2005) and myelodysplastic syndrome (MDS) (Yamaguchi et al, 2003), and in diseases not typically associated with blood disorders such as idiopathic pulmonary ﬁbrosis (IPF) (Armanios et al, 2007). In AA, 3 of 200 patients were found to have mutations in hTERC (Yamaguchi et al, 2003) and an additional 3.5% (7/200) had mutations in hTERT (Yamaguchi et al, 2005). In IPF, 1.4% (1/73) of patients were identiﬁed with hTERC mutations, whereas 6.8% (5/73) of patients with familial IPF had mutations in hTERT (Armanios et al, 2007). Families with mutations in telomerase genes typically dis- play disease ‘anticipation’, meaning that the disease typically presents at an earlier age in each subsequent generation (Vulliamy et al, 2004; Armanios et al, 2005). The most likely explanation for disease anticipation in telomerase disorders is that limiting amounts of telomerase activity in the germline result in gametes with shorter telomeres and, consequently, offspring with shorter telomeres. Shorter telomeres in stem cells at birth reduce the number of stem cell divisions before short telomeres trigger a DNA damage response and, even- tually, senescence or cell death. It is implied here that all disease manifestations of telomerase disorders are likely to result from compromised cell and tissue renewal. From the spectrum of phenotypes of patients with known telomerase deﬁciencies, one can deduce that the stem cells of the oral mucosa, the skin (especially in the head and neck area), the nails, the lung, the bone marrow and the liver rely on telomerase to sustain proliferation the most or have the highest turnover of all the stem cells in the human body. Why speciﬁc tissues seem to be affected more than others in individual patients is incompletely understood. It seems possible that environmental factors contribute to disease manifestations, for example smoking in patients with pulmonary ﬁbrosis or alcohol consumption in patients presenting with hepatic cirrhosis. In such patients, a reduced stem cell reserve could lead to symptoms by increasing the demand on the turnover of remaining tissue-speciﬁc stem cells by environmental toxins. Among environmental ‘toxins’, factors induced by viral or other infections, such as interferon alpha (Essers et al, 2009), or factors stimulated by, for example, sustained psychological stress (Epel et al, 2004) should probably be included. Indeed, such factors are likely to accelerate tissue turnover and thereby ageing even in individuals without speciﬁc ‘telomere maintenance’ disor- ders. Other known or unknown ‘extrinsic’ factors, including speciﬁc diseases, could also affect tissue-speciﬁc stem cell numbers. The role of telomere attrition in cardiovascular disease is of particular interest. Telomere length was found to be much shorter in endothelial cells from the aorta compared with those from pulmonary arteries of the same organ donor, and it was suggested that this could reﬂect differences in hemodynamic stress to the vessel wall (Chang and Harley, 1995). Striking cytogenetic abnormalities have also been described to accumulate in aorta endothelial cells with age (Aviv et al, 2001). Despite uncertainties about the replicative or regenerative potential of endothelial cells, it seems plausible that this capacity will not exceed that of other somatic (stem) cells. Extrinsic factors, such as smoking, diabetes, high blood pressure, diet, etc., could result in loss of endothelial cells or function and trigger cardiovascular dis- ease in the absence of additional genetic factors that com- promise the replicative potential of cells such as heritable telomerase deﬁciencies (Farhat et al, 2008; Wong et al, 2009). & 2009 European Molecular Biology Organization Telomeres and disease PM Lansdorp Reduced telomerase levels as well as short telomeres are expected to compromise the number as well as the replicative potential of stem cells that remain in speciﬁc tissues after extrinsic or intrinsic damage from the environment. Alternatively, disease could be triggered by additional genetic factors. For example, cell-speciﬁc turnover could be increased by a speciﬁc genetic defect or a polymorphic trait that increases the likelihood of cell death in response to injury. Presumably, such genetic co-factors can be distinguished from environmental co-factors by careful studies of both environmental exposure as well as the genotype of a given patient relative to family members that are not affected or that display other disease manifestations. Finally, it seems possible that disease manifestations of human telomerase disorders are the result of stochastic telo- mere loss events at individual telomeres during development. Telomere repeats are lost not only as a result of the ‘end- replication problem’, but also as a result of sporadic ‘trunca- tion’ events that could have several different causes (Lansdorp, 2005). Recently, it was found that within the haematopoietic system the most primitive haematopoietic cells have fewer abruptly shortened telomeres compared with more differentiated cells (Hills et al, 2009). The level of telomerase could be important when more than a few spora- dic telomere loss events occur or accumulate in a cell at any given time (Aubert and Lansdorp, 2008). In cells with overall shorter telomeres and lower telomerase levels to start with, cell death events could occur more frequently during normal development. Both the number and the replicative potential of remaining tissue-speciﬁc stem cells could be compromised stochastically depending on when cell death occurred during development and whether remaining cells had to go through extra divisions to make up for the loss of cells. The distinction between environmental, genetic and stochastic reasons for the variable clinical presentation of patients with telomerase disorders is a major research challenge. This challenge is augmented further by the distinct possibility that the speciﬁc disease manifestation in an individual patient results from a combination of these and other factors. Telomere defects and cancer predisposition Telomerase is upregulated in a majority of human cancers (Kim et al, 1994; Cao et al, 2008). This upregulation is believed to be required to allow malignant cells to divide after genetic rearrangements enabled by telomere dysfunc- tion. In view of the telomerase requirement in (late stage) cancer growth, the recent ﬁnding that heritable defects appear to predispose for the development of acute myeloid leukaemia seems perhaps counterintuitive (Calado et al, 2009). However, patients with DC or bone marrow failure resulting from mutations in telomerase genes often develop leukaemia or other types of cancer (Alter et al, 2009). Leukaemia and other malignancies are also well-known complications of high-dose chemotherapy regimens and MDS. Most likely, the loss of stem cells by telomere dysfunc- tion or treatment creates an environment in which abnormal cells can ﬂourish. This could reﬂect persistent feedback signals stimulating stem cell proliferation from the microen- vironment. With many stem cells present, such stimulation is expected to occur only transiently, whereas with few or no normal stem cells responding, such stimulatory signals could The EMBO Journal VOL 28 | NO 17 | 2009 2537