The induction of the fibroblast extracellular senescence metabolome is a dynamic process
Author(s)
James, Emma NL
Bennett, Mark H
Parkinson, E Kenneth
Type
Journal Article
Abstract
Cellular senescence is often associated with irreparable DNA double strand breaks (IrrDSBs) which
accumulate with chronological age (IrrDSBsen). The removal of senescent cells ameliorates several
age-related diseases in mice but the translation of these fndings into a clinical setting would be aided
by the characterisation of non-invasive biomarkers of senescent cells. Several serum metabolites
are independent indicators of chronological age and some of these accumulate outside senescent
fbroblasts independently of cell cycle arrest, repairable DNA breaks and cell size (the extracellular
senescence metabolome, or ESM). The post-mitotic phase of senescence is dynamic, making the
detection of senescent cells in vivo difcult. An unbiased metabolomic screen of the IrrDSBsen fbroblast
ESM also showed diferences in the times of initiation and maintenance of diferent metabolites but
generally the ESM altered progressively over the 20 day study period unlike the reported transcriptional
profles. This more detailed analysis of IrrDSBsen identifed several new ESM metabolites that are
associated with chronological ageing. Targeted analysis of citrate confrmed the dynamic nature of
this metabolite in two cell lines and revealed its independence from the senescence efector p16INK4A.
These data will aid our understanding of metabolic signatures of ageing and their relationship to cellular
senescence and IrrDSBs.
accumulate with chronological age (IrrDSBsen). The removal of senescent cells ameliorates several
age-related diseases in mice but the translation of these fndings into a clinical setting would be aided
by the characterisation of non-invasive biomarkers of senescent cells. Several serum metabolites
are independent indicators of chronological age and some of these accumulate outside senescent
fbroblasts independently of cell cycle arrest, repairable DNA breaks and cell size (the extracellular
senescence metabolome, or ESM). The post-mitotic phase of senescence is dynamic, making the
detection of senescent cells in vivo difcult. An unbiased metabolomic screen of the IrrDSBsen fbroblast
ESM also showed diferences in the times of initiation and maintenance of diferent metabolites but
generally the ESM altered progressively over the 20 day study period unlike the reported transcriptional
profles. This more detailed analysis of IrrDSBsen identifed several new ESM metabolites that are
associated with chronological ageing. Targeted analysis of citrate confrmed the dynamic nature of
this metabolite in two cell lines and revealed its independence from the senescence efector p16INK4A.
These data will aid our understanding of metabolic signatures of ageing and their relationship to cellular
senescence and IrrDSBs.
Date Issued
2018-08-14
Date Acceptance
2018-07-17
Citation
SCIENTIFIC REPORTS, 2018, 8, pp.1-14
ISSN
2045-2322
Publisher
NATURE PUBLISHING GROUP
Start Page
1
End Page
14
Journal / Book Title
SCIENTIFIC REPORTS
Volume
8
Copyright Statement
© Te Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Identifier
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Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
AMINO-ACID-METABOLISM
DNA-DAMAGE
REPLICATIVE SENESCENCE
TRIGGERS SENESCENCE
CELLULAR SENESCENCE
LIFE-SPAN
CELLS
P16(INK4A)
INVOLVEMENT
TELOMERASE
Publication Status
Published
Article Number
ARTN 12148
Date Publish Online
2018-08-14