November 30, 2010

expert reaction to research in Nature on reversing age-related tissue degeneration

New research published in Nature suggests it is possible to halt and even reverse age-related tissue degeneration in mice.

Dr. Lynne Cox, Lecturer in Biochemistry, University of Oxford, said:

“”In this landmark paper by the DePinho group, the researchers show for the first time that it is possible to rejuvenate old tissues such as the gut, spleen and perhaps most importantly, the brain, by turning on the enzyme telomerase that restores chromosome ends or telomeres.

“Telomeres provide a mechanism for cells to ‘count’ how old they are, since they shorten every time a cell divides. Once the telomeres reach a certain critically short length, the cell detects this as DNA damage and stops dividing. This is an important mechanism to prevent cancer development – cells with damaged DNA are much more likely to give rise to cancers unless they can be stopped from dividing. Two key molecules, the tumour suppressor p53 and its target, the cell cycle inhibitor p21 Cip1, are responsible for much of the signalling to stop damaged cells dividing.

“In this paper, the researchers generate a strain of mice which do not make functional telomerase unless the drug 4-hydroxytamoxifen (4-OHT) is added. They bred the mice until their telomeres were every short, and showed that such mice had DNA damage in their intestines and spleen, reduced fecundity and decreased brain size and myelination, as observed in normal ageing. Excitingly, when they reactivated telomerase for only 4 weeks in the adult mice by 4-OHT treatment, marked regeneration of critical tissues was observed. In terms of human ageing, one of the biggest concerns is ‘losing one’s marbles’ – loss of cognitive ability with age, forgetfulness or even full-blown senile dementia. However, reactivation of telomerase for 4 weeks in the experimentally-aged mice restored the ability of neuronal stem cells to divide and repopulate the brain, including re-myelinating neurones (which is anticipated to improve their activity). They even showed that the treatment could restore the ability of old mice to smell unpleasant smells (loss of smell is a marked problem in mammalian ageing, including in humans).

“This paper is thus extremely important as it provides proof of principle that short-term treatment to restore telomerase in adults already showing age-related tissue degeneration can rejuvenate aged tissues and restore physiological function. There is a major caveat in that telomerase reactivation can promote progression of already established tumours – apparently the short-term treatment in itself did not lead to increased carcinogenesis. It is also important to appreciate that these were genetically engineered mice and that reactivation of telomerase by 4-OHT only works in these mice because of the gene fusion that they carry. However, telomerase reactivation agents are in development that may act in normal cells in which telomerase has been ‘switched off’ during development.””

Prof Tom Kirkwood, Director of Institute for Ageing and Health, Newcastle University, said:

“”The essential role of vitamin C for human health came to light when sailors, deprived of fresh fruit and vegetables for long periods, developed scurvy, which was cured by restoration of normal foodstuffs or by use of lemon or lime juice. In one sense, therefore, there is nothing very remarkable about the claim made in the paper by DePinho and colleagues that “telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice”. The pathology seen in telomerase-deficient mice is the direct consequence of removing telomerase from an animal in which it would normally be found. Therefore, is it surprising that putting it back again sets things right? Actually, this is an elegantly executed study revealing that restoring telomerase does indeed restore function where it was beginning to be lost, in particular by reversing important aspects of neurodegeneration.

“The key question is, however, what might this mean for human therapies against age-related diseases? In humans, telomere erosion in somatic tissues occurs because telomerase is usually absent, different from the normal situation in mice. While there is some evidence that telomere erosion contributes to age-associated human pathology it is surely not the only, or even dominant, cause, as it appears to be in mice engineered to lack telomerase. Furthermore, there is the ever present anxiety that telomerase reactivation is a hallmark of most human cancers.

“In summary, this is important research establishing firmly the principle that telomerase restoration, even when pathology has arisen through telomere erosion, is feasible. Just how significant it will prove for potential interventions in humans, where both the pattern of telomerase expression and the mechanistic basis of age-related diseases are somewhat different, is as yet uncertain.””