Theory of Aging and Disease - Please Comment
asha at sk.sympatico.ca
Sat Jan 18 00:08:39 EST 1997
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 asha at 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. 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.
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
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. Although deletions of mt DNA increase with age, 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. 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.
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.
The concentration of ubiquinone falls with increasing age in all
tissues analyzed in both humans, and rats. 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. This shift in the pathway could alter the role of
ubiquinone in signaling for cell growth, and a reduction of ubiquinones
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. Ubiquinone is the
rate-limiting compound of the activity of complexes I and III but not of
complexes II and IV. 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 cells 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
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. Various ubiquinone homologs stimulate respiratory
activities in isolated mitochondria. In cultured myocardial cells,
only long chain ubiquinone homologs stimulate the formation of ATP,
homologs with shorter side chains are toxic.
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, and can significantly
increase myocardial function and work capacity in normal sedentary people
and in patients with mitochondrial disease. Potential therapeutic
uses include arterial hypertension, mitochondrial myopathies, muscular
dystrophies, angina pectoris, and periodontal diseases, and
preliminary results from case trials have yielded remarkable results in
the treatment of breast cancer. Statistical data support prediction
of death within 6 months in hospitalized patients with low blood levels
of ubiquinone, and deficiency of ubiquinone is observed in several
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
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. The dietary
restriction model of senescence is likely interrelated to the alterations
in regulation of the mevalonate pathway, and indeed may be explained by
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. 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.
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 pathway. In
addition, an increased level of glucagon itself is sufficient to inhibit
HMG-CoA reductase, and thereby would actually decrease the level of
mevalonate. Mevalonate is at a major control point in this pathway, and
is converted into farnesyl pyrophosphate, common precursor to the
cholesterol, ubiquinone, and dolichol synthetic pathways. Due to the
differential Km of squalene synthase, cis-prenyl transferase, and
trans-prenyl transferase, a decreased level of the substrate farnesyl
pyrophosphate would lead to a shift in the production of the three end
products, and to a shift in the dolichol/ubiquinone ratio. This shift in
regulation resulting from dietary restriction could explain the unique
effectiveness of dietary restriction as a method of retarding the
actuarial rate of aging and of extending mean and maximum life span in
Asha Pharma Co.
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