3.4. EVIDENCE THAT INHIBITION OF TELOMERE SHORTENING EXTENDS CELLULAR LIFESPAN
The mechanisms regulating organismal aging are complex and it is unlikely that any single mechanism will explain all or even most of the molecular and physiological changes that occur as we age. However, it is theoretically possible that slowing down the rate of telomere shortening could slow down the aging process in specific tissues where proliferative senescence is known to occur. While there have been many studies indicating that there is a correlation between telomere shortening and proliferative failure, the evidence that it is causal has only recently been demonstrated (13, 14), the first evidence for causality showed that telomere shortening caused the M2 mechanism. Telomere length determines the proliferative capacity of human cells (13), besides telomere shortening controls the onset of the M2 mechanism.
Experimental work made with telomerase RNA, hTR (30) and its catalytic reverse transcriptase protein subunit, hTERT (31-32), showed that hTERT is the main catalytic protein component of telomerase. Further investigations with normal human cells expressing telomerase showed that hTERT is the limiting component necessary for restoration of telomerase activity in normal cells (33), telomerase activity is sufficient to stop telomere erosion and result in extension of proliferative lifespan (14), telomere shortening determines the onset of the M1 mechanism.
|• Cells in the germline express telomerase without increased oncogenesis|
|• In the absence of other mutations, telomerase is not sufficient for tumor development|
|• Telomerase repression generally but not always imposes a blockade to oncogenesis|
|• In the presence of other mutations, telomerase may be permissive for tumor development|