Citations 3
Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function
Laux, L , Aristel, Alisha, Ali, Syed, Evensen, K. Garrett , Havas, Aaron , Miao, Zhen , Zhang, Jane, Peters, Samuel, Hu, Jiayi , Angelini, Luise, Klaers, Maggie, Brocksome, Jennie, Lewis, Adam , Paidimukkala, N., Brown, Mary E., Carver, Chase M., Albrecht, Jeffrey H. , Wehner, April , Adams, Peter, Aliferis, Constantin, Adeyi, Oyedele, Dong, Xiao, Wang, Jinhua, Zhang, Nancy, Adeyi, Oyedele , Adeyi, Oyedele , Lande, Kathryn , Li, Meiyi , Havas, Aaron , Zhang, Jane, Peters, Sam , Angelini, Luise, Brown, Mary E., Carver, Chase Matthew , Schafer, Marissa , Khosla, Sundeep , Wang, Jinhua , Robbins, Paul D. , Niedernhofer, Laura J.
No container title available | August 10, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.
Failure to Repair Endogenous DNA Damage in β-Cells Causes Adult-Onset Diabetes in Mice
Yousefzadeh, Matthew J. , O’Kelly, Ryan, Wade, Erin A., Gonzalez-Espada, Lisa V., Henessy-Wack, Danielle, Howard, Shannon, Rozgaja, Tania A., Eggen, Bart J. L. , Jonker, Johan W. , Kruit, Janine K. , Guevara, Ana, Postmus, Andrea C. , Flores, Rafael R. , Sano, Tokio , Jurdzinski, Angelika, Angelini, Luise, McGowan, Sara J., Trussoni, Christy E. , Jonker, Johan W , O'Kelly, Ryan D., Wade, Erin A., Gonzalez-Espada, Lisa V., Henessy-Wack, Danielle, LaRusso, Nicholas F. , Robbins, Paul D. , Niedernhofer, Laura J. , McGowan, Sara
Aging Biology | October 26, 2023 | Volume: 1 | Issue: 1 | Pages: 20230015
Adenoviral gene transfer of a single‐chain IL‐23 induces psoriatic arthritis–like symptoms in NOD mice
Flores, Rafael R. , Carbo, Lana, Meter, Montina Van, Padilla, Consuelo M. López de , Zhao, Jing , Colangelo, Debora , Yousefzadeh, Negar , Angelini, Luise, Zhang, Lei , Pola, Enrico , Evans, Christopher H. , Gambotto, Andrea , Niedernhofer, Laura J. , Robbins, Paul D. , De Padilla, Consuelo M Lopez, Niedernhofer, Laura J , Robbins, Paul D , Zhang, Lei , Kim, Eun Young , Yousefzadeh, Matthew J., Vo, Nam
The FASEB Journal | June 6, 2019 | Volume: 33 | Issue: 8 | Pages: 9505-9515
ABSTRACT Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single‐chain (sc) IL‐23 (Ad.scIL‐23) was able to induce systemic antitumor immunity. Here, we examined the role of IL‐23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL‐23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL‐23–treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL‐17–producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti–IL‐17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL‐23–treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.—Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single‐chain IL‐23 induces psoriatic arthritis–like symptoms in NOD mice. FASEB J. 33, 9505–9515 (2019). www.fasebj.org