X-Message-Number: 31296
Date: Tue, 23 Dec 2008 09:59:18 -0800 (PST)
From: 
Subject: do shortened telomeres cause aging in humans?

[Probably not, since EPC telomeres are not reduced in middle aged humans.
Rather than being a prime cause of aging, shortened telomeres, which do
characterize old humans, are probably an effect of aging, rather than a
cause. IMHO, EPC telomere length is maintained for as long as the EPC
environment is maintained. When this environment deteriorates with age, then
telomere length is reduced. Again IMHO, aging is a series of dominos falling
down. No significant advances against this process can occur until the
identity of the initial dominos to fall can be conclusively identified.
Forcing "downstream" dominos to stay erect, will not have the same global
effect as doing the same with these initial dominos.]

Clin Chem Lab Med. 2008 Dec 5. [Epub ahead of print]
Aging and endothelial progenitor cell telomere length in healthy men.
  Kushner EJ, Van Guilder GP, Maceneaney OJ, Cech JN, Stauffer BL, Desouza
CA. 1Department of Integrative Physiology, Integrative Vascular Biology
Laboratory, University of Colorado, Boulder, CO, USA.
  Abstract Background: Telomere length declines with age in mature
endothelial cells and is thought to contribute to endothelial dysfunction
and atherogenesis. Bone marrow-derived circulating endothelial progenitor
cells (EPCs) are critical to vascular health as they contribute to both
reendothelialization and neovascularization. We tested the hypothesis that
EPC telomere length decreases with age in healthy adult humans. Methods:
Peripheral blood samples were collected from 40 healthy, non-obese,
sedentary men: 12 young (age 21-34 years), 12 middle-aged (43-55 years) and
16 older (57-68 years). Putative EPCs were isolated from peripheral blood
mononuclear cells and telomere length was determined using genomic DNA
preparation and Southern hybridization techniques. Results: EPC telomere
length (base pairs) was approximately 20% (p=0.01) lower in the older
(8492+/-523 bp) compared to the middle-aged (10,565+/-572 bp) and young
(10,205+/-501 bp) men. Of note, there was no difference in EPC telomere
length between the middle-aged and young men. Conclusions: These results
demonstrate that EPC telomere length declines with age in healthy, sedentary
men. Interestingly, telomere length was well preserved in the middle-aged
compared to young men, suggesting that EPC telomere shortening occurs after
the age of 55 years. Clin Chem Lab Med 2008;47.
PMID: 19055473

  [Here's an example of the sort of research that could be done on old
humans to determine the cause(s) of their shortened EPC telomeres. In the
case of diabetic humans, the nature of the deleterious effect of high
glucose on EPCs is known, and has an available cure. Doing the same sort of
research on old humans could have a very large effect on reducing age
associated cardiovasclar mortality, once the cause(s) of age-associated EPC
telomere shortening are fully understood. The conventional wisdom has it
that effective antiaging drugs will not become available for another 50 or
even 100 years. IMHO, this time frame would become open to rapid revision
once the true prime causes of human aging are understood. Once this
understanding occurs development of effective antiaging drugs would likely
enter the rapid prototype phase, with commercial availablity conceivably
occuring in less than 10 years. Whether middle aged humans will eventually
benefit from this development, will be dependant on how quickly a full
understanding of human aging is achieved.
  If a case could be made for a "Manhatten Aging Project" understanding the
root causes of aging in humans would be it. This will not happen in the
forseeable future, as long as resources are diverted to low productivity
areas such as lifespan extension tests in short lived animals. Not only are
these lifespan tests very expensive and time consuming, but the results
are not likely to be directly applicable to humans, since basic aging
processes are apparently different between long lived mammals such as
humans, in contrast with short lived mammals (with long telomeres) such as
rodents, not to mention flies, or nematodes. I suggest human aging
biomarker trials investigating the causes of EPC telomere shortening would
be an example of a potentially far more productive avenue of
investigation. Comments, anyone?]

Diabetes. 2006 Aug;55(8):2231-7.
Benfotiamine counteracts glucose toxicity effects on endothelial progenitor
cell differentiation via Akt/FoxO signaling.
  Marchetti V, Menghini R, Rizza S, Vivanti A, Feccia T, Lauro D, Fukamizu
A, Lauro R, Federici M. Department of Internal Medicine, University of Rome
Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
  Dysfunction of mature endothelial cells is thought to play a major role in
both micro- and macrovascular complications of diabetes. However, recent
advances in biology of endothelial progenitor cells (EPCs) have highlighted
their involvement in diabetes complications. To determine the effect of
glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood
mononuclear cells of healthy donors and cultured in the presence or absence
of high glucose (33 mmol/l) or high glucose plus benfotiamine to scavenge
glucotoxicity. Morphological analysis revealed that high glucose
significantly affected the number of endothelial cell colony forming units,
uptake and binding of acLDL and Lectin-1, and the ability to differentiate
into CD31- and vascular endothelial growth factor receptor 2-positive cells.
Functional analysis outlined a reduced EPC involvement in de novo tube
formation, when cocultured with mature endothelial cells (human umbilical
vein endothelial cells) on matrigel. To explain the observed phenotypes, we
have investigated the signal transduction pathways known to be involved in
EPC growth and differentiation. Our results indicate that hyperglycemia
impairs EPC differentiation and that the process can be restored by
benfotiamine administration, via the modulation of Akt/FoxO1 activity.
PMID: 16873685

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