Albert Einstein College of Medicine: CMA decline lets senescent cells persist in aged mice
In mouse experiments, age-related loss of chaperone-mediated autophagy impaired macrophage clearance of senescent cells; a CMA-activating compound reduced their burden.
Researchers at the Albert Einstein College of Medicine report in Nature Aging, as described on nature.com, that the age-related decline of chaperone-mediated autophagy (CMA) changes the properties of senescent cells and impairs their immune clearance. The work was done in mouse cells and in mice nature.com
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CMA is a pathway of selective protein degradation in lysosomes. Proteins carrying a KFERQ-like motif are recognized by the chaperone HSC70 and delivered to the receptor LAMP2A. CMA activity falls with age in most tissues.
Aged cells and the secretory phenotype
The authors used ear fibroblasts from 23-month-old and 4-month-old mice. Aged cells were not more senescent at baseline, but could still be driven into senescence with palbociclib. Unlike young cells, they failed to upregulate CMA upon senescence induction.
CMA loss on its own did not induce senescence, but the cells acquired proteomic, metabolic and secretory features resembling those of aged senescent cells. Their senescence-associated secretory phenotype (SASP) had stronger pro-senescence effects on neighboring cells and inhibited CMA in macrophages, according to the authors nature.com
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Macrophages, wound healing and fibrosis
With CMA suppressed, macrophages were less able to engulf senescent cells. The authors link this to defective internalization of phagocytosis-inhibitory receptors. Blocking CMA specifically in macrophages increased the accumulation of senescent cells in mice and delayed the resolution of senescence during wound healing.
The team also tested an experimental compound that activates CMA. Aged mice received it for five months, after which fewer senescent cells were found in several organs, along with reduced signs of inflammation and fibrosis. In a mouse model of pulmonary fibrosis, CMA activation reduced disease severity. In lung tissue from people with idiopathic pulmonary fibrosis, the researchers observed lower activity of the pathway.
The authors conclude that CMA decline is a driver of senescent cell persistence in aged organisms. All interventions described were tested in mice and cell models; the compound is experimental.
