Search

Your search keyword '"Lagnado, Anthony B."' showing total 24 results
Start Over Author "Lagnado, Anthony B."
24 results on '"Lagnado, Anthony B."'

1. Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Victorelli, Stella, Salmonowicz, Hanna, Chapman, James, Martini, Helene, Vizioli, Maria Grazia, Riley, Joel S., Cloix, Catherine, Hall-Younger, Ella, Machado Espindola-Netto, Jair, Jurk, Diana, Lagnado, Anthony B., Sales Gomez, Lilian, Farr, Joshua N., Saul, Dominik, Reed, Rebecca, Kelly, George, Eppard, Madeline, Greaves, Laura C., Dou, Zhixun, Pirius, Nicholas, Szczepanowska, Karolina, Porritt, Rebecca A., Huang, Huijie, Huang, Timothy Y., Mann, Derek A., Masuda, Claudio Akio, Khosla, Sundeep, Dai, Haiming, Kaufmann, Scott H., Zacharioudakis, Emmanouil, Gavathiotis, Evripidis, LeBrasseur, Nathan K., Lei, Xue, Sainz, Alva G., Korolchuk, Viktor I., Adams, Peter D., Shadel, Gerald S., Tait, Stephen W. G., and Passos, João F.

Published
2023
Full Text
View/download PDF

2. Spatial mapping of cellular senescence: emerging challenges and opportunities

Author

Gurkar, Aditi U., Gerencser, Akos A., Mora, Ana L., Nelson, Andrew C., Zhang, Anru R., Lagnado, Anthony B., Enninful, Archibald, Benz, Christopher, Furman, David, Beaulieu, Delphine, Jurk, Diana, Thompson, Elizabeth L., Wu, Fei, Rodriguez, Fernanda, Barthel, Grant, Chen, Hao, Phatnani, Hemali, Heckenbach, Indra, Chuang, Jeffrey H., Horrell, Jeremy, Petrescu, Joana, Alder, Jonathan K., Lee, Jun Hee, Niedernhofer, Laura J., Kumar, Manoj, Königshoff, Melanie, Bueno, Marta, Sokka, Miiko, Scheibye-Knudsen, Morten, Neretti, Nicola, Eickelberg, Oliver, Adams, Peter D., Hu, Qianjiang, Zhu, Quan, Porritt, Rebecca A., Dong, Runze, Peters, Samuel, Victorelli, Stella, Pengo, Thomas, Khaliullin, Timur, Suryadevara, Vidyani, Fu, Xiaonan, Bar-Joseph, Ziv, Ji, Zhicheng, and Passos, João F.

Published
2023
Full Text
View/download PDF

3. Author Correction: Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Victorelli, Stella, Salmonowicz, Hanna, Chapman, James, Martini, Helene, Vizioli, Maria Grazia, Riley, Joel S., Cloix, Catherine, Hall-Younger, Ella, Machado Espindola-Netto, Jair, Jurk, Diana, Lagnado, Anthony B., Sales Gomez, Lilian, Farr, Joshua N., Saul, Dominik, Reed, Rebecca, Kelly, George, Eppard, Madeline, Greaves, Laura C., Dou, Zhixun, Pirius, Nicholas, Szczepanowska, Karolina, Porritt, Rebecca A., Huang, Huijie, Huang, Timothy Y., Mann, Derek A., Masuda, Claudio Akio, Khosla, Sundeep, Dai, Haiming, Kaufmann, Scott H., Zacharioudakis, Emmanouil, Gavathiotis, Evripidis, LeBrasseur, Nathan K., Lei, Xue, Sainz, Alva G., Korolchuk, Viktor I., Adams, Peter D., Shadel, Gerald S., Tait, Stephen W. G., and Passos, João F.

Published
2024
Full Text
View/download PDF

4. Characterization of cellular senescence in aging skeletal muscle

Author

Zhang, Xu, Habiballa, Leena, Aversa, Zaira, Ng, Yan Er, Sakamoto, Ayumi E., Englund, Davis A., Pearsall, Vesselina M., White, Thomas A., Robinson, Matthew M., Rivas, Donato A., Dasari, Surendra, Hruby, Adam J., Lagnado, Anthony B., Jachim, Sarah K., Granic, Antoneta, Sayer, Avan A., Jurk, Diana, Lanza, Ian R., Khosla, Sundeep, Fielding, Roger A., Nair, K. Sreekumaran, Schafer, Marissa J., Passos, João F., and LeBrasseur, Nathan K.

Published
2022
Full Text
View/download PDF

6. Local senolysis in aged mice only partially replicates the benefits of systemic senolysis

Author

Farr, Joshua N., Saul, Dominik, Doolittle, Madison L., Kaur, Japneet, Rowsey, Jennifer L., Vos, Stephanie J., Froemming, Mitchell N., Lagnado, Anthony B., Zhu, Yi, Weivoda, Megan, Ikeno, Yuji, Pignolo, Robert J., Niedernhofer, Laura J., Robbins, Paul D., Jurk, Diana, Passos, Joao F., LeBrasseur, Nathan K., Tchkonia, Tamara, Kirkland, James L., Monroe, David G., and Khosla, Sundeep

Subjects
Aging -- Health aspects -- Physiological aspects, Cell development (Biology) -- Research, Cell cycle -- Research, Bone diseases -- Development and progression, Translational research, Health care industry
Abstract

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging., Introduction The aging population and life expectancy continue to increase (1), and while unlikely to reverse course, this trend of more people living longer creates challenges that society remains poorly [...]

Published
2023
Full Text
View/download PDF

7. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

Author

Hickson, LaTonya J., Langhi Prata, Larissa G.P., Bobart, Shane A., Evans, Tamara K., Giorgadze, Nino, Hashmi, Shahrukh K., Herrmann, Sandra M., Jensen, Michael D., Jia, Qingyi, Jordan, Kyra L., Kellogg, Todd A., Khosla, Sundeep, Koerber, Daniel M., Lagnado, Anthony B., Lawson, Donna K., LeBrasseur, Nathan K., Lerman, Lilach O., McDonald, Kathleen M., McKenzie, Travis J., Passos, João F., Pignolo, Robert J., Pirtskhalava, Tamar, Saadiq, Ishran M., Schaefer, Kalli K., Textor, Stephen C., Victorelli, Stella G., Volkman, Tammie L., Xue, Ailing, Wentworth, Mark A., Wissler Gerdes, Erin O., Zhu, Yi, Tchkonia, Tamara, and Kirkland, James L.

Published
2019
Full Text
View/download PDF

8. A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation

Author

Miller, Karl N, primary, Li, Brightany, additional, Pierce-Hoffman, Hannah R, additional, Lei, Xue, additional, Havas, Aaron P, additional, Patel, Shreeya, additional, Cano Macip, Carolina, additional, Victorelli, Stella G, additional, Woo, Seung-Hwa, additional, Lagnado, Anthony B, additional, Liu, Tianhui, additional, Dasgupta, Nirmalya, additional, Lyu, Jun, additional, Altman, Yoav, additional, Porritt, Rebecca A, additional, Garcia, Guillermina, additional, Mogler, Carolin, additional, Dou, Zhixun, additional, Chen, Chongyi, additional, Passos, Joao F, additional, and Adams, Peter D, additional

Published
2023
Full Text
View/download PDF

10. Apoptotic stress causes mtDNA release during senescence and drives the SASP

Author

Mann, Derek Austin, Victorelli, Stella; Salmonowicz, Hanna; Chapman, James; Martini, Helene; Vizioli, Maria Grazia; Riley, Joel S.; Cloix, Catherine; Hall-Younger, Ella; Machado Espindola-Netto, Jair; Jurk, Diana; Lagnado, Anthony B.; Sales Gomez, Lilian; Farr, Joshua N.; Saul, Dominik; Reed, Rebecca; Kelly, George; Eppard, Madeline; Greaves, Laura C.; Dou, Zhixun; Pirius, Nicholas; Szczepanowska, Karolina; Porritt, Rebecca A.; Huang, Huijie; Huang, Timothy Y.; Masuda, Claudio Akio; Khosla, Sundeep; Dai, Haiming; Kaufmann, Scott H.; Zacharioudakis, Emmanouil; Gavathiotis, Evripidis; LeBrasseur, Nathan K.; Lei, Xue; Sainz, Alva G.; Korolchuk, Viktor I.; Adams, Peter D.; Shadel, Gerald S.; Tait, Stephen W. G.; Passos, João F., School of Medicine, Mann, Derek Austin, Victorelli, Stella; Salmonowicz, Hanna; Chapman, James; Martini, Helene; Vizioli, Maria Grazia; Riley, Joel S.; Cloix, Catherine; Hall-Younger, Ella; Machado Espindola-Netto, Jair; Jurk, Diana; Lagnado, Anthony B.; Sales Gomez, Lilian; Farr, Joshua N.; Saul, Dominik; Reed, Rebecca; Kelly, George; Eppard, Madeline; Greaves, Laura C.; Dou, Zhixun; Pirius, Nicholas; Szczepanowska, Karolina; Porritt, Rebecca A.; Huang, Huijie; Huang, Timothy Y.; Masuda, Claudio Akio; Khosla, Sundeep; Dai, Haiming; Kaufmann, Scott H.; Zacharioudakis, Emmanouil; Gavathiotis, Evripidis; LeBrasseur, Nathan K.; Lei, Xue; Sainz, Alva G.; Korolchuk, Viktor I.; Adams, Peter D.; Shadel, Gerald S.; Tait, Stephen W. G.; Passos, João F., and School of Medicine

Abstract

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan., This work was funded by NIH grants R01AG068048 (to J.F.P.), UG3CA268103 (to J.F.P.), P01 AG062413 (to S.K., J.N.F., N.K.L. and J.F.P.), P01 AG073084 and R01 AR069876 (to G.S.S.), F31 AG062099 (to A.G.S.), R01 AG068182-01 (to D.J.), R01 CA225996 (to S.H.K. and H.D.), R01 DK128552 (to J.N.F.), R01 AG071861-01 (to X.L. and P.D.A.), P01 AG073084 (to P.D.A. and X.L.), R01 AG076515 (to S.K.), U54 AG079754 (to S.K.), R01 AG061875 and RF1 AG070391 (to T.Y.H.), R01AG071861 (to P.D.A.) and R33AG61456-4 and R01AG064165; Department of Defense grant W81XWH-20-1-0792 (to E.G.); U54 AG79754 (to S.K. and N.K.L.); Cancer Research UK grants C40872/A2014, DRCNPG-Jun22\100011 (to S.W.G.T.); the Ted Nash Long Life Foundation (to J.F.P. and D.J.); The Glenn Foundation For Medical Research (to J.F.P. and N.K.L.); Hevolution/AFAR (to D.J.); a Robert and Arlene Kogod Center on Aging Career Development Award (to S.V.); a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (Capes)—Finance Code 001 and by the Universidade Federal do Rio de Janeiro (to C.A.M.); Cancer Research UK grant DRCPFA-Nov22/100001 and Wellcome grant 203105/Z/16/Z0 to L.C.G., BBSRC PhD studentship BB/R506345/1 (to G.K. and V.I.K.); UKRI cross-council Newcastle University Centre for Ageing and Vitality Ph.D. studentship MR/L016354/1 (to J.C.) and CRUK Awards C18342/A23390 and DRCRPG-Nov22/100007 and MRC MR/R023026/1 (to D.A.M.). G.S.S. holds the Audrey Geisel Chair in Biomedical Science. MS interactome analysis was performed at the Proteomic Core Facility of IMol Polish Academy of Sciences and supported by ReMedy International Research Agenda (Foundation of Polish Science, MAB/2017/2) and EMBO Installation Grant 5040-2022 (to K.S.). scRNA-seq was performed by the Sanford Burnham Prebys Genomics Core. G.S.S. holds the Audrey Geisel Chair in Biomedical Science and is supported by P30AG068635 as director of the San Diego Nathan Shock Center. We thank G. Nelson and the members of the Newcastle U

Published
2023

11. A chronic wound model to investigate skin cellular senescence

Author

Wyles, Saranya P., primary, Dashti, Parisa, additional, Pirtskhalava, Tamar, additional, Tekin, Burak, additional, Inman, Christina, additional, Gomez, Lilian Sales, additional, Lagnado, Anthony B., additional, Prata, Larissa, additional, Jurk, Diana, additional, Passos, João F., additional, Tchkonia, Tamar, additional, and Kirkland, James L., additional

Published
2023
Full Text
View/download PDF

13. Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

Author

Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Medical Research Council (UK), Fernández-Duran, Irene, Quintanilla, Andrea, Tarrats, Núria, Birch, Jodie, Hari, Priya, Millar, Fraser R., Lagnado, Anthony B., Smer-Barreto, Vanessa, Muir, Morwenna, Brunton, Valerie G., Passos, João F., Acosta, Juan C., Cancer Research UK, University of Edinburgh, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), Biotechnology and Biological Sciences Research Council (UK), Wellcome Trust, Medical Research Council (UK), Fernández-Duran, Irene, Quintanilla, Andrea, Tarrats, Núria, Birch, Jodie, Hari, Priya, Millar, Fraser R., Lagnado, Anthony B., Smer-Barreto, Vanessa, Muir, Morwenna, Brunton, Valerie G., Passos, João F., and Acosta, Juan C.

Abstract

Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.

Published
2022

14. Targeted clearance of p21 ‐ but not p16 ‐positive senescent cells prevents radiation‐induced osteoporosis and increased marrow adiposity

Author

Chandra, Abhishek, primary, Lagnado, Anthony B., additional, Farr, Joshua N., additional, Doolittle, Madison, additional, Tchkonia, Tamara, additional, Kirkland, James L., additional, LeBrasseur, Nathan K., additional, Robbins, Paul D., additional, Niedernhofer, Laura J., additional, Ikeno, Yuji, additional, Passos, João F., additional, Monroe, David G., additional, Pignolo, Robert J., additional, and Khosla, Sundeep, additional

Published
2022
Full Text
View/download PDF

16. Supplemental Materials.docx

Author

Aghali, Arbi, Khalfaoui, Latifa, Lagnado, Anthony B., Drake, Li, Teske, Jacob, Pabelick, Christina M., F Passos, João, and YS, Prakash

Abstract

Scripts and tables

Published
2022
Full Text
View/download PDF

17. Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

Author

Fernández-Duran, Irene, primary, Quintanilla, Andrea, additional, Tarrats, Núria, additional, Birch, Jodie, additional, Hari, Priya, additional, Millar, Fraser R., additional, Lagnado, Anthony B., additional, Smer-Barreto, Vanessa, additional, Muir, Morwenna, additional, Brunton, Valerie G., additional, Passos, João F., additional, and Acosta, Juan Carlos, additional

Published
2021
Full Text
View/download PDF

19. Corrigendum to ‘Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456

Author

Hickson, LaTonya J., Langhi Prata, Larissa G.P., Bobart, Shane A., Evans, Tamara K., Giorgadze, Nino, Hashmi, Shahrukh K., Herrmann, Sandra M., Jensen, Michael D., Jia, Qingyi, Jordan, Kyra L., Kellogg, Todd A., Khosla, Sundeep, Koerber, Daniel M., Lagnado, Anthony B., Lawson, Donna K., LeBrasseur, Nathan K., Lerman, Lilach O., McDonald, Kathleen M., McKenzie, Travis J., Passos, João F., Pignolo, Robert J., Pirtskhalava, Tamar, Saadiq, Ishran M., Schaefer, Kalli K., Textor, Stephen C., Victorelli, Stella G., Volkman, Tammie L., Xue, Ailing, Wentworth, Mark A., Wissler Gerdes, Erin O., Allison, David B., Dickinson, Stephanie L., Ejima, Keisuke, Atkinson, Elizabeth J., Lenburg, Marc, Zhu, Yi, Tchkonia, Tamara, and Kirkland, James L.

Published
2020
Full Text
View/download PDF

20. Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Author

Eckhardt, Brittany A., primary, Rowsey, Jennifer L., additional, Thicke, Brianne S., additional, Fraser, Daniel G., additional, O’Grady, Katherine L., additional, Bondar, Olga P., additional, Hines, Jolaine M., additional, Singh, Ravinder J., additional, Thoreson, Andrew R., additional, Rakshit, Kuntol, additional, Lagnado, Anthony B., additional, Passos, João F., additional, Vella, Adrian, additional, Matveyenko, Aleksey V., additional, Khosla, Sundeep, additional, Monroe, David G., additional, and Farr, Joshua N., additional

Published
2020
Full Text
View/download PDF

22. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence

Author

Vizioli, Maria Grazia, primary, Liu, Tianhui, additional, Miller, Karl N., additional, Robertson, Neil A., additional, Gilroy, Kathryn, additional, Lagnado, Anthony B., additional, Perez-Garcia, Arantxa, additional, Kiourtis, Christos, additional, Dasgupta, Nirmalya, additional, Lei, Xue, additional, Kruger, Patrick J., additional, Nixon, Colin, additional, Clark, William, additional, Jurk, Diana, additional, Bird, Thomas G., additional, Passos, João F., additional, Berger, Shelley L., additional, Dou, Zhixun, additional, and Adams, Peter D., additional

Published
2020
Full Text
View/download PDF

23. Senescent cell transplantation into the skin induces age‐related peripheral dysfunction and cognitive decline.

Author

Franco, Ana Catarina, Martini, Helene, Victorelli, Stella, Lagnado, Anthony B., Wyles, Saranya P., Rowsey, Jennifer L., Pirius, Nicholas, Woo, Seung‐Hwa, Costa, Daniela G., Chaib, Selim, Tullius, Stefan G., Tchkonia, Tamar, Kirkland, James L., Khosla, Sundeep, Jurk, Diana, Cavadas, Claudia, and Passos, João F.

Subjects
*SKIN grafting, *COGNITION disorders, *CELL transplantation, *AGING, *BRAIN diseases, *SKIN aging, *CELLULAR aging
Abstract

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

24. Linked regulation of genome integrity and senescence-associated inflammation by p53.

Author

Miller KN, Li B, Pierce-Hoffman HR, Patel S, Lei X, Rajesh A, Teneche MG, Havas AP, Gandhi A, Macip CC, Lyu J, Victorelli SG, Woo SH, Lagnado AB, LaPorta MA, Liu T, Dasgupta N, Li S, Davis A, Korotkov A, Hultenius E, Gao Z, Altman Y, Porritt RA, Garcia G, Mogler C, Seluanov A, Gorbunova V, Kaech SM, Tian X, Dou Z, Chen C, Passos JF, and Adams PD

Abstract

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit driven by p53 and cytoplasmic chromatin fragments (CCF). We show, through activation or inactivation of p53 by genetic and pharmacologic approaches, that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), without affecting cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, and this is reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reversed signatures of aging, including age- and senescence-associated transcriptomic signatures of inflammation and age-associated accumulation of monocytes and macrophages in liver. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation. This pathway is immunomodulatory in mice and a potential target for healthy aging interventions by small molecules already shown to activate p53.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results