Citations 2
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.
The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset
Liu, Haiyan , Marsh, Thomas W. , Shi, Xinyu , Bowling, Kevin M. , Ziegemeier, Ellen , Wang, Guoqiao , Cao, Yuchen , Aristel, Alisha, Li, Jessie, Dickson, Alexa , Perrin, Richard J. , Goate, Alison , Fernández, María Victoria , Day, Gregory S. , Doering, Michelle , Daniels, Alisha , Hassenstab, Jason , Supnet, Charlene , Xiong, Chengjie , Berman, Sarah , Ryan, Natalie S. , Huey, Edward D. , Noble, James M. , Roh, Jee Hoon , Laske, Christoph , Sánchez‐Valle, Raquel , Méndez, Patricio Chrem, Chhatwal, Jasmeer P. , Farlow, Martin R. , Xiong, Chengjie , Gordon, Brian A , Ibanez, Laura , Vöglein, Jonathan , Roh, Jee Hoon , Ikeuchi, T , Sánchez-Valle, Raquel , Chhatwal, Jasmeer , Xiong, Chengjie , Rosa-Neto, Pedro , Schofield, Peter R , Bateman, Randall J , Cruchaga, Carlos , Day, Gregory S , Hassenstab, Jason , Fernandez, Maria , Goate, Alison M , Supnet-Bell, Charlene , Berman, Sarah , Noble, James M , Renton, Alan , Gordon, Brian A. , Benzinger, Tammie L.S. , Allegri, Ricardo , Fox, Nick C. , Vöglein, Jonathan , Jucker, Mathias , Ikeuchi, Takeshi , Schofield, Peter R. , Lee, Jae‐Hong , Levey, Allan I. , Lopera, Francisco Javier , Martins, Ralph N. , Niimi, Yoshiki , Bateman, Randall J. , Karch, Celeste M. , McDade, Eric , Llibre‐Guerra, Jorge J.
Brain | February 4, 2025 | Volume: 148 | Issue: 7 | Pages: 2429-2440
Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.