Balancing regeneration and cancer

The proliferation of cells must balance the longevity assured by tissue renewal against the risk of developing cancer. The tumour-suppressor protein p16INK4a seems to act at the pivot of this delicate equilibrium.

Tissue repair and regeneration are essential for longevity in complex animals, and often depend on the proliferation of unspecialized cells known as stem or progenitor cells. In many tissues, the regenerative capacity of such cells declines with age, and it is thought that this decline drives many age-related symptoms1. But stem/progenitor-cell proliferation is a double-edged sword. Although it ensures tissue repair and regeneration, it also puts tissues at risk of hyperproliferative diseases, the most deadly of which is cancer. This risk is mitigated by tumour-suppressor mechanisms, which either eliminate potential cancer cells by programmed cell death (apoptosis) or prevent their proliferation, often by permanently halting the cell division cycle (senescence). Therefore, the benefits to longevity afforded by stem/progenitor-cell proliferation might be compromised by mechanisms that prevent life-threatening cancer2. Three papersFootnote 1 in this issue now find that this is indeed the case3,4,5.

In mammals, the p16INK4a protein inhibits cell-cycle progression and induces cellular senescence6, and its expression rises with age in many tissues, as does the accumulation of dysfunctional senescent cells7,8. Janzen et al.3 (page 421) find that p16INK4a levels increase with age in mouse 'haematopoietic' stem cells (HSCs) derived from the bone marrow. Other bone-marrow cells did not express p16INK4a in an age-dependent manner, so p16INK4a is a bio-marker of ageing HSCs in the bone marrow.

But is this rise in p16INK4a expression biologically important? HSCs give rise to mature white blood cells. They can reconstitute these immune cells after being transplanted into mice that have been irradiated, and so have no HSCs. This reconstitution ability declines with age. Janzen et al.3 report that young mice (2–3 months old) that lack the p16INK4a protein (p16INK4a−/− mice) have similar numbers of HSCs to normal, 'wild-type' mice of the same age. Moreover, the wild-type and p16INK4a−/− HSCs are equally able to reconstitute an immune system after transplantation.

Later in life (14–20 months), however, the p16INK4a−/− mice had significantly more HSCs than wild-type mice. The older p16INK4a−/− HSC populations also had more dividing cells and were better able to reconstitute an immune system than were wild-type HSCs from mice of the same age. So lack of p16INK4a slows the age-associated decline in HSC function. Unexpectedly, however, the young p16INK4a−/− HSCs were less effective at reconstituting an immune system than were wild-type HSCs of either age. These findings suggest that, in young animals, p16INK4a prevents premature HSC exhaustion under the intense proliferative demand following transplantation. But in older animals, p16INK4a restricts HSC proliferation both under normal steady-state conditions and after transplantation.

Krishnamurthy et al.4 (page 453) studied a very different tissue in mice — the pancreas, which also shows an age-associated decline in function (here measured by insulin production) and in regenerative capacity. Expression of p16INK4a also increased in the pancreas during ageing (3–4 months compared with 16–20 months). This rise was confined mainly to the pancreatic islets, the cell clusters that contain insulin-producing β-cells and their progenitors.

The authors report two lines of evidence that p16INK4a limits islet-cell proliferation during ageing. First, mice genetically engineered to overexpress p16INK4a at young ages — to levels found in older wild-type animals — showed reduced islet-cell proliferation at all ages. Second, in mice deficient in p16INK4a, the age-associated decline in islet-cell proliferation was markedly diminished. When older wild-type mice were given a toxin that selectively kills β-cells, they developed diabetes that was eventually fatal. But, importantly, older mice deficient in p16INK4a developed only mild diabetes when exposed to the toxin. Recovery from the toxin requires β-cell proliferation and the regeneration of functional islets. After toxin treatment, the p16INK4a−/− mice had better islet-cell regeneration, greater insulin production and reduced blood-glucose levels than did wild-type mice. These differences occurred only between mice from the older age group, suggesting that the age-associated rise in p16INK4a impairs islet-cell regeneration and function, presumably by inhibiting the proliferation of β-cells and/or their progenitors.

In the third paper, Molofsky et al.5 (page 448) link p16INK4a expression in mice to decreased formation of neurons originating in the forebrain 'subventricular zone' (SVZ). As with HSCs and the pancreas, p16INK4a expression increased in the SVZ with ageing (from 2 to 24 months). Moreover, SVZ cell proliferation declined in vivo with age, as did the number of stem/progenitor cells that form clusters that can proliferate and retain the ability to differentiate in culture. Deficiency of p16INK4a partially mitigated both of these traits in older animals, but there was no effect in young animals. Lack of p16INK4a also slowed the age-associated decline in the formation of neurons in the olfactory bulb. Olfactory neurons are known to originate in the SVZ. Notably, p16INK4a deficiency slowed the age-dependent loss of SVZ stem cells (which divide continually but slowly), rather than stimulating the rapid proliferation of progenitor cells (the progeny of stem cells).

These findings suggest that p16INK4a causes a substantial part of the age-associated decline in the potential to form new SVZ neurons. However, p16INK4a deficiency did not prevent age-associated declines in cell proliferation in the dentate gyrus region of the brain or the enteric nerves in the gut, so different mechanisms may drive the ageing of stem/progenitor cells in other parts of the nervous system.

These three papers uncover a novel role for the p16INK4a tumour suppressor in promoting ageing (Fig. 1), a role shared by the p53 tumour suppressor9,10. But they also raise many questions. Does p16INK4a drive stem/progenitor-cell ageing by inducing an irreversible senescence arrest, a reversible quiescent state or another mechanism? What causes the age-dependent rise in p16INK4a expression? Is it induced by hormones such as those that regulate the insulin/IGF pathway during ageing11? Or is it caused by stress or damage signals within the cells? Given that p16INK4a deficiency only partly mitigates most of the ageing effects studied, what other mechanisms cause stem/progenitor-cell ageing? Finally, how important is the ageing of cells, in this case stem/progenitor cells, for the longevity of an organism? Does it depend on the type or level of stress that the organism experiences?

Figure 1: Dual activities of p16INK4a during ageing.

Ageing causes an increase in p16INK4a, a potent tumour suppressor that promotes longevity by suppressing the development of cancer. Three papers show that p16INK4a suppresses the proliferation of stem or progenitor cells in the bone marrow, pancreas and brain3,4,5. The mechanisms that induce p16INK4a during ageing are not known (black box). Once expressed, p16INK4a causes cellular senescence (grey box), a permanent growth-arrested state, which may be the mechanism by which this protein suppresses the proliferation of stem/progenitor cells. The decline in stem/progenitor-cell proliferation compromises tissue regeneration and repair, which is likely to reduce longevity.

Answers to these questions might clarify whether drugs that blunt p16INK4a expression or activity will ameliorate certain age-related diseases. Whatever the answers, it is important to remember that p16INK4a-deficient mice frequently succumb to cancer in mid-life (1.5–2 years). We will therefore need to know much more about the regulators and effectors of p16INK4a before these remarkable findings can be harnessed to make effective longevity-promoting therapies.


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    This article and the papers concerned3,4,5 were published online on 6 September 2006.


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Beausejour, C., Campisi, J. Balancing regeneration and cancer. Nature 443, 404–405 (2006).

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