Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE284342 | GEO | 2025/12/15
REPOSITORIES: GEO
Similar Datasets
Project description:During human evolution, lifestyles including dietary choices have had a major impact on shaping of human physiology and health, including aging. However, the underlying mechanisms remain largely unknown. Here, we use a blood nutrient compound library-based screening approach to demonstrate that dietary supplement vanadyl sulfate (VS) selectively induces cell death in senescent cells and ameliorates phenotypes of aging and age-related disorders in vivo. Integrated chemical biology and multi-omics studies reveal that senescent cells are specifically sensitive to VS due to reduced cysteine reactivity with accumulated glutathione disulfide. VS selectively inactivates reactive cysteines on proteins to induce formation of incorrect disulfide bonds in senescent cells with imbalanced cellular redox status, causing aberrant protein misfolding and aggregation and eventual cell death. Our findings uncover a new senolytic mechanism to mitigate age-related disorders and reshape human physiology.
2025-09-22 | GSE243912 | GEO
Project description:Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.
2020-12-09 | GSE124609 | GEO
Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.
2022-09-06 | GSE210020 | GEO
Project description:In the course of aging, the long term retention of senescent cells in vivo, a process mainly attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells accelerates aging and contributes to age-related diseases. Indeed, senescent cells can be removed by several strategies, thus preventing occurrence of chronic disorders and prolonging lifespan and healthspan. Senolytics, which eliminate senescent cells by pharmacological intervention, have recently emerged as a new line of therapeutic agents to ameliorate diverse age-related pathologies. Achieving the goal using natural or synthetic agents would have a tremendous impact on the quality of life. We report the potential of procyanidin C1 (PCC1), an epicatechin trimer natural product derived from plant sources including grape, apple, and cocoa, in targeting senescent cells via induction of apoptosis. This study demonstrates the efficacy of PCC1 in minimizing the influence of senescent cells in tissue microenvironment and provides a strong rationale for its future use in aging control and geriatric medicine.
2021-10-04 | GSE164012 | GEO
Project description:Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino- p -cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino- p -cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.
2023-08-30 | GSE227126 | GEO
Project description:Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells, but the function of AGR2 has been obscure. Here we show that AGR2 is expressed in the ER of secretory cells and is essential for in vivo production of intestinal mucin, a large cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, consistent with a direct role for AGR2 in mucin processing. Despite a complete absence of intestinal mucin, mice lacking AGR2 appeared healthy but were highly susceptible to dextran sodium sulfate-induced experimental colitis, indicating a critical role for AGR2 in protection from environmental insults. We conclude that AGR2 is a unique member of the PDI family that has a specialized and non-redundant role in intestinal mucus production. Keywords: small intestine and colon gene expression profiles for Agr2-/- and littermate control mice
2009-05-15 | GSE12503 | GEO
Project description:Doxorubicin (Dox) is a widely used treatment for cancer, which can result in chemotherapy induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging, since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves induction of peripheral cellular senescence and the release ofsenescence-associated secretory phenotype (SASP) factors, which enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. While Dox treatment influenced several measures linked to aging, including peripheral inflammation, morphological measure of microglial activation, cognition, and synaptic function,the effects of Dox treatment on brain (i.e. dentate gyrus) gene expression did not approximate aging to the same degree as other measures.Regardless, ABT-263 prevent or limited most of the Dox induced effects, including brain gene expression. The resultsemphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate thatdifferences between aging and Dox treatment on brain gene expression are important in considering Dox treatment as a model of aging.
2024-02-26 | GSE236404 | GEO
Project description:Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells, but the function of AGR2 has been obscure. Here we show that AGR2 is expressed in the ER of secretory cells and is essential for in vivo production of intestinal mucin, a large cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, consistent with a direct role for AGR2 in mucin processing. Despite a complete absence of intestinal mucin, mice lacking AGR2 appeared healthy but were highly susceptible to dextran sodium sulfate-induced experimental colitis, indicating a critical role for AGR2 in protection from environmental insults. We conclude that AGR2 is a unique member of the PDI family that has a specialized and non-redundant role in intestinal mucus production. Keywords: small intestine and colon gene expression profiles for Agr2-/- and littermate control mice DNA miocroarrays were used to analyze small intenstine and colon mRNA expression of AGR2 KO and littermate control mice. The experiment incorporated a 1 color design and used Agilent arrays that contained roughly 44,00 60mer probes that provide complete coverage of the mouse genome. 12 arrays were hybridized and represent 8 small intestine samples ( 4 each KO and WT) and 4 colon samples (2 each KO and WT)
2010-05-19 | E-GEOD-12503 | biostudies-arrayexpress
Project description:Organismal homeostasis is dependent on efficient tissue regeneration. Embedded within the highest self-renewing organ, intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. During aging, however, their regenerative capacity is significantly reduced albeit the exact mechanisms behind this decrease remain to be fully understood. Cellular senescence is a key feature of the aging process; yet little is known about the in vivo presence and functional consequences of senescent cells on the intestinal stem cell niche. Here, we identify, isolate and characterize the accumulation of senescent cells in the murine and human aging guts. To achieve their in vivo targeted ablation, we harness autologous senolytic CAR T cells, and uncover a detrimental impact of senescent cells on ISC function in natural aging and injury. Thus, therapeutic and prophylactic elimination of intestinal senescent cells is sufficient to either rejuvenate or prevent the functional decline in the regenerative potential of aged ISCs resulting in improvements in both epithelial integrity and mucosal immune function. Overall, these findings identify the in vivo deleterious role of senescent cells on the aged intestinal stem cell niche and provide proof of concept of the potential of targeted cell therapies to enhance tissue regeneration in aging organisms.
2025-11-05 | GSE301362 | GEO
Project description:The healthspan of mice is enhanced by selectively killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. As senescent cells resist apoptosis, we used microarrays to identify transcripts and pathways that differ between senescent and non-senescent preadipocytes, and might be involved in resistance to apoptosis. Primary human abdominal subcutaneous preadipocytes were isolated from 8 healthy lean kidney donors. All subjects were matched by age,gender and BMI. The protocol was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Preadipocytes were radiated at 10 Gy to induce senescence or were sham-radiated. From senescent cells RNA was isolated 20 days after irradiation.
2015-03-10 | E-GEOD-66236 | biostudies-arrayexpress