Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells1,2. It has been proposed that this is at least partially caused by the senescence of progenitors with age3,4; 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 p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence5. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a 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 p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
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This work was supported by the National Institute on Aging (grants to S.J.M. and N.E.S.) and the National Institute of Neurological Disorders and Stroke (to S.J.M.). S.J.M. is an Investigator of the Howard Hughes Medical Institute. N.E.S. is supported by the Sidney Kimmel Foundation for Cancer Research, the Paul Beeson Physician Scholars program, and the Ellison Medical Foundation. A.V.M. and N.M.J. were supported by National Research Service Awards from the National Institutes of Health. We thank K. Yeager for tissue sectioning and C. Mountford for mouse colony management. Author Contributions A.V.M. studied the effect of age on forebrain progenitors, p16INK4a expression and function during ageing in the subventricular zone (Figs 1 and 2), and Bmi1 expression during ageing (Supplementary Fig. 3). S.G.S. contributed to studies of p16INK4a expression during ageing, and the effect of p16INK4a on proliferation and neurogenesis in the subventricular zone and hippocampus (Figs 2 and 3 and Supplementary Fig. 1). N.M.J. studied neurogenesis in the olfactory bulb and hippocampus (Fig. 3 and Supplementary Fig. 1). S.H. and R.P. examined p16INK4a expression in the ageing enteric nervous system and its effect on neural crest stem cells (Supplementary Fig. 2). J.K. and N.E.S. provided ageing p16INK4a-deficient and control mice for some of the experiments and discussed results throughout the project. S.J.M. helped to design and interpret experiments and wrote the manuscript with help from A.V.M., S.G.S. and N.M.J.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Ink4a does not significantly affect proliferation or neurogenesis in the dentate gyrus of old mice. (JPG 61 kb)
Neural crest stem cell frequency decreases, and p16Ink4a expression increases with age in the gut but Ink4a deficiency does not rescue stem cell frequency. (JPG 30 kb)
Bmi-1 mRNA and protein levels did not detectably change with age in the subventricular zone of 60 day old, 1 year old, or 2 year old mice. (JPG 15 kb)
This file contains Supplementary Figure Legends and Supplementary Methods. (DOC 48 kb)
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Molofsky, A., Slutsky, S., Joseph, N. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006). https://doi.org/10.1038/nature05091
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