Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan

Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3.

Abstract

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / pathology
  • Adipocytes / physiology
  • Aging / pathology*
  • Aging / physiology*
  • Animals
  • Apoptosis
  • Cell Separation
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology
  • Female
  • Health*
  • Kidney / cytology
  • Kidney / pathology
  • Kidney / physiology
  • Kidney / physiopathology
  • Lipodystrophy / pathology
  • Longevity / physiology*
  • Male
  • Mice
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Organ Specificity
  • Stem Cells / cytology
  • Stem Cells / pathology
  • Time Factors

Substances

  • Cyclin-Dependent Kinase Inhibitor p16