Telomeres get shortened with each replicative cycle and are thus crucial for genome integrity. Telomere lengths are species-specific; however, there is a week correlation between telomere length and lifespan. Moreover ultra-long telomeres in laboratory mice appear to arise from excessive cross-mating with in small colonies. Most of the knowledge about telomeres arise from replication competent tissues however the importance of telomere attrition in low level replicative CNS is unknown. Here we determined the impact of ageing and genetic refreshment on the relative telomere length (RTL) in the brain of two C57BL/6 strains as a function of cell cycle activity. We show that telomere shortening eventuates in the ageing murine brain in both replication-dependent and -independent manner but in the absence of genetic refreshment. Hermetically inbred mice exhibited a substantially faster rate of age-associated telomere erosion in neural cells compared to genetically refreshed mice. Additionally, telomerase enzyme activity responsible for de novo addition of telomere repeats, remained unchanged with ageing in genetically non-refreshed strain relative to conventionally inbred strain which coincided with upregulated levels of RelA, a subunit of the classical NF-B cascade for which a feed-forward interaction with TERT has recently been demonstrated in a malignant environment. Additionally, we analyzed the telomere length and telomerase activity in a murine model mimicking amyotrophic lateral sclerosis (ALS) pathology. ALS is a neurodegenerative disorder with complex pathomechanism. Our data revealed unexpected telomere lengthening in the cortex and spinal cord with disease progression. Furthermore, we showed specific disease-associated patterns of telomerase activity for different CNS regions Thus, differential regulation of telomere length and telomerase activity occurs in the ageing and diseased CNS and it will be interesting to investigate the role of specific neural cell types in the telomere erosion process and its link to the ageing and neurodegenerative brain.