The role of telomerase in brain during ageing and under dietary restriction

PhD ThesisTelomerase is best known for its nuclear telomere maintenance function via its enzymatic activity requiring the two major components TERT (protein) and TERC (RNA). However, telomere and TERC-independent functions for TERT have been described recently. Our group and others have previously shown that telomerase shuttles to mitochondria improving their function and decreasing cellular oxidative stress. Oxidative stress and mitochondrial dysfunction are well known to increase during ageing and have been implicated as a cause for age-related neurodegenerative diseases. I report that TERT protein localises in mammalian brain mitochondria specifically in neurons. Moreover, although telomerase activity is negligible in brain, I found considerable amounts of the telomerase protein TERT in mouse and human brain by independent techniques. Dietary restriction (DR) is known as a condition that improves mitochondrial function, delays or prevents age related diseases and improves cognitive function. In this study mTert was detected in brain mitochondria under basic conditions, and it becomes elevated in brain mitochondria of animals in three independent experiments of short term (3-6 months) DR. Decreased signalling through mTOR has been described as a major mechanism of the DR response. Accordingly, I found that mTOR phosphorylation was down regulated in brains from DR animals. Moreover, to analyse whether decreased mTOR signalling causes mitochondrial redistribution of mTert, mTert wild type and mTert knock-out mice were treated with rapamycin what resulted in increased mTert protein in brain mitochondria and correlated with decreased mitochondrial ROS production. The conclusion is that down-regulation of mTOR is a possible mechanism to increase mTert protein levels within mitochondria under DR. Together, this data shows that mitochondrial mTert might be an important new player in the protection of neurons and improve brain function during agein