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Criticisms of the Telomere Theory


Criticisms

Initial telomere aging theories were crude and in some circles appear to still be alive: the telomeres were necessary to hold together the structural integrity of the chromosomes that they capped, and when they get too short, the cells would enter crisis and senesce. The accumulation of senescent cells was aging.

This quickly lead to some apparent paradoxes - why are the telomeres of mice longer than humans and yet they live shorter lives? If telomeres cause aging, why are the telomeres of some species still very long when they typically die of old age? Even in humans, the typical journey of telomere length is from 12 to 7 'kilobase pairs'. Doesn't that leave plenty of room to 'cap' the chromosomes? There also has been some debate as to whether older people possessed enough senescent cells to justify the physical aging of their tissues.  Finally, many cells such as muscle, cardiac and nervous system cells do not divide, so should not be affected by telomeres and yet they still age.

Resolutions

Certainly a great deal of complexity in telomere biology is yet to be unraveled, but a more nuanced concept of the telomere and its function has emerged to resolve these issues. It is now understood that telomore shortening does more than march one step closer to ‘fraying’, or compromising genomic stability caused by the cap wearing away to the end. Additionally, it controls the gene expresssion of all the genes on that chromosome through the Telomere Position Effect (TPE). Again, how this works is unknown (some have suggested a hood mechanism), but somehow the genes on the outer ends of the chromosomes, that is the ones closest to the telomeres, are being induced to change their expression, as the ends of the telomere erode and come closer to them. Furthermore, Dr. Michael Fossel, probably the premier advocate of the strong version of the telomere theory of aging to which we subscribe, makes a very persuasive argument in his book Cells, Aging and Human Disease, (pg 36) that it is not the absolute length which controls this, but the relative erosion of the telomere from the time the egg was fertilized. As he puts it, “Telomere length is irrelevant, telomere loss is critical”. If true, this would explain how mice can have long telomeres compared to ours but still have shorter life spans. The telomere loss (and not the telomere length) alters gene expression with each division and it is thereby aging the mouse regardless of how long the telomeres were at the beginning, or end, of the process. The cell then most likely enters senescence not because the chromosomes are not properly capped, but because the gene expression has been so radically altered that the cell ceases to be functional.  The possible controversy over whether some older people had enough senescent cells to explain their aged tissue is resolved by the fact that cell senescence is only part of the picture.  Gene expression patterns are causing all the cells in an older person to be less functional and express a phenotype of an older cell.  And senescent cells are playing their part as well. They are simply part of the larger picture of increasingly 'older' and dysfunctional cells and represent the worst and most dysfunctional of that lot - being incapable of division and in fact highly toxic to neighboring cells.

The criticism that neuron cells, heart cells and muscle cells do not divide is a strong objection, but the response to this, outlined very thoroughly in Cells, Aging and Human Disease is that these cells simply need support from the team. Each neuron, for example, is surrounded by many glial cells, which do divide and whose telomeres do erode. Consequently, in old age these cells are lost and the neurons lose their support from them.9  Furthermore, blood supply to the brain is significantly compromised as the cells of the inner lining of the arteries begin aging and 'senescing' due to telomere erosion10.  Dr. Fossel, who in addition to holding a PhD in Nuerobiology from Stanford is also a medical doctor, dedicates a chapter in his book for each tissue type made of non-dividing cells and chronicles in great detail how loss of support from dividing cells would be very consistent with the pathology that we observe in the non-dividing tissues as we age.   We highly recommend his book overall and in particular to anyone interested in hearing a thorough and painstakingly referenced response to this objection.

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