Cells become senescent constantly throughout life. A senescent cell ceases replication, increases in size, and generates disruptive inflammatory signaling. In youth those senescent cells that fail to undergo programmed cell death are removed by the immune system, but this clearance falters with advancing age. The result is a growing burden of senescent cells that disrupt tissue structure and function, contributing to age-related conditions. The research community is thus very interested in finding ways to selectively remove senescent cells, particularly given the evidence for rejuvenation to result from senescent cell clearance in aged mice.
The metabolism of senescent cells is very different from that of normal cells. Unlike normal cells they are primed to undergo programmed cell death, but held back by a range of mechanisms. Sabotage the those mechanisms and a senescent cell dies, but a normal cell is largely unaffected. This is far from the only possible approach to the problem, and new approaches are discovered on a fairly regular basis. Today's open access paper focuses on the regulation of increased glycolysis as an energy source in senescent cells, analogous to the Warburg effect observed in cancer cells. A senescent cell has sizable energy needs, given its activities and size. If this regulation of glycolysis is sabotaged, the senescent cell can no longer support itself and dies.
Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a non-cell autonomous manner.
This pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses pro-apoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.
Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.
View the full article at FightAging
