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Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease.

Authors :
James EL
Michalek RD
Pitiyage GN
de Castro AM
Vignola KS
Jones J
Mohney RP
Karoly ED
Prime SS
Parkinson EK
Source :
Journal of proteome research [J Proteome Res] 2015 Apr 03; Vol. 14 (4), pp. 1854-71. Date of Electronic Publication: 2015 Feb 26.
Publication Year :
2015

Abstract

Cellular senescence can modulate various pathologies and is associated with irreparable DNA double-strand breaks (IrrDSBs). Extracellular senescence metabolomes (ESMs) were generated from fibroblasts rendered senescent by proliferative exhaustion (PEsen) or 20 Gy of γ rays (IrrDSBsen) and compared with those of young proliferating cells, confluent cells, quiescent cells, and cells exposed to repairable levels of DNA damage to identify novel noninvasive markers of senescent cells. ESMs of PEsen and IrrDSBsen overlapped and showed increased levels of citrate, molecules involved in oxidative stress, a sterol, monohydroxylipids, tryptophan metabolism, phospholipid, and nucleotide catabolism, as well as reduced levels of dipeptides containing branched chain amino acids. The ESM overlaps with the aging and disease body fluid metabolomes, supporting their utility in the noninvasive detection of human senescent cells in vivo and by implication the detection of a variety of human pathologies. Intracellular metabolites of senescent cells showed a relative increase in glycolysis, gluconeogenesis, the pentose-phosphate pathway, and, consistent with this, pyruvate dehydrogenase kinase transcripts. In contrast, tricarboxylic acid cycle enzyme transcript levels were unchanged and their metabolites were depleted. These results are surprising because glycolysis antagonizes senescence entry but are consistent with established senescent cells entering a state of low oxidative stress.

Details

Language :
English
ISSN :
1535-3907
Volume :
14
Issue :
4
Database :
MEDLINE
Journal :
Journal of proteome research
Publication Type :
Academic Journal
Accession number :
25690941
Full Text :
https://doi.org/10.1021/pr501221g