The in vivo relevance and specific roles of telomeres in the processes of ageing, degenerative diseases and cancer development were initially defined by the generation and characterization of laboratory mice null for either the Terc or Tert gene. Remarkably, mice null for either Terc or Tert seemed healthy and phenotypically unaffected, establishing that telomerase activity is dispensable for life57,58. This notable lack of a phenotype was postulated to be due to generous telomere reserves that retain capping function in first-generation (G1) Terc−/− mice57. Indeed, successive generations of Terc−/− mice had critically short telomeres and chromosomal end-to-end fusions. Coincident with cytogenetic evidence of telomere dysfunction (signal-free ends and end-to-end fusions), late-generation (G3 and beyond) Terc−/− mice had a shortened lifespan, overall frailty, decreased fecundity and tissue atrophy with impaired organ function59 (Fig. 2). The widespread tissue degenerative phenotypes included anaemia and lymphopenia, kyphosis and osteoporosis, mild glucose intolerance and other classic age-related phenotypes26. The severity of these degenerative phenotypes parallels the degree of telomere dysfunction in successive Terc−/− generations, as measured by the number of chromosomal fusions and anaphase bridges and,
