Telomeres and disease PM Lansdorp Table I Phenotype of telomerase reverse transcriptase gene mutations Species Homozygous ( / ) Heterozygous ( /+) References Budding yeast Viable for up to many (410) generations Fission yeast Delayed growth defect Caenorhabditis elegans Viable for up to 6 generations Arabidopsis Viable for up to 10 generations Mouse Viable for up to 6 generations Human Not known (lethal?) No overt phenotype No overt phenotype No overt phenotype No overt phenotype No overt phenotype Various disorders including Dyskeratosis Congenita, aplastic anemia and pulmonary ﬁbrosis. Cancer predisposition Reviewed in Lundblad (2002) Haering et al (2000) Cheung et al (2006) Fitzgerald et al (1999) Liu et al (2000) Vulliamy et al (2001), Fogarty et al (2003), Yamaguchi et al (2005), Armanios et al (2007), Calado et al (2009) Figure 1 What came ﬁrst, the chicken or the egg? Chickens (and hens) can be regarded as the mortal carriers of immortal germline DNA. Natural selection results in somatic (stem) cells that do not devote more energy on DNA repair and tissue maintenance than is required for the reproductive strategy and corresponding lifespan of a particular species. According to the ‘disposable soma’ theory, ageing is not actively programmed, but results from the accumulation of damage after reproduction (Kirkwood and Holliday, 1979). Long-lived species that reproduce after many years need more efﬁcient DNA repair and better protection against tumour development than comparable species that reproduce within weeks or months. Somatic cells from long-lived species show loss of telomeric DNA with each division. Telomere loss is not readily observed in cells from most short-lived species. Most likely loss of telomeric DNA represents a tumour suppressor mechanism that does not exist as such in somatic cells from short-lived species. telomere biology and DNA repair between cells, tissues and species. At the single cell level, many signalling and cell cycle checkpoint pathways are integrated to allow cells to make life or death decisions (Cook et al, 2009). Many of the molecules involved in such decisions are highly conserved between species. However, constant selective pressure has also resulted in very speciﬁc differences between cells and between species. No doubt, many aspects of the pathways involved in cell signalling and cell cycle checkpoints and their connectivity remain to be uncovered and better understood within speciﬁc cells. Differences in such pathways within cells of a given species need to be understood better before the added complexity of species-speciﬁc differences can be fruitfully dissected. However, in the context of growth control and malignant transformation, some differences between species have already been described. For example, DNA damage foci originating from short, dysfunctional telomeres (d’Adda di Fagagna et al, 2003) increase in number with accumulated cell divisions and with age in human and primate cells, but not in murine somatic cells and tissues (Sedivy, 2007). These and other observations (Hahn et al, 1999; Smogorzewska and de Lange, 2002) support the idea that loss of telomeric DNA prevents tumour growth and contributes to ageing in human beings and primates, but probably does not function in this way in laboratory mice (with long telomeres), plants, worms, ﬂies and yeast. Interestingly, telomere loss can be made to also limit cell proliferation and tissue renewal in mice (Hao et al, 2005; Deng et al, 2008). In these studies, cell proliferation appears & 2009 European Molecular Biology Organization to be limited primarily by telomere loss and only indirectly by telomerase levels. Differences in DNA repair between cells and species? Consider two species with a greatly different lifespan. The comparable somatic (stem) cells from such species are ex- pected to have different requirements in terms of the type and efﬁciency of various DNA repair pathways to ensure that germline DNA is successfully propagated across generations. According to the ‘disposable soma’ hypothesis, ageing results primarily from failure to maintain genome integrity in so- matic cells after reproduction (Kirkwood and Holliday, 1979). The key concept here is that organisms with cells that do spend more energy on DNA repair and other cellular ‘main- tenance’ functions than is strictly required for production of viable offspring are likely to be at a disadvantage relative to those that do not. Thus, differences in lifespan and repro- ductive strategy between species will be reﬂected in differ- ences between the type and efﬁciency of various DNA repair pathways. The notion that the efﬁciency of DNA repair is subject to natural selection is not as popular as the more commonly emphasized ideas that evolution proceeds by selection of variants within a species that carry favourable DNA mutations or the simpler notion that ageing is a consequence of DNA damage (Schumacher et al, 2008). The emphasis on DNA repair rather than DNA damage in the context of ageing has practical implications: a focus on increasing the efﬁciency of DNA repair is not the same as a The EMBO Journal VOL 28 | NO 17 | 2009 2533