Telomeres and disease PM Lansdorp focus on reducing DNA damage. Indeed, limited exposure to DNA damage could stimulate repair and be more effective at increasing lifespan (Kaiser, 2003) than attempts to limit DNA damage altogether (e.g. with ‘anti-oxidants’). This line of reasoning is supported by the known beneﬁt of (moderate) exercise and low-dose irradiation on the lifespan in various organisms (Calabrese and Baldwin, 2003; Radak et al, 2008). No doubt, many differences in the type and efﬁciency of DNA repair pathways in speciﬁc cells within tissues and comparable (stem) cells between species remain to be un- covered. However, some notable differences have already been described. For example, DNA repair changes dramati- cally during neuronal differentiation (Nouspikel and Hanawalt, 2000) and the repair of double strand (ds) DNA breaks through molecules such as Ku70/80 and DNA-PK in the non-homologous end joining (NHEJ) pathway is much more efﬁcient in human than in murine cells (Banuelos et al, 2008 and references therein). Differences in NHEJ between mice and man could reﬂect the fact that human (stem) cells reside for much longer periods in a dormant G0 or G1 state of the cell cycle compared with their murine counterparts. Repair of ds DNA breaks through homologous recombination is less efﬁcient in G0 or G1 (Aylon et al, 2004) and better NEJH repair of DNA (ds) breaks in human cells may reﬂect the slower turnover of human cells (Wilson et al, 2008). The main point here is that the efﬁciency and the type of DNA repair in somatic as well as germline cells have been and are subject to natural selection. As a result, the efﬁciency of DNA repair in stem cells from species that reproduce rapidly is expected to be less than that in stem cells from species that take years to reproduce.3 Highly effective DNA repair required in somatic stem cells from long-lived species creates a novel risk: abnormal so- matic stem cells, though perhaps less likely to arise, are more likely to propagate their abnormal genomes and survive. Such risks are superimposed on the inherent risk of living longer: more time for mutations to accumulate. It seems plausible that the additional risks to stem cells in long-lived species have favoured the evolution of telomere attrition as a tumour suppression mechanism (reviewed in Aubert and Lansdorp, 2008). The lack of a similar telomere-related counting mechanism in short-lived species and model organ- isms provides an explanation for the different consequences of telomerase deﬁciency in human beings and model organ- isms (Table I). Unfortunately, the tumour suppressor function of telomeres in human cells poses a major hurdle in studies of human telomere biology. For example, suitable murine mod- els for human carcinomas, the most common type of human malignancies, are only obtained after telomere function is severely compromised (Artandi et al, 2000). The difference in telomere biology between mice and man has also hampered the development of suitable murine models for other human diseases including Werner’s syndrome (Chang et al, 2004). If one accepts that telomere loss indeed evolved to limit the growth of pre-malignant cells in human beings, it should be noted that this mechanism has two serious ﬂaws (Figure 2). First, the mechanism is subject to failure when two chromo- 3 In this context, it is perhaps of interest to consider that the presence of many error-prone DNA polymerases in various genomes could reﬂect an evolutionary advantage of cells capable of generating many mutations in times of stress; e.g. see Tippin et al, 2004. 2534 The EMBO Journal VOL 28 | NO 17 | 2009 some ends with insufﬁcient telomere repeats fuse with each other. Such fusion events (e.g. between sister chromatids or between different chromosome ends) will extinguish the DNA damage signals that originated from the short telomeres. The removal of this checkpoint is predicted to allow cells to enter mitosis. Dicentric chromosomes formed by end-to-end fusion are likely to break on mitosis and initiate cycles of chromosome bridge/breakage/fusion (de Lange, 1995). This type of genome instability greatly facilitates deletion and ampliﬁcation of genes and, as a result, the malignant evolu- tion of (pre-) malignant cells. Second, by limiting the growth of (pre-) malignant cells, the DNA damage response triggered by short telomeres (d’Adda di Fagagna et al, 2003) will become subject to strong negative selective pressure. Such selection favours cells with defective DNA damage responses. Indeed, this seems a plausible mechanism, whereby most human tumours acquire defective DNA damage responses (e.g. over half of all human cancers have mutations in the p53 gene (Vousden and Lane, 2007)). As DNA damage responses are upstream in many different DNA repair pathways, cells selected on the basis of their inability to respond appropri- ately to short telomeres will display defects in several differ- ent DNA repair pathways. Indeed, it seems plausible that genome instability triggered by unstable chromosome ends in cells with defective DNA damage response result in the ‘mutator cell’ phenotype that is characteristic of many tumour cells (Loeb, 2001). That chromosomal instability can be initiated by disruption of telomere function and that microsatellite instability and other genomic alterations often seen in cancer cells could arise from defective DNA damage responses indirectly selected by telomere shortening does not seem to be widely accepted (Michor et al, 2005). These ideas nevertheless seem plausible and worthy of further investiga- tion. Apart from the difﬁculty of ﬁnding suitable model organisms, such studies are complicated by the transient period of rampant genome instability driven by telomere dysfunction. Sooner or later, most abnormal cells typically stabilize their chromosome ends (and at that stage typically highly abnormal genomes) by upregulation of telomerase activity (Kim et al, 1994). The frequent ampliﬁcation of the telomerase reverse transcriptase gene in human lung cancer suggests that break–fusion–bridge cycles involving chromo- some 5p is frequently involved in the upregulation of telomerase activity in those cells (Weir et al, 2007; Kang et al, 2008). How many stem cell divisions? If telomere attrition evolved to limit the number of somatic cell divisions in long-lived species, one might ask how many times stem cells in tissues actually divide. Unfortunately, and perhaps surprisingly, no clear answer to this important question is currently available. Haematopoietic stem cells (HSCs) are probably the most extensively studied stem cell population. From studies of both human and murine HSCs, it has become clear that HSCs represent a very heterogeneous population of cells that do not self-renew in the absolute sense of the word (Lansdorp, 1997). The functional proper- ties of puriﬁed ‘candidate’ stem cell populations change markedly during development in both man (Lansdorp et al, 1993) and mouse (Bowie et al, 2006; Kim et al, 2007). Such functional changes correspond to a rather abrupt change in & 2009 European Molecular Biology Organization