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We quantified the hepatic proteome of male C57BL\/6 mice exposed to graded levels of CR (0%\u201340% CR) for 3\u00a0months, and evaluated which signaling pathways were most affected. The metabolic pathways most significantly stimulated by the increase in CR, included the glycolysis\/gluconeogenesis pathway, the pentose phosphate pathway, the fatty acid degradation pathway, the valine, leucine, and isoleucine degradation pathway, and the lysine degradation pathway. The metabolism of xenobiotics by cytochrome P450 pathway was activated and feminized by increased CR, while production in major urinary proteins (Mups) was strongly reduced, consistent with a reduced investment in reproduction as predicted by the disposable soma hypothesis. However, we found no evidence of increased somatic protection, and none of the 4 main pathways implied to be linked to the impact of CR on life span (insulin\/insulin-like growth factor [IGF-1], nuclear factor-\u03baB [NF-\u03baB], mammalian Target of Rapamycin [mTOR], and sirtuins) as well as pathways in cancer, were significantly changed at the protein level in relation to the increase in CR level. This was despite previous work at the transcriptome level in the same individuals indicating such changes. On the other hand, we found Aldh2, Aldh3a2, and Aldh9a1 in carnitine biosynthesis and Acsl5 in carnitine shuttle system were up-regulated by increased CR, which are consistent with our previous work on metabolome of the same individuals. Overall, the patterns of protein expression were more consistent with a \u201cclean cupboards\u201d than a \u201cdisposable soma\u201d interpretation.<\/jats:p>","DOI":"10.1093\/gerona\/glad017","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T17:31:13Z","timestamp":1675963873000},"page":"1125-1134","source":"Crossref","is-referenced-by-count":12,"title":["The Effects of Graded Levels of Calorie Restriction: XIX. Impact of Graded Calorie Restriction on Protein Expression in the\u00a0Liver"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1654-3259","authenticated-orcid":false,"given":"Lu","family":"Wang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University , Yantai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9041-4607","authenticated-orcid":false,"given":"Davina","family":"Derous","sequence":"additional","affiliation":[{"name":"Institute of Biological and Environmental Sciences, University of Aberdeen , Aberdeen , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6495-2594","authenticated-orcid":false,"given":"Xiahe","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Chaoyang, Beijing , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3941-0309","authenticated-orcid":false,"given":"Sharon\u00a0E","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Institute of Biological and Environmental Sciences, University of Aberdeen , Aberdeen , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Douglas","sequence":"additional","affiliation":[{"name":"Institute of Biological and Environmental Sciences, University of Aberdeen , Aberdeen , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lusseau","sequence":"additional","affiliation":[{"name":"Institute of Biological and Environmental Sciences, University of Aberdeen , Aberdeen , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-3556","authenticated-orcid":false,"given":"Yingchun","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Chaoyang, Beijing , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0R","family":"Speakman","sequence":"additional","affiliation":[{"name":"Institute of Biological and Environmental Sciences, University of Aberdeen , Aberdeen , UK"},{"name":"State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences , Chaoyang, Beijing , China"},{"name":"CAS Centre for Excellence in Animal Evolution and Genetics (CCEAEG) , Kunming , China"},{"name":"Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced technology, Chinese Academy of Sciences , Shenzhen , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"issue":"6","key":"2023070809265550300_CIT0001","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.2337\/db11-1300","article-title":"The critical role of metabolic pathways in aging","volume":"61","author":"Barzilai","year":"2012","journal-title":"Diabetes."},{"key":"2023070809265550300_CIT0002","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1126\/science.45.1160.294","article-title":"The effect of retardation of growth upon the breeding period and duration of life of rats","volume":"45","author":"Osborne","year":"1917","journal-title":"Science."},{"issue":"3","key":"2023070809265550300_CIT0003","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.mam.2011.07.001","article-title":"Caloric restriction","volume":"32","author":"Speakman","year":"2011","journal-title":"Mol Aspects Med."},{"issue":"31","key":"2023070809265550300_CIT0004","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2101977118","article-title":"The effects of graded calorie restriction XVII: multitissue metabolomics reveals synthesis of carnitine and NAD, and tRNA charging as key pathways","volume":"118","author":"Garcia-Flores","year":"2021","journal-title":"Proc Natl Acad Sci USA."},{"issue":"8","key":"2023070809265550300_CIT0005","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1093\/gerona\/glt160","article-title":"Lifelong caloric restriction reprograms hepatic fat metabolism in mice","volume":"69","author":"Kuhla","year":"2014","journal-title":"J Gerontol A\u00a0Biol Sci Med Sci"},{"issue":"3","key":"2023070809265550300_CIT0006","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/acel.12570","article-title":"The effects of graded levels of calorie restriction: IX. 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