Oxidative Damage and Aging
G. Libertini
Independent researcher, Naples, Italy
The risk of cardiovascular diseases is positively related to hypercholesterolemia, hypertension,
diabetes, smoking, age, etc. and lowered by preventive lifestyle measures and by
anti-hypertensive, hypoglycaemic and anti-dislipidemic drugs.
The common interpretation is that modifiable risk factors increase oxidative damage while
preventive lifestyle measures and lowering-risk-factors drugs reduce this harm. Moreover,
aging, interpreted as consequence of cumulative oxidative damage, is necessarily the cause
of age-related cardiovascular increasing risks and is not modifiable with preventive
measures and drugs.
Statins, ace-ACE-inhibitors and sartans (“protective drugs”) are known to be effective
in reducing the cardiovascular risk even without acting on risk factors, namely with a
direct action on atherogenesis but this is compatible with the above-said general
interpretation.
These ideas are challenged by the observation that the number of circulating endothelial
progenitor cells (EPC) is negatively related to the cardiovascular risk and to the increasing
age and that the intake of protective drugs is associated with higher values of EPC.
A likely deduction is that: 1) Excessive stress (oxidative or of other types) increases the
apoptotic rate of endothelial cells (which show continuous cell turnover ensured by EPC)
and quickens their turnover, so lowering renewal capacities and reducing EPC count; 2)
Older endothelial cells, which suffer by cell senescence, increase the probability of
atherosclerosis; 3) In old individuals, with or without excessive stress, EPC are reduced
because of EPC stem cell exhaustion by telomere shortening: diseases derived from
compromised blood circulation are a common end to the life of healthy old individuals
with no particular risk factor.
In short, oxidative damage is important in atherogenic process and in aging but the key
actor is the progressive failure of cell turnover caused by cell duplication limits, which
are determined by the genetic regulation of telomere-telomerase system.
The scheme proposed for endothelial cells and atherogenesis is likely valid for other
organs and tissues and for the whole organism.
This stimulates a general view where: I) Organism shows a continuous renewal of its
cells; II) Aging is the consequence of the progressive slackening of this turnover and
can be described as the progressive atrophy of each tissue and organ; III) Many
diseases are the effect of the acceleration of the physiologic turnover of some cell
types and the consequent exhaustion of their renewal capacities; IV) Many risk factors
and many drugs contrasting these factors act by increasing or reducing, respectively,
the turnover acceleration.
However, a well-founded objection needs a sound justification: some cells or tissues
(as muscle and heart myocytes, eye crystalline lens, photoreceptor cells and neurons of
central nervous system) appear to have no turnover and so should not be included in
this scheme, thus greatly weakening it.
But: A) Muscle and heart myocytes are cells with turnover; B) The functionality of
crystalline lens depends on lens epithelial cells that show turnover; C) Photoreceptor
cells, particularly exposed to oxidative damage, and neurons of central nervous system,
which have high metabolic activity, both depend from specialized types of gliocytes that
show turnover. Turnover decline of these cells is a likely cause of age-related macular
degeneration (ARMD) and of Alzheimer disease (AD), respectively; D) Smoking,
diabetes, and obesity are risk factors for these diseases while "protective drugs"
lower the risk.
Cures for ARMD and for AD that try to contrast ARMD and AD by lowering the
oxidative damage or reducing the accumulation of metabolic substances result ineffective.
A rational cure should contrast the decline of gliocyte turnover by the activation of
telomerase, a possibility that is well documented in vitro by important experiments.
This type of cures for ARMD and AD would be very important per se but would
be as much important in a more general perspective: ARMD and AD are the pivotal
expression of aging for the nervous system and the control of these diseases would be
an important step in the control of aging.
Workshop presentation (slides)
Homo Sapiens Liberatus Workshop, Moscow State University, May 2010