Staying Young with p16
INK4a
Authors: Adler Elizabeth M. 
Published: December 2006

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]