Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage.

Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC-/-) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis. Specific changes in gene expression were associated with telomere shortening and chronic liver damage and these gene expression changes were partially reversed by adenovirus mediated telomerase gene delivery. This study gives experimental evidence that the negative impact of telomere shortening on organ homeostasis and organismal survival can surpass the beneficial effects of telomere shortening on suppression of tumor growth in the setting of chronic organ damage.