsson, T., & Timmons, A. H. A. J. A. (2015). A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status. Genome Biology, 16(1), 1-17. https://doi.org/10.1186/s13059-015-0750-x

• Journal Article Type: Article
• Acceptance Date: Aug 12, 2015
• Online Publication Date: Sep 7, 2015
• Publication Date: Sep 7, 2015
• Deposit Date: Sep 6, 2018
• Publicly Available Date: Aug 8, 2019
• Print ISSN: 1474-760X
• Electronic ISSN: 1465-6906
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 1
• Article Number: 185
• Pages: 1-17
• DOI: https://doi.org/10.1186/s13059-015-0750-x
• Public URL: https://nottingham-repository.worktribe.com/output/1111007
• Publisher URL: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-015-0750-x
• Related Public URLs: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84940877487&partnerID=40&md5=773d886d48dc13077d55444a7dabfd0e
• Additional Information: The Correspondence to this article has been published in Genome Biology 2019 20:152
• Contract Date: Aug 8, 2019