Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation
Huabo Wang,
Jie Lu,
Taylor Stevens,
Alexander Roberts,
Jordan Mandel,
Raghunandan Avula,
Bingwei Ma,
Yijen Wu,
Jinglin Wang,
Clinton Van’t Land,
Toren Finkel,
Jerry E. Vockley,
Merlin Airik,
Rannar Airik,
Radhika Muzumdar,
Zhenwei Gong,
Michel S. Torbenson,
Edward V. Prochownik
Affiliations
Huabo Wang
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Jie Lu
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Taylor Stevens
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Alexander Roberts
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Jordan Mandel
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Raghunandan Avula
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; The University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
Bingwei Ma
Tongji University School of Medicine, Shanghai, China
Yijen Wu
Department of Developmental Biology, The University of Pittsburgh, Pittsburgh, PA, USA
Jinglin Wang
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Central South University, Xiangya School of Medicine, Changsha, Hunan 410013, P.R. China
Clinton Van’t Land
Division of Medical Genetics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Toren Finkel
Division of Cardiology, The Department of Internal Medicine and the UPMC Aging Institute, Pittsburgh, PA 15224, USA
Jerry E. Vockley
Division of Medical Genetics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Merlin Airik
Division of Nephrology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Rannar Airik
Division of Nephrology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Radhika Muzumdar
Division of Endocrinology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Zhenwei Gong
Division of Endocrinology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Michel S. Torbenson
Division of Laboratory Medicine and Pathology, The Mayo Clinic, Rochester, MN 55905, USA
Edward V. Prochownik
Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Microbiology and Molecular Genetics, UPMC, Pittsburgh, PA 15261, USA; Hillman Cancer Center of UPMC, Pittsburgh, PA 15232, USA; Pittsburgh Liver Research Center, UPMC, Pittsburgh, PA 15261, USA; Corresponding author
Summary: MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/− mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.
