Lysosomal control of senescence and inflammation through cholesterol partitioning

Roh, Kyeonghwan; Noh, Jeonghwan; Kim, Yeonju; Jang, Yeji; Kim, Jaejin; Choi, Haebeen; Lee, Yeonghyeon; Ji, Moongi; Kang, Dong‐Hyun; Kim, Mi-Sung; Paik, Man‐Jeong; Chung, Jongkyeong; Kim, Jin Hong; Kang, Chanhee

doi:10.1038/s42255-023-00747-5

Cited by 47 publications

(28 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ceramides, a common class of sphingolipids, accumulate in aging muscle and reduce its function, impacting the functional capacity of older adults. − Dysregulation of cholesterol metabolism. Senescent cells pile up cholesterol in the lysosomes to support the senescence-associated secretory phenotype (SASP) …”

Section: Mechanisms and Physiology Of Agingmentioning

confidence: 99%

See 1 more Smart Citation

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

Tenchov,

Sasso,

Wang

et al. 2023

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, ageassociated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.

show abstract

Section: Mechanisms and Physiology Of Agingmentioning

confidence: 99%

“…Dysregulation of cholesterol metabolism. Senescent cells pile up cholesterol in the lysosomes to support the senescence-associated secretory phenotype (SASP) …”

Section: Mechanisms and Physiology Of Agingmentioning

confidence: 99%

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

Tenchov,

Sasso,

Wang

et al. 2023

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Elevated lysosomal substrate delivery and hydrolytic breakdown generate higher levels of intracellular amino acids, which, in turn, supports constant activation of the mTORC1 nutrient‐sensing complex (Herranz et al , 2015; Laberge et al , 2015; Carroll et al , 2017), consistent with increased lysosomal association of mTORC1 in senescence (Narita et al , 2011; Rovira et al , 2022). Multiple senescence inducers such as DNA damage, oncogene activation, and replicative exhaustion also trigger abnormal mTORC1 signaling through lysosomal accumulation of cholesterol mediated by a lysosomal cholesterol importer ABCA1 (Roh et al , 2023) and potentially lysosomal stress‐induced ER‐to‐lysosome cholesterol transfer by the PITT pathway (Tan & Finkel, 2022). Thus, increased lysosomal degradation and constitutive mTORC1 activation (Herranz et al , 2015, Laberge et al , 2015) underlie accelerated protein turnover, synthesis, and secretion in senescent cells.…”

Section: Introductionmentioning

confidence: 99%

Lysosomes in senescence and aging

Tan,

Finkel

2023

EMBO Reports

View full text Add to dashboard Cite

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.

show abstract

“…It has been reported that low cellular cholesterol levels may inhibit the activity of mammalian target of rapamycin complex 1 (mTORC1), 41,42 which is a key regulator of cellular ROS levels. 43 Mechanistically, the deactivation of mTORC1 promotes the dephosphorylation of transcription factor EB (TFEB), which then enters the nucleus and promotes the expression of superoxide dismutase 1 (SOD1) to reduce cellular ROS.…”

mentioning

confidence: 99%

“…43−45 Thus, reducing cholesterol level in cells may enhance their tolerance to FSS-induced ROS, at least in the short term, as mTORC1 deactivation can also activate cholesterol synthesis. 41,41,42 Hence, it is possible to improve the performance of living cell-based delivery systems by reducing cellular cholesterol. Notably, cholesterol is abundant in the plasma membrane and is constantly cycled, 46 which makes the removal of cholesterol from the cell membrane a viable way to reduce the cellular cholesterol level.…”

mentioning

confidence: 99%

Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation

Zhang,

Li,

et al. 2023

Nano Lett.

View full text Add to dashboard Cite

In recent years, live-cell-based drug delivery systems have gained considerable attention. However, shear stress, which accompanies blood flow, may cause cell death and weaken the delivery performance. In this study, we found that reducing cholesterol in macrophage plasma membranes enhanced their tumor targeting ability by more than 2-fold. Our study demonstrates that the reduced cholesterol level deactivated the mammalian target of rapamycin (mTOR) and consequently promoted the nuclear translocation of transcription factor EB (TFEB), which in turn enhanced the expression of superoxide dismutase (SOD) to reduce reactive oxygen species (ROS) induced by shear stress. A proof-of-concept system using low cholesterol macrophages attached to MXene (e.g., l-RX) was fabricated. In a melanoma mouse model, l-RX and laser irradiation treatments eliminated tumors with no recurrences observed in mice. Therefore, cholesterol reduction is a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.

show abstract

Lysosomal control of senescence and inflammation through cholesterol partitioning

Cited by 47 publications

References 83 publications

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

Lysosomes in senescence and aging

Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation

Contact Info

Product

Resources

About