1. Howard Hughes Medical Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA
2. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA
3. †Present address: Laboratorio de Investigaciones Biomedicas, Hospital Universitario Virgen del Rocio, Universidad de Sevilla, E-41013 Seville, Spain
4. *These authors contributed equally to this work

Correspondence to: Sean J. Morrison¹ Correspondence and requests for materials should be addressed to S.J.M. (Email: seanjm@umich.edu).

Abstract

Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells^{1, 2}. It has been proposed that this is at least partially caused by the senescence of progenitors with age^{3, 4}; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16^INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence⁵. Ageing p16^INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16^INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16^INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16^INK4a expression.

1. Howard Hughes Medical Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA
2. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA
3. †Present address: Laboratorio de Investigaciones Biomedicas, Hospital Universitario Virgen del Rocio, Universidad de Sevilla, E-41013 Seville, Spain
4. *These authors contributed equally to this work

Correspondence to: Sean J. Morrison¹ Correspondence and requests for materials should be addressed to S.J.M. (Email: seanjm@umich.edu).

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