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Crossing <jats:italic>Ripk3<\/jats:italic>-KI or <jats:italic>Mlkl<\/jats:italic>-KI mice to albumin-Cre transgenic mice produced hepatocyte specific <jats:italic>hRipk3<\/jats:italic>-KI or <jats:italic>hMlkl<\/jats:italic>-KI mice, which express the two transgenes only in the liver. Ripk3 and Mlkl proteins were overexpressed 10- and fourfold, respectively, in the livers of the <jats:italic>hRipk3<\/jats:italic>-KI or <jats:italic>hMlkl<\/jats:italic>-KI mice. Treating young (2-month) <jats:italic>hRipk3<\/jats:italic>-KI or <jats:italic>hMlkl<\/jats:italic>-KI mice with carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>), a chemical inducer of oxidative stress, resulted in increased necroptosis (Mlkl-oligomers) and inflammation in the liver compared to control mice receiving CCl<jats:sub>4<\/jats:sub>. Mlkl-oligomerization also was significantly increased in old (18-month) <jats:italic>hRipk3<\/jats:italic>-KI and <jats:italic>hMlkl<\/jats:italic>-KI mice compared to old control (Cre negative, <jats:italic>Ripk3<\/jats:italic>-KI and <jats:italic>Mlkl<\/jats:italic>-KI) mice. The increase in necroptosis was associated with an increase in inflammation, e.g., inflammatory cytokines (TNF\u03b1, IL-6) and macrophage markers (F4\/80, CD68). Importantly, steatosis (triglycerides) and fibrosis (e.g., picrosirius red staining, hydroxyproline levels, and transcripts for TGF\u03b2, Col1\u03b11, and Col3\u03b11) that increase with age were significantly higher in the livers of the old <jats:italic>hRipk3<\/jats:italic>-KI or <jats:italic>hMlkl<\/jats:italic>-KI mice compared to old control mice. In addition, markers of cellular senescence were significantly increased in the livers of the old <jats:italic>hRipk3<\/jats:italic>-KI and <jats:italic>hMlkl<\/jats:italic>-KI mice. Thus, the first mouse models have been developed that allow researchers to study the impact of inducing necroptosis in specific cells\/tissues on chronic inflammation in aging and age-related diseases.<\/jats:p>","DOI":"10.1007\/s11357-023-00955-7","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T06:01:53Z","timestamp":1696399313000},"page":"3241-3256","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Characterization of novel mouse models to study the role of necroptosis in aging and age-related diseases"],"prefix":"10.1007","volume":"45","author":[{"given":"Ramasamy","family":"Selvarani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoang","family":"Van Michelle Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidheesh","family":"Thadathil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman F.","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willard M.","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Wiley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathyaseelan S.","family":"Deepa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlan","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"issue":"Suppl 1","key":"955_CR1","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1093\/gerona\/glu057","volume":"69","author":"C Franceschi","year":"2014","unstructured":"Franceschi C, Campisi J. 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