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 findings 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 fibroblasts 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 difficult. An unbiased metabolomic screen of the IrrDSBsen fibroblast ESM also showed differences in the times of initiation and maintenance of different metabolites but generally the ESM altered progressively over the 20 day study period unlike the reported transcriptional profiles. This more detailed analysis of IrrDSBsen identified several new ESM metabolites that are associated with chronological ageing. Targeted analysis of citrate confirmed the dynamic nature of this metabolite in two cell lines and revealed its independence from the senescence effector p16INK4A. These data will aid our understanding of metabolic signatures of ageing and their relationship to cellular senescence and IrrDSBs.
Highlights
The continuous culturing of human cells until they stop proliferating after a variable number of divisions is known as replicative senescence or proliferative exhaustion (PEsen) and is countered by telomerase; an enzyme that maintains the telomere repeats at the ends of chromosomes
The metabolite had to be elevated compared to growing cells in more than one PEsen line but not elevated in quiescent cells induced by serum-starvation or confluence, and elevated in more than one line induced to senesce by irreparable DNA double strand breaks (IrrDSBs) but not elevated in cells with repairable levels of DNA damage[22]
Of the 23 IrrDSBsen metabolites that were not associated with chronological age in vivo 7 were depleted, and would be expected to be inversely associated with human chronological age and of the remaining 16 only 5 were detectable in other screens of IrrDSBsen and PEsen
Summary
The continuous culturing of human cells until they stop proliferating after a variable number of divisions is known as replicative senescence or proliferative exhaustion (PEsen) and is countered by telomerase; an enzyme that maintains the telomere repeats at the ends of chromosomes. In addition to becoming growth arrested, senescent cells secrete an array of molecules known as the senescence-associated secretory phenotype (SASP) that consists of cytokines, growth factors and tissue remodelling enzymes[7]. While these factors are part of the important role played by senescent cells in wound healing[8,9], if present in the wrong context they can cause inflammation and damage to surrounding cells Some of the SASP factors have been shown to spread the senescent phenotype both in vitro and in vivo[11] and so a small number of senescent cells within a tissue can cause more widespread damage. If any anti-senescence therapy is to work, including dietary supplements, biomarkers of their action in the pathologies where senescent cells are suspected to be involved will be required to monitor their effectiveness, and the molecular and cellular basis of these markers will need to be understood
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