The lysosomal proteome of senescent cells contributes to the senescence secretome

Abstract

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Autophagy orchestrates the crosstalk between cells and organs

“…As such, autophagy can be regarded as having cytokine-and vesicle-secreting and nutrient-generating roles, shaping cell fate decisions, tissue microenvironment, and supporting systemic metabolic well-being. Notably, lysosomal exocytosis is an alternative pathway to secretory autophagy and obviously autophagy contributes to lysosomal content (Martins et al, 2014;Rovira et al, 2022). In the future, it will be even more important to clearly differentiate the contribution of the two pathways to the secretion of autophagosomal cargo versus lysosomal Currently known mechanistic insights into lysosomal exocytosis would be valuable for a further discussion in a separate review.…”

The Skin Microbiome: Current Landscape and Future Opportunities

“…Cellular senescence is a mechanism whereby cells undergo transient or permanent cessation of proliferative capacity in response to intrinsic and/or extrinsic stressors linked to the ageing process, such as DNA damage, oxidative stress, mitochondrial dysfunction, inflammation and telomere shortening [ 150 ]. Senescent cells remain viable yet have significant metabolic and genetic alterations compared to their non-senescent counterparts, including the reorganisation of chromatin [ 151 ], increased lysosomal activity [ 152 , 153 ] and activation of a DNA damage response [ 154 ]. The central dogma is that senescence evolved to suppress tumours in young organisms by preventing neoplastic growth [ 155 ].…”

Lysosomes in senescence and aging

“…Senescence induction by telomere shortening stimulates augmented expression of LAMP1, the autophagy proteins ATG5 and ATG12, increased LC3 lipidation, and a simultaneous reduction in the level of the autophagy adaptor p62 (Zlotorynski, 2019). Although overall LAMP2A levels are reduced with age (Cuervo & Dice, 2000a), in multiple in vitro models, LAMP2A expression is dramatically increased after senescence induction (Rovira et al , 2022), consistent with higher CMA activity in these senescent cells. Due to their higher lysosomal degradation activity (Basisty et al , 2020), senescent cells are also likely more vulnerable to lysosomal inhibition and therefore more dependent on rapid lysosomal repair pathways (e.g.…”

“…Depending on the level of cellular damages, cellular stresses may either be resolved or otherwise trigger senescence and/or cell death. Senescence inducers typically stimulate higher lysosomal degradative activity including substrates delivered by endocytosis, macroautophagy, and CMA (Ha et al , 2021; Rovira et al , 2022). Senescence induction by telomere shortening stimulates augmented expression of LAMP1, the autophagy proteins ATG5 and ATG12, increased LC3 lipidation, and a simultaneous reduction in the level of the autophagy adaptor p62 (Zlotorynski, 2019).…”

“…In such contexts, disruption of RagC/D‐mediated TFEB loading to mTORC1 is emerging as a major mechanism underlying TFEB activation (Goodwin et al , 2021; Malik et al , 2023). Even when canonical mTORC1 signaling is hyperactivated such as in senescent cells (Herranz et al , 2015; Laberge et al , 2015; Carroll et al , 2017), TFEB can still be highly activated for profound lysosomal expansion (Rovira et al , 2022; Curnock et al , 2023). Thus, downstream of various cellular stresses, modification of mTORC1 signaling leads to upregulation of multiple aspects of LYPAS including macroautophagy, lysosomal biogenesis, and V‐ATPase‐mediated lysosomal acidification.…”