title: Reduced expression of MYC increases longevity and enhances healthspan.
abstract: MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Hofmann
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Xiaoai
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: De Cecco
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Peterson
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pagliaroli
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Jayameenakshi
authors.initials: J
authors.lastname: Manivannan
authors.affiliation: Department of Cellular and Structural Biology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Gene B
authors.initials: GB
authors.lastname: Hubbard
authors.affiliation: Department of Cellular and Structural Biology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912, USA.
authors.forename: Xiaxi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Serre
authors.affiliation: Department of Cellular and Structural Biology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Cellular and Structural Biology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.affiliation: Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Bath
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Neretti
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address: john_sedivy@brown.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Sedivy
mesh_terms: D000375:Aging; D000818:Animals; D049628:Body Size; D005260:Female; D008136:Longevity; D008223:Lymphoma / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc