title: Systemic regulation of the age-related decline of pancreatic β-cell replication.
abstract: The frequency of pancreatic β-cell replication declines dramatically with age, potentially contributing to the increased risk of type 2 diabetes in old age. Previous studies have shown the involvement of cell-autonomous factors in this phenomenon, particularly the decline of polycomb genes and accumulation of p16/INK4A. Here, we demonstrate that a systemic factor found in the circulation of young mice is able to increase the proliferation rate of old pancreatic β-cells. Old mice parabiosed to young mice have increased β-cell replication compared with unjoined old mice or old mice parabiosed to old mice. In addition, we demonstrate that old β-cells transplanted into young recipients have increased replication rate compared with cells transplanted into old recipients; conversely, young β-cells transplanted into old mice decrease their replication rate compared with young cells transplanted into young recipients. The expression of p16/INK4A mRNA did not change in heterochronic parabiosis, suggesting the involvement of other pathways. We conclude that systemic factors contribute to the replicative decline of old pancreatic β-cells.
authors: Department of Developmental Biology and Cancer Research and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors: Seth J
authors: SJ
authors: Salpeter
authors: Abed
authors: A
authors: Khalaileh
authors: Noa
authors: N
authors: Weinberg-Corem
authors: Oren
authors: O
authors: Ziv
authors: Benjamin
authors: B
authors: Glaser
authors: Yuval
authors: Y
authors: Dor
mesh_terms: D000367:Age Factors; D000375:Aging / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010227:Parabiosis; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16
references: Nature. 2011 Oct 12;478(7369):349-55
references: 21993628
references: Cell Cycle. 2012 Jun 15;11(12):2260-7
references: 22617385
references: J Biol Chem. 2012 Aug 10;287(33):27407-14
references: 22740691
references: Cell Rep. 2013 Feb 21;3(2):401-10
references: 23375376
references: Endocrinology. 1997 Apr;138(4):1736-41
references: 9075738
references: Diabetes. 2009 Jun;58(6):1365-72
references: 19265026
references: Transplantation. 2003 Jun 15;75(11):1812-9
references: 12811239
references: Diabetologia. 2011 Mar;54(3):572-82
references: 20936253
references: Am J Physiol. 1999 May;276(5):E822-7
references: 10329974
references: Nature. 2006 Sep 28;443(7110):453-7
references: 16957737
references: Diabetes. 2005 Sep;54(9):2557-67
references: 16123343
references: Nature. 2011 Aug 31;477(7362):90-4
references: 21886162
references: Wound Repair Regen. 2010 Jul-Aug;18(4):426-32
references: 20546556
references: Cell Metab. 2011 Apr 6;13(4):440-449
references: 21459328
references: Dev Cell. 2009 Jul;17(1):142-9
references: 19619499
references: FASEB J. 1988 Sep;2(12):2807-11
references: 3044905
references: Development. 2010 Oct;137(19):3205-13
references: 20823063
references: Int J Biochem Cell Biol. 2005 May;37(5):961-76
references: 15743671
references: Nature. 2008 Jul 24;454(7203):528-32
references: 18552838
references: Nat Cell Biol. 2011 May;13(5):506-12
references: 21540846
references: Genes Dev. 2009 Apr 15;23(8):975-85
references: 19390090
references: Nature. 2005 Feb 17;433(7027):760-4
references: 15716955
references: Endocrinology. 2011 Jul;152(7):2589-98
references: 21521747
references: Transplantation. 2009 Aug 27;88(4):496-503
references: 19696632
references: J Mol Endocrinol. 2000 Jun;24(3):297-302
references: 10828822