Cells become senescent in response to stress and damage, in response to tissue injury, but most commonly upon reaching the Hayflick limit to replication. A senescent cell ceases to replicate, grows in size, and generates a potent mix of pro-growth, pro-inflammatory signals. Senescent cells are created throughout life in tissues throughout the body, but an established population of lingering senescent cells only begins to accumulate in later life. In youth, the immune system efficiently clears senescent cells, allowing senescence to be a beneficial state in the coordination of regeneration and in drawing the attention of the immune system to potentially cancerous cells. In later life, the immune system falters in this task. An established population of senescent cells that generates signaling constantly, even in relatively small numbers compared to the overall count of cells in a tissue, is highly disruptive to tissue structure and function.
To what degree is the age-related failure of immune clearance of senescent cells a consequence of harmful changes in the immune system versus harmful changes in the senescent cells themselves? This is an interesting and unresolved question, though there is at least some degree of evidence for contributions from both sides. Today's open access paper from a research group with a long history of work on the cellular maintenance processes of autophagy provides evidence for a loss of capacity in chaperone-mediated autophagy in aged senescent cells to induce a loss of chaperone-mediated autophagy in aged innate immune cells, which contributes to the inability of the immune system to efficiently clear senescent cells. In chaperone-mediated autophagy, an target unwanted or damaged protein is bound by a chaperone protein, and that chaperone protein facilitates the entry of the target into a lysosome for disassembly. It is a complex business, and so it seems likely there will be many possible targets for future drug candidates intended to improve this form of autophagy in senescent cells or immune cells.
Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells
Here we focus on the role of chaperone-mediated autophagy (CMA) during establishment, maintenance, and immune resolution of senescence in the aging context. CMA selectively degrades in lysosomes proteins containing a KFERQ-like motif, recognized by the cytosolic chaperone heat shock cognate protein of 71 kDa (HSC70). Substrate delivery to the CMA receptor, the lysosome-associated membrane protein 2A (LAMP2A), triggers its multimerization into a translocation complex for substrate entry into the lysosomal lumen. CMA declines with age in most tissues, and its malfunction is linked to neurodegenerative conditions, metabolic syndrome of aging, and atherosclerosis.
Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic, and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells.
Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
View the full article at FightAging
