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Before the discovery of telomeres, all cells were thought to be immortal and aging was therefore thought to exist at the higher level of the organism, usually couched in vague terms of wear-and-tear or cumulative damage. But in the past 15 years, the genetic causes of the family of related diseases known as Progeria, where aging appears to be accelerated, have been progressively uncovered and they have shown us unequivocally that in these diseases, and therefore most likely in 'normal' aging, the root cause is in fact cellular aging. As such, they provide compelling evidence for the telomere theory of aging.

Progerias Seem to Hold the Key

Hutchinson-Gilford Progeria Syndrome (HGPS), the most commonly known of the progerias and typically the one associated with the term, displays a long list of symptoms synonymous with aging including wrinkled skin, balding, atherosclerosis, osteoporosis, hip dislocation, prominent veins, joint problems, slow healing and cerebrovascular disease. Progeric children die at a mean age of 12.7 years overwhelmingly from atherosclerosis - the hardening and thickening of the arteries usually associated with much older people.

If the negligible senesence of the lobster seems to strongly suggest one mechanism for aging, rather than a host of unrelated wear-and-tear causes which the lobster is somehow uniquely able to battle on a myriad of different fronts, then Progeria hits us over the head with this conclusion. One cannot seem to help but come to the verdict that all of these characteristics of Progeria are the symptoms of one underlying cause which is also shared with aging. And above all, it suggests that aging is not the gradual, haphazard falling apart of the body in the way that a car might 'age'. If it were, how could this disease mirror aging so well and in so many ways, all at an accelerated pace?

The Cause of HGPS and Werner Syndrome

We are fortunate to be living in a time where the causes of these tragic diseases have been discovered and therapeutic treatment, both for Progeria (3) and normal aging may be on the way. A 2003 report in Nature, now generally accepted in the scientific community, concluded that the cause of the HGPS is a mutation in the LMNA gene that develops during cell division in a newly conceived child. The LMNA gene, located on chromosome 1, codes for the Lamin A protein, the substance that creates an insoluble barrier around the nucleus of a cell and protects its contents from damage. In particular, the recognition site that the enzyme required for the cleavage of Prelamin A to Lamin A is mutated, and Prelamin A builds up on the nuclear membrane, causing a mishapen nucleus and 'blebbing'.

A follow-up study entitled Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis found that the compromised nucleus was no longer protecting the nuclear DNA from damage, which was leading to aptopsis - cell suicide - and causing the remaining cells throughout the body to hyperproliferate in a desperate attempt to replace the lost cells. So in other words, most remaining cells in the body of these patients are ones that are burning through their 50-70 divisions that the telomeres allow them in 12 short years. And as a result, the authors of the study find a far greater percentage of senescent cells in the Progeric individuals (as is the case in the elderly) when compared to healthy individuals, which is the result of those cells hitting the Hayflick limit. (4) What the authors did not mention, as in 2003 the Telomere Position Effect was a relatively nascent theory, was that as these cells hyperproliferate and consequently burn down their telomere length at an accelerated rate, it is now known that the gene expression in those cells was being altered as well.  

Werner Syndrome (WS), an adult-onset accelerated aging disease that usually strikes in the mid-30s, shares many of the accelerated characteristics of HGPS, including poor wound healing, cataracts, gray hair, sarcopenia and osteoporosis. Its cause is an abnormal WRN gene, which is now known to code for proteins that play a role in telomere maintainance. 8 When telomerase expression postponed WS cells senescence in vitro it became more clear that Werner syndrome is most likely a case of some sort of malfunction in telomere maintaince. The exact nature of the problem, though is not known. Michael Fossel has suggested that the WRN mutation might cause an increase in the 'telomeric overhang', which defines the rate of telomeric loss per cell division, which would cause a larger chunk of the telomere to be lost with each cell division.

HGPS and Werner Syndrome Causes Support the Telomere Theory

These syndromes provide strong evidence in favor of the telomere theory. Finally after more than a century since these diseases were diagnosed, an advanced understanding of the human genome has allowed us at last to discover their cause, and thereby peer into the heart of aging. And the cause was not a hormonal imbalance, overexposure of toxins, high LDL count, increased metabolic rate, vulnerabilty to free radicals or other such high-level phenomenon that some modern aging theories would predict. The cause was inside the cell. The cause was cellular aging, apparently mediated by telomere loss attendant to cell division.

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