Lysosomes in senescence and aging

Abstract

Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age-related diseases and potentially for aging itself.

Keywords: LYPAS; age-related disease; autophagy; lysosomal quality control; senescence.

Figure 1. The lysosomal processing and adaptation system (LYPAS)

Lysosomal function is maintained by the entire LYPAS depicted here as 12 integrated components within five major categories. All LYPAS components are critical for the proper function of lysosomes. Upregulating lysosomal activity involves the coordinated mobilization of various LYPAS components. Graphics were created with BioRender.com.

Figure 2. Diverse cellular stresses trigger LYPAS upregulation

The components of the LYPAS are upregulated in response to many different types of cellular stresses. (1) Regulation of mTORC1 activity by various stressors modulates the level of substrate delivery and lysosomal capacity through autophagy and TFEB activation. (2) Ca²⁺ signaling provides another common stress‐induced signal that activates many downstream effectors in autophagy initiation, TFEB activation, lysosomal acidification, and lysosomal repair pathways including ESCRT and PITT. (3) Cytosolic DNA exposure is a common stress response signal that activates non‐canonical autophagy as well as SASP through the cGAS/STING pathway of DNA sensing. CMA, one of the lysosomal substrate delivery mechanisms, is also activated as part of a stress response potentially by protein misfolding. Graphics were created with BioRender.com.

Figure 3. A lysosomal‐centric model of senescence and cell death—LYPAS overload in senescence induction

(A) Cellular stress triggers LYPAS upregulation to process an increase in damaged macromolecules caused by stress. (1) Cellular stresses are resolved without senescence induction when the substrate processing capacity of the upregulated LYPAS is above the substrate‐producing (macromolecule‐damaging) level. Upon stress clearance, the LYPAS is returned to its basal level. (2) Senescence is induced when higher levels of persistent cellular stress causes LYPAS overload which cannot be resolved effectively, causing a permanent cell cycle arrest with potential progression to LYPAS exhaustion. Persistent damage continues to cause more macromolecule damage, leading to damage accumulation and gradual dysfunction of expanded lysosomes. (3) LYPAS exhaustion breaks the equilibration in senescence and causes cell death. In some situations, the cellular stress directly causes LYPAS exhaustion and thus causes cell death without a detectable senescence stage. (B) Distinctive feature of LYPAS overload in senescence versus the lysosomal overload observed in lysosomal storage disease (LSD). Graphics were created with BioRender.com.

Figure 4. Boosting the capacity of the lysosomal processing and adaptation system for disease treatment and healthy aging

(A) An illustration of the relationship between LYPAS capacity and age in different contexts. (B) Schematic graph showing the relationship between cell fate and stress‐related LYPAS substrate loading in high or low LYPAS capacity individuals. (C) Strategies to potentially boost LYPAS capacity for treating disease and promoting healthy aging. Green arrows indicate strategies that can boost the LYPAS capacity, thereby shifting the curves in (A) and (B) rightward. Graphics were created with BioRender.com.