I suggest that you borrow a copy of "Clock of Ages" from
the nearest library and read it carefully. Aging is complex
and involves many processes.
Stewart Rowe sr…@tso.cin.ix.net
In a previous article, a…@sk.sympatico.ca (Asha) says:
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>Hello,
> Please reply I am looking for comments or input on the following
>theory of aging.
>Anyone interested in further information on this topic or on Coenzyme Q10
>can refer to our internet site at http://www.nethomes.com/asha
> Please mail your comments to a…@sk.sympatico.ca
> Ubiquinone is an essential electron and protein carrier in ATP
>synthesis in the mitochondrial inner membrane. Besides its
>well-established role in energy production in aerobic organisms,
>ubiquinone is required for transmembrane electron transport that
>activates signals in the cell which stimulate cell growth.[2] Ubiquinol,
>the reduced form of ubiquinone, acts as a lipophilic antioxidant,
>preventing initiation and/or propagation of free radicals and lipid
>peroxidation in biological membranes, and is the only known lipid
>soluble antioxidant that animal cells can synthesize de novo.[9]
> There is accumulating evidence that ubiquinone and possibly other
>components of the mevalonate pathway, such as dolichol and dolichyl
>phosphate, could be important in various disease and senescence
>mechanisms. The evidence relates to mitochondrial and cell energetics,
>accumulation of damage to DNA, cell signaling, saturation kinetics of
>mitochondrial enzymes, and clinical data.
> Aged cells contain partly altered mitochondria that are less able
>to fulfill their energy requirements so that a general lowering of
>homeostasis and increased susceptibility is obtained.[16,21] When
>oxidative phosphorylation decreases below an energetic threshold, disease
>symptoms appear and cell degeneration results if energy production
>decreases further.[16]
> Analysis of mitochondrial respiratory chain function and
>mitochondrial DNA deletion with aging has shown that between the ages of
>20-30 and 60-90, there are large and significant decreases in the
>activities of Complexes I and IV, which decrease by 59% and 47%
>respectively.[1] Although deletions of mt DNA increase with age,[1] it
>is not certain whether this is in itself responsible for the decline in
>ATP production. At least one type of fatal mitochondrial disease due to
>mt DNA depletion has been shown to be under control of the nuclear
>genome.[3] It is possible that general lowered homeostasis due to a
>related process results in accumulation of errors in those regions of the
>nuclear genome that control mt DNA depletion. Evidence to support an
>accumulation of errors is that the repair of carcinogen-induced DNA
>damage is age dependent, and falls rapidly with increasing age.[5]
>Alteration and decline of respiratory chain enzyme activity decreases the
>maximal rate of ATP formation in old cells, forcing the cells to adapt to
>a declining availability of energy for biosynthesis and repair. A new
>equilibrium will be established for the particular level of energy that
>is available to the cell.[16]
> The concentration of ubiquinone falls with increasing age in all
>tissues analyzed in both humans, and rats.[14] As ubiquinone levels
>decrease dolichol levels increase, indicating a shift in the regulation
>of the related pathways of dolichol, ubiquinone, and cholesterol
>synthesis. Dolichol destabilizes model membranes and increases fluidity
>and permeability.[17] This shift in the pathway could alter the role of
>ubiquinone in signaling for cell growth, and a reduction of ubiquinone s
>mitogenic properties could indirectly lead to accumulation of DNA damage
>and reduction of cell viability.
> Complex I activity shows a drastic decrease in activity in rats
>and humans, resulting from a defect in the complex. Levels of complex
>III activity and ubiquinone in the inner membrane of the mitochondria
>remain unaltered with increasing age in rats.[10] Ubiquinone is the
>rate-limiting compound of the activity of complexes I and III but not of
>complexes II and IV.[18] Therefore lowered ATP synthesis results both
>directly and indirectly from the shift in mevalonate regulation, and not
>from an actual lack of ubiquinone in the mitochondria. This regulation
>of the cell s energy and developmental program could function as a type
>of feedback amplification, where a small shift in regulation is the
>direct cause of further shifts. If these shifts in regulation are major
>inducers of pathological conditions, then their specific mechanisms would
>explain the widely observed exponential increase of disease and disease
>related mortality.
> Under conditions in which the activities of the various complexes
>are sub-optimal, increasing the concentration of ubiquinone within the
>mitochondrial inner membrane will cause an increase in the production of
>ATP due to ubiquinone being the rate limiting compound for complex I.
>Ubiquinone concentration within the mitochondrial inner membrane can
>control the efficiency of oxidative phosphorylation, and addition of
>exogenous ubiquinone enhances respiratory turnover above the
>physiological rate but without reaching theoretical maximum velocity of
>the reaction.[4] Various ubiquinone homologs stimulate respiratory
>activities in isolated mitochondria.[15] In cultured myocardial cells,
>only long chain ubiquinone homologs stimulate the formation of ATP,
>homologs with shorter side chains are toxic.[6]
> Ubiquinone is currently being investigated as a treatment for
>various diseases, and is already in use as a safe and effective treatment
>for heart failure. Administration of ubiquinone improves contractility
>and ejection fraction in heart failure,[12] and can significantly
>increase myocardial function and work capacity in normal sedentary people
>and in patients with mitochondrial disease.[20] Potential therapeutic
>uses include arterial hypertension, mitochondrial myopathies, muscular
>dystrophies, angina pectoris, and periodontal diseases,[7] and
>preliminary results from case trials have yielded remarkable results in
>the treatment of breast cancer.[11] Statistical data support prediction
>of death within 6 months in hospitalized patients with low blood levels
>of ubiquinone,[13] and deficiency of ubiquinone is observed in several
>pathological conditions.
> The major degenerative diseases that are leading causes of
>mortality, increase at an exponential rate that is independent of various
>environmental factors recognized as being causal in the development of
>these diseases. Although different epidemiological sub-populations have
>different risks of succumbing to a particular degenerative disease, each
>population will experience a similar if not identical exponential
>increase in disease frequency. The dramatic increase of degenerative
>diseases seen with increasing age may be the results of a common
>mechanism. One underlying factor is the cause of the major disease of
>morbidity and mortality in humans.
> Research on the mevalonate pathway, primarily those branches
>leading to the synthesis of dolichol and ubiquinone, when analyzed
>statistically and linked to a novel theory of disease etiology, lead to
>the possibility that these branches are directly involved in the
>progression of the major degenerative diseases.
> I have compiled several charts using tissue lipid data taken from
>reference 14, combined these data with age specific death rates and
>analyzed the result statistically. There is a very strong statistical
>correlation between the increase in mortality (and of the incidence of
>degenerative disease) of human populations beginning at approximately age
>20, and the shift in the regulation of the related pathways of
>ubiquinone, dolichol and cholesterol synthesis.
> When different tissues from human and rats of varying ages are
>analyzed for concentrations of cholesterol, dolichol , and dolichyl
>phosphate, and these results are regressed against expected age-specific
>rates of mortality, very high correlation coefficients are produced.
>These show that the regulation of the pathway is altered with age in both
>humans and rats, in the direction of increased cholesterol, dolichol, and
>dolichyl phosphate, and lowered ubiquinone. Furthermore, for seven
>different human tissues, the dolichol/ubiquinone ratio, when regressed
>against age specific death rates, produces correlation coefficients which
>range between r=0.9858 and r=0.999954. The one factor underlying
>morbidity and mortality in humans may be this alteration in the
>mevalonate pathway.
> It has been thoroughly established that caloric restriction can
>lengthen both mean and maximum life span in mammals, reduce the frequency
>of degenerative diseases, and delay their onset.[21] The dietary
>restriction model of senescence is likely interrelated to the alterations
>in regulation of the mevalonate pathway, and indeed may be explained by
>it.
> Dietary restriction leads to low blood glucose levels, which in
>turn stimulate the release of glucagon. Glucagon has a range of effects
>on different pathways, including the mevalonate pathway.[22] Increased
>glucagon levels inhibit glycolysis by lowering the level of the
>intermediate fructose-2,6-bisphosphate, which is an inhibitor of
>fructose-1,6-phosphatase and an activator of phosphofructokinase-1.
>Glucagon also inhibits pyruvate kinase, so that pyruvate is prevented
>from entering the citric acid cycle, and the resulting accumulation of
>phosphoenol pyruvate favors gluconeogenesis.[22]
> As long as caloric restriction is not too severe, and is
>maintained over long period of time, there should be no increase in
>acetyl-CoA due to fatty acid metabolism, and there would not be an
>increase in the level of precursors of the mevalonate
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Stewart Rowe wrote:
> I suggest that you borrow a copy of "Clock of Ages" from
> the nearest library and read it carefully. Aging is complex
> and involves many processes.
Is it???