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.