Telomere Shortening reduces Survival despite Suppression of Carcinoma Formation during Chronic Liver Damage

Telomere shortening limits the regenerative capacity during aging and chronic disease but at the same time inhibits tumor progression. To use telomerase-therapy for the treatment of regenerative disorders it will be important to analyze which of these mechanisms dominantly affects survival.

In HBV-transgenic mice, a model of chronic liver damage, crossed with telomerase deficient (mTERC-/-) mice the impact of telomere shortening on hepatocellular cancer (HCC) and liver regeneration was tested. We analyzed mTERC+/+ wildtype mice and late generation G3mTERC-/- mice, both either HBV-positive or negative. The animals were sacrificed at 5, 10 and 15 month resp. and livers were histological characterized.

In this telomerase knockout mouse model we show that during chronic liver damage telomere shortening significantly reduces survival. Specifically, 50% of the HBV-positive G3mTERC-/- mice were dead at a time point of 14 month whereas in the TERC+/+ cohort at this time point 81% were still alive. Interestingly, the survival of G3mTERC-/- mice was reduced despite significant inhibition of hepatocellular carcinoma (HCC) formation in these mice compared to mTERC+/+ mice. Specifically 45% of the mTERC+/+ mice developed HCC at an age of 15 month, whereas non of the G3mTERC-/- mice developed HCC. Decreased survival induced by telomere shortening correlated with impaired liver regeneration and reduced liver function. Especially the ratio of cell apoptosis/regeneration was disturbed in HBV-positive G3mTERC-/- mice compared to mTERC+/+ mice. In line with reduced liver regeneration the size and growth of HBV-negative foci was reduced in G3mTERC-/- compared to mTERC+/+ mice.

This study gives first experimental evidence that telomere stabilization during chronic organ damage could be beneficial for survival.