The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults
The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults
Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.
Aged, Biomarkers, Female, Humans, Insulin Resistance/genetics, MicroRNAs/genetics, Muscles/metabolism, Piwi-Interacting RNA, RNA, Small Untranslated/genetics, RNA, Transfer/genetics, Sarcopenia/genetics, ageing, noncoding RNA, epigenetics, HOMA2-IR, serum, insulin resistance, sarcopenia
Burton, Mark
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Antoun, Elie
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Garratt, Emma S.
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Westbury, Leo
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Dennison, Elaine M.
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Harvey, Nicholas C.
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Cooper, Cyrus
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Patel, Harnish P.
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Godfrey, Keith M.
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Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
15 February 2024
Burton, Mark
250319ad-90dc-4651-b118-d5dbe5eaafa6
Antoun, Elie
23e4ee54-9652-41cd-9eb0-066cfcc598c9
Garratt, Emma S.
66ddd4cb-19a2-4d08-889b-12f418e6878b
Westbury, Leo
5ed45df3-3df7-4bf9-bbad-07b63cd4b281
Dennison, Elaine M.
ee647287-edb4-4392-8361-e59fd505b1d1
Harvey, Nicholas C.
ce487fb4-d360-4aac-9d17-9466d6cba145
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Patel, Harnish P.
e1c0826f-d14e-49f3-8049-5b945d185523
Godfrey, Keith M.
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burton, Mark, Antoun, Elie, Garratt, Emma S., Westbury, Leo, Dennison, Elaine M., Harvey, Nicholas C., Cooper, Cyrus, Patel, Harnish P., Godfrey, Keith M. and Lillycrop, Karen A.
(2024)
The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.
The FASEB Journal, 38 (3), [e23423].
(doi:10.1096/fj.202301089RR).
Abstract
Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.
Text
The FASEB Journal - 2024 - Burton - The serum small non‐coding RNA SncRNA landscape as a molecular biomarker of age
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Accepted/In Press date: 29 December 2023
e-pub ahead of print date: 31 January 2024
Published date: 15 February 2024
Additional Information:
Funding Information:
This work was supported by grant funding from the Medical Research Council (MC_U47585827, MC_ST_U2055, MC_PC_21003; MC_PC_21001), Arthritis Research UK, Royal Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, NIHR Southampton Biomedical Research Centre, University of Southampton, and University Hospital Southampton NHS Foundation Trust, NIHR Musculoskeletal Biomedical Research Unit, and University of Oxford. KAL is supported by the Rosetrees Trust, Wessex Medical Trust, Gerald kerkut Trust and Rank Prize K.M.G. is supported by the UK Medical Research Council (MC_UU_20/4), the US National Institute On Aging of the National Institutes of Health (award number U24AG047867), the UK Economic and Social Research Council and the Biotechnology and Biological Sciences Research Council (award number ES/M0099X/), the National Institute for Health Research (as an NIHR Senior Investigator (NF‐SI‐055‐0042)), and through the NIHR Southampton Biomedical Research Centre, and the European Union's Erasmus + Capacity‐Building ImpENSA Project. H.P.P. is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre. This report is independent research, and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The grant funders had no role in the design, collection, analysis, and interpretation of data, writing of the paper, or decision to submit for publication.
For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission.
Keywords:
Aged, Biomarkers, Female, Humans, Insulin Resistance/genetics, MicroRNAs/genetics, Muscles/metabolism, Piwi-Interacting RNA, RNA, Small Untranslated/genetics, RNA, Transfer/genetics, Sarcopenia/genetics, ageing, noncoding RNA, epigenetics, HOMA2-IR, serum, insulin resistance, sarcopenia
Identifiers
Local EPrints ID: 486800
URI: http://eprints.soton.ac.uk/id/eprint/486800
ISSN: 0892-6638
PURE UUID: 597c85cd-8013-4fcb-9c9d-9d6d8fe81fcf
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Date deposited: 06 Feb 2024 17:41
Last modified: 18 Mar 2024 03:28
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Contributors
Author:
Elie Antoun
Author:
Emma S. Garratt
Author:
Harnish P. Patel
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