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p16INK4a induces an age-dependent decline in islet regenerative potential

Nature volume 443, pages 453–457 (2006)Cite this article

Abstract

The p16INK4a tumour suppressor accumulates in many tissues as a function of advancing age1,2,3. p16INK4a is an effector of senescence4,5 and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic β-cell proliferation in adult mammals7,8. Here we show that p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16INK4a, but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16INK4a accumulation on islet function, we assessed the impact of p16INK4a deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific β-cell toxin. Transgenic mice that overexpress p16INK4a to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16INK4a deficiency in young mice, but was relatively increased in p16INK4a-deficient old mice. Survival after toxin-mediated ablation of β-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16INK4a demonstrated enhanced islet proliferation and survival after β-cell ablation. These genetic data support the view that an age-induced increase of p16INK4a expression limits the regenerative capacity of β-cells with ageing.

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Figure 1: Islet gene expression and proliferation in young versus old mice.
Figure 2: Islet regeneration after STZ treatment.
Figure 3: Metabolic effects of p16 INK4a expression after STZ treatment.
Figure 4: Influence of p16 INK4a expression on islet regeneration after STZ treatment.

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Acknowledgements

We thank J. Lock, S. Alson, M. Zhang, Y. Xiong and G. Enders for advice, reagents and technical support, and R. DePinho and K. Wong for comments on the manuscript. This work was supported by grants from the Sidney Kimmel Cancer Foundation for Cancer Research, the Paul Beeson Physician Scholars program, the Ellison Medical Foundation, and the National Institutes of Health.

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Authors and Affiliations

  1. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599, USA

    Janakiraman Krishnamurthy, Matthew R. Ramsey, Chad Torrice & Norman E. Sharpless

  2. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA

    Keith L. Ligon

  3. Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, 02115, USA

    Angela Koh & Susan Bonner-Weir

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  1. Janakiraman Krishnamurthy
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Correspondence to Norman E. Sharpless.

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DThis file contains the Supplementary Methods, Supplementary Figure Legends, Supplementary Table 1 and additional references. (DOC 75 kb)

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Krishnamurthy, J., Ramsey, M., Ligon, K. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006). https://doi.org/10.1038/nature05092

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