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Mutations and duplication events in <jats:italic>AT\u20101\/SLC33A1<\/jats:italic> are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT\u20101 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT\u20101 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a\u2010Fam134b\u2010LC3\u03b2 and Atg9a\u2010Sec62\u2010LC3\u03b2 interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1\/ATase2 acetyltransferase enzymes downstream of AT\u20101 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl\u2010CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl\u2010CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol\u2010to\u2010ER flux of acetyl\u2010CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl\u2010CoA\u2010dependent homeostatic mechanisms linked to metabolism and inflammation.<\/jats:p>","DOI":"10.1111\/acel.12820","type":"journal-article","created":{"date-parts":[[2018,7,27]],"date-time":"2018-07-27T09:05:57Z","timestamp":1532682357000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Increased transport of acetyl\u2010CoA into the endoplasmic reticulum causes a progeria\u2010like phenotype"],"prefix":"10.1111","volume":"17","author":[{"given":"Yajing","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Medicine University of Wisconsin\u2010Madison Madison Wisconsin"},{"name":"Waisman Center University of Wisconsin\u2010Madison Madison 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Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Hewitt","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology University of Wisconsin\u2010Madison Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emery H.","family":"Bresnick","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology University of Wisconsin\u2010Madison Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyao","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology University of Wisconsin\u2010Madison Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cell and Regenerative Biology University of Wisconsin\u2010Madison Madison 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