Staying Young with p16 INK4a

Abstract

In long-lived organisms, cells in many tissues are replaced from a population of stem or progenitor cells that retain the capacity to proliferate. The ability of these cells to proliferate decreases with age, which may be linked to a reduced capacity to repair or regenerate tissue. Three studies, focused on three different tissues, investigated the role of the cyclin-dependent kinase inhibitor p16 INK4a , the abundance of which increases in some cell types with age, in this loss of proliferative and regenerative capacity. Janzen et al . found that p16 INK4a mRNA expression increased in the bone marrow-derived hematopoietic stem cells (HSCs) of older mice. Older mice that lacked p16 INK4a had more HSCs than did older wild-type mice, and the ability of HSCs from older mice lacking p16 INK4a to reconstitute the immune system through bone marrow transplants was superior to that of HSCs from older wild-type mice. Expression of the Notch effector Hes1, which has been implicated in regulating HSC cycling and preserving their function, was enhanced in HSCs from mice lacking p16 INK4a and decreased in HSCs from mice overexpressing p16 INK4a . Molofsky et al . investigated the role of p16 INK4a in neural progenitor cell proliferation in the subventricular zone (SVZ) and olfactory bulb neurogenesis in aging mice. They found an increase in SVZ p16 INK4a mRNA expression with aging and observed an age-related decrease in SVZ proliferation, in the number of SVZ cells that could form multipotent colonies in culture, and in olfactory bulb neurogenesis. In older mice lacking p16 INK4a , the decreases in SVZ proliferation and olfactory bulb neurogenesis were attenuated and the decline in colony-forming cells was abolished (suggesting an effect on stem cells rather than downstream progenitor cells). However, p16 INK4a did not appear to affect progenitor cell function or neurogenesis in the dentate gyrus or in the enteric nervous system. Krishnamurthy et al . showed that p16 INK4a mRNA expression increased with age in mouse pancreatic islet cells. Transgenic mice with an additional copy of the p16 INK4a gene (in which young mice expressed p16 INK4a to an extent comparable to that of old wild-type mice) showed a reduction in islet proliferation, whereas an age-related decrease in proliferation seen in wild-type mice was profoundly attenuated in mice lacking p16 INK4a . Islet regeneration and the ability of mice to survive treatment with streptozotocin, a β cell toxin, decreased with age; both islet proliferation after streptozotocin treatment and survival were enhanced in older mice lacking p16 INK4a . Thus, in at least some tissues, p16 INK4a appears to play a role in aging-related loss of progenitor cell proliferation and regenerative capacity. Beausejour and Campisi discuss the research in the context of the role of stem cell proliferation in both regeneration and susceptibility to cancer, noting that p16 INK4a is a tumor suppressor and that mice lacking it are prone to tumor formation. V. Janzen, R. Forkert, H. E. Fleming, Y. Saito, M. T. Waring, D. M. Dombkowski, T. Cheng, R. A. DePinho, N. E. Sharpless, D. T. Scadden, Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16 INK4a . Nature 443 , 421-426 (2006). [PubMed] J. Krishnamurthy, M. R. Ramsey, K. L. Ligon, C. Torrice, A. Koh, S. Bonner-Weir, N. E. Sharpless, p16 INK4a induces an age-dependent decline in islet regenerative potential. Nature 443 , 453-457 (2006). [PubMed] A. V. Molofsky, S. G. Slutsky , N. M. Joseph, S. He, R. Pardal, J. Krishnamurthy, N. E. Sharpless, S. J. Morrison, Increasing p16 INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443 , 448-452 (2006). [PubMed] C. M. Beausejour, J. Campisi, Balancing regeneration and cancer. Nature 443 , 404-405 (2006). [PubMed]