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.

Persister cancer cells are characterized by H4K20me3 heterochromatin that defines a low inflammatory profile

“…To further extend the comparison between persister/diapause-like and senescent cancer cells, we analyzed cellular features that have been previously described as hallmarks of senescence. Senescent cells are characterized by an increased lysosomal content and this is also reflected in high levels of the lysosomal enzyme β-galactosidase (SA-β-GAL) 11,12,51,52 . Both persister/diapause-like and senescent cancer cells showed increased lysosomal mass ( Figures 2E, S2D-E ), but only senescent cells had increased SA-β-GAL activity ( Figure 2F and S2G ).…”

“…Among the common traits between senescent and persister/diapause-like cancer cells is the expansion of the lysosomal compartment, which is likely attributable to an increased autophagic activity 11,75 . Interestingly, the senescence-associated β-galactosidase activity (SA-β-GAL) which is a lysosomal enzyme detected at a sub-optimal pH in senescent cells was absent persister cells, therefore disconnecting lysosomal expansion from SA-β-GAL.…”

“…Extensive research on senescence has identified a number of cellular and molecular features frequently present in this form of cell cycle arrest 8,9 . These include morphological alterations of the cytoplasm that becomes flattened and larger 10 , expansion of the lysosomal compartment 11 associated to increased activity of the enzyme β-galactosidase 12 , high levels of reactive oxygen species (ROS) 13 , and significant alterations in chromatin structure, characterized by the loss of Lamin B1 (LMNB1) from the nuclear envelope and the formation of senescence-associated heterochromatin foci (SAHF) 14–16 . Senescent cells are also characterized by the senescence-associated secretory phenotype (SASP), which is composed of a complex and dynamic mixture of cytokines, chemokines, and matrix remodeling proteins 17,18 .…”

Human Skin Aging and the Anti-Aging Properties of Retinol

“…Three distinct types of autophagy exist: macroautophagy, microautophagy, and chaperone-mediated autophagy. In the process of organismal aging, autophagy and various other lysosomal transport pathways demonstrate diminished activity [43][44][45]. The skin, being an organ with limited access to nutrients, relies on autophagy to preserve its scarce resources and maintain homeostasis.…”

Multiplexed DNA-PAINT Imaging of the Heterogeneity of Late Endosome/Lysosome Protein Composition

“…However, our current understanding has significantly advanced beyond this historical view, revealing lysosomes as much more dynamic organelles that regulate nutrient sensing, metabolic signaling, membrane repair and several other cellular processes (Lawrence and Zoncu, 2019; Reddy et al, 2001; Settembre et al, 2013; Trivedi et al, 2020) . Additionally, lysosomes are increasingly implicated in numerous neurodegenerative diseases and the aging process (Chen et al, 2019; Malik et al, 2019; Settembre et al, 2013; Tan and Finkel, 2023; Udayar et al, 2022). Given their emerging importance beyond the canonical degradative function, a more in-depth knowledge of lysosomal homeostasis will enable a better understanding of their vital roles in both health and disease.…”