Why does loss of telomerase activity in humans lead to severe phenotypes in the first generation, while loss of telomerase activity in laboratory mice takes several generations to exhibit any sort of phenotype?

Human telomeres are short.

Explanation:

Telomeres are the short stretches of DNA present at the end of chromosome. The telomerase enzyme regulates the maintenance and replication of telomeres.

Human telomeres are short and the loss of telomerase activity can cause cancer and ageing problem in the humans. Mouse have long telomerase and loss of telomerase activity does not cause any serious harm.