Kyoto, Japan -- Aged and frail people often suffer a decline in tissue reserve capacity during aging. This reserve, called resilience, helps the body maintain homeostasis through various defense, compensation, modulation, and repair responses. When resilience is impaired, elderly people tend to experience a gradual waning of their daily activity and an increase in multimorbidity, or dealing with multiple chronic illnesses.
One major cause of resilience decline is an increase in senescent cells that have stopped dividing. The human body has a natural mechanism for eliminating these cells called senolysis, but as we age this 'clearing' mechanism becomes less efficient.
Senescent cells exert harmful effects through the senescence-associated secretory phenotype, or SASP: the release of pro-inflammatory molecules that can adversely affect surrounding cells. This leads to chronic inflammation and age-related diseases, partly explaining why elderly people suffer impaired resilience. Yet how metabolic resilience is involved in survival capacity and SASP has remained unclear.
These questions motivated a team of researchers at Kyoto University to investigate the mechanisms behind senescent cells. The scientists noticed that the cells tend to have enhanced glycolysis, the breakdown of glucose into energy, which is also a common feature of cancer cells. They then focused on the enzymes glycolytic phosphoglycerate mutase, or PGAM, and Chk1 kinase, which bind in cancer cells to increase glycolysis.
To evaluate the interaction between PGAM and Chk1 in senescent cells, the team established a NanoBiT assay, which uses bioluminescence to detect protein interactions. They observed that PGAM-Chk1 binding is enhanced in senescent cells to support glycolysis and the cells' viability. This enabled the team to alleviate lung fibrosis in mice, demonstrating that the inhibition of this binding can efficiently induce senolysis both in vitro and in vivo.
The team also found that the transcription factor FoxM1, a crucial driver of the cell cycle, is a target of the PGAM-Chk1 binding. The team discovered that the FoxM1 protein suppresses the protein BIM, which induces apoptosis, or cell self-destruction, and that FoxM1 also induces DNA repair machinery in senescent cells. Therefore, targeting the binding that prevents FoxM1 from carrying out these tasks could help prevent a decline in resilience.
Eventually, the results of this study could be applicable clinically in senotherapy, which employs novel strategies to target aging-related diseases. In particular, this approach could contribute to senolytics, which focuses on eliminating senescent cells through the use of senolytic drugs, inducing apoptosis of senescent cells.
"Our findings in glycolytic regulation suggest that impaired metabolic resilience in aging is one of the targets for senotherapy, to aid in preservation of resilience in aging," says corresponding author Hiroshi Kondoh.
