Disease states associated with telomerase deficiency appear earlier in mice with short telomeres

Mice deficient for the mouse telomerase RNA (mTR(-/-)) and lacking telomera se activity can only be bred for approximately six generations due to decre ased male and female fertility and to an increased embryonic lethality asso ciated with a neural tube closure defect, Although late generation mTR(-/-) mice show defects in the hematopoietic system, they are viable to adulthoo d, only showing a decrease in viability in old age, To assess the contribut ion of genetic background to the effect of telomerase deficiency on viabili ty, we generated mTR(-/-) mutants on a C57BL6 background, which showed shor ter telomeres than the original mixed genetic background C57BL6/129Sv. Inte restingly, these mice could be bred for only four generations and the survi val of late generation mTR(-/-) mice decreased dramatically with age as com pared with their wild-type counterparts. Fifty percent of the generation 4 mice die at only 5 months of age, This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, spl enic atrophy, reduced proliferative capacity of B and T cells, abnormal hem atology and atrophy of the small intestine, These results indicate that tel omere shortening in mTR(-/-) mice leads to progressive loss of organismal v iability.