Theory of Aging and Disease - Please Comment

[Asha]

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	Please reply I am looking for comments or input on the following 
theory of aging.
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	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 pathway.  In 
addition, an increased level of glucagon itself is sufficient to inhibit 
HMG-CoA reductase,[22] 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 
mammals.

Arin Elliott
Asha Pharma Co.
http://www.nethomes.com/asha

References

1.   Cooper, J.  Analyses of mitochondrial respiratory chain function and 
 
      mitochondrial DNA deletion in human skeletal muscle:  effect of 
ageing.  
      Journal of Neurological Science (1992) 113(1): 91-8.
2.   Sun, I.  Requirement for coenzyme Q in plasma membrane electron 
transport.  
      Proc-Natl-Acad-Sci-USA (1992) 89: 11126-30.
3.   Bodnar, A.  Nuclear complementation restores mt DNA levels in 
cultured cells 
      from a patient with mt DNA depletion.  American Journal of Human 
Genetics. 
      (1993) 53(3): 663-9.
4.   Battino, M.  Coenzyme Q can control the efficiency of oxidative 
      phosphorylation.  International Journal of Tissue Reactions. (1990) 
12(3); 137-
      44.
5.   Ball, S.  DNA damage and repair in female C57BL/10 mice of different 
ages 
      injected with the carcinogen benzo(a)pyrene-trans-7,8-diol. 
Mutation 
      Research. (1989) 219(4): 241-6.
6.   Kishi, T.  Cardiostimulatory action of coenzyme Q homologs on 
cultured 
      myocardial cells and their biochemical mechanisms. Clinical 
Investigator 
      (1993) 71: S71-5.
7.   Mortensen, S.  Perspectives on therapy of cardiovascular disease 
with 
      coenzyme Q (ubiquinone).  Clinical Investigator (1993) 71: S116-23.
8.   Crane, F.  The essential functions of coenzyme Q. Clinical 
Investigator (1993) 
      71: S55-9.
9.   Ernster, L.  Ubiquinol: an endogenous antioxidant in aerobic 
organisms. 
      Clinical Investigator (1993) 71: S60-5.
10. Lenaz, G. The function of coenzyme Q in mitochondria. Clinical 
Investigator 
      (1993) 71: S66-70.
11. Lockwood, K.  Partial and complete regression of breast cancer in 
patients in 
      relation to dosage of coenzyme Q10. Biochemical and Biophysical 
Research 
      Communications (1994) 199(3): 1504-8.
12. Rengo, F.  Role of metabolic therapy in cardiovascular disease.  
Clinical 
      Investigator (1993) 71: S124-8.
13. Jameson, S.  Statistical data support prediction of death within 6 
months on 
      low levels of coenzyme Q10 and other entities.  Clinical 
Investigator (1993) 
      71: S137-9.
14. Kalen, A.  Age related changes in the lipid compositions of rat and 
human 
      tissues. Lipids (1989) 24(7): 579-84.
15. Lenaz, G.  Coenzyme Q saturation kinetics of mitochondrial enzymes:  
theory, 
      experimental aspects and biomedical implications. Biomedical and 
Clinical 
      Aspects of Coenzyme Q. (1991) 11-18.
16. Corbisier, P.  Influence of the energetic pattern of mitochondria in 
cell ageing. 
      Mechanisms of Ageing and Development (1993) 71: 47-58.
17. Appelkvist, E.  Effects of inhibitors of hydroxymethylglutaryl 
coenzyme A 
      reductase on coenzyme Q and dolichol biosynthesis.  Clinical 
Investigator 
      (1993) 71: S97-102.
18. Maurer, I.  Positive correlation between aortic valve pressure 
gradient and 
      mitochondrial respiratory chain capacity in hypertrophied human 
left 
      ventricles. Clinical Investigator (1992) 70: 896-901.
19. Kanazawa, M.  Coenzyme Q10 by fermentation. Biomedical and Clinical 
      aspects of coenzyme Q volume 3. (1981) 31-42.
20. Zeppilli, P.  Influence of coenzyme Q10 on physical work capacity in 
athletes, 
      sedentary people and patients with mitochondrial disease. 
Biomedical and 
      Clinical Aspects of Coenzyme Q volume 6 (1991) 541-5.
21. Walford, R.  The Retardation of Aging and Disease by Dietary 
Restriction. 
      (1986).
22. Lehninger, A.  Principles of Biochemistry. (1993).