Oxidative Damage and Aging
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