Carbonic Anhydrase Enzymes are ancient Zinc enzymes which are further divided into Alpha, Beta and Gamma carbonic anhydrase enzymes. The Alpha group belongs to mammals and are thought to be 200 TO 300 million years old. The Beta group belongs to plants. They are thought to be about 3.5 billion years old. The Gamma group belongs to the methane-producing bacteria which are also thought to be about 4 billion years old. These Carbonic Anhydrase Enzymes are structurally distinct from each other except they contain the same Zinc ion and catalyzing the same reversible reaction H2O+CO2—H++HCO3—
Carbonic anhydrase enzymes are the fastest enzymes doing 10(6) power reactions per second. In mammals their activities are not limited to the acid base balance, maintaining the PO2/Co2 ratio, ester hydrolysis, ion transport, phosphatase activity, CO2 hydration, maintaining the equilibrium between H2O, Co2 and H+HC03- in all spaces, cellular, interstitial and vascular spaces as illustrated in FIG. 3.
In mammals Carbonic anhydrase isozymes are further divided into: Carbonic Anhydrase I to XXV:    CA I—are cystosolic enzymes are mostly found in Red blood Cells, vascular endothelial cells, gastrointestinal mucosa    CA II—cystosolic enzyme found in almost all tissues but mainly in the Brain, Bones, Kidneys    CA III—cystosolic enzyme mostly found in muscles, synovial tissues    CA IV—is membrane bound, found in the capillary endothelial cells, brain, kidney    CA V—mitochondrial—beta cells, pancreas    CA VI—secretory mostly found in tears saliva, milk, mammary gland, nasal and repiratory mucosa    CA VII—cystosolic Enzyme—(brain) hippocampal, CA I pyramidal cells, salivary    CA VIII—CARP (carbonic anhydrase related protein)    CA IX—Membrane Bound MN/protein (tumor associated)-Catalytic    CA X—CARP (carbonic anhydrase related protein)    CA XI—CARP (carbonic anhydrase related protein)    CA XII—Membrane Bound    CA XIII—cystosolic    CA XIV—membrane bound
Normal aging in humans is recognized as producing some or all of the following typical physiological results but not limited to:
1. Brain weight is reduced by 15%
2. Blood flow to the brain is reduced by 20%
3. Body water content is reduced by 18%
4. Body weight is reduced by 12%
5. Nerve conduction velocity is reduced by 10%
6. Number of nerve fibers is reduced by 37%
7. Decreased amounts of enzymes and coenzymes
8. Decreased amounts of neurotransmitters
9. Depletion of phosphorelative enzymes
10. Apostosis-chronic neuronal atrophy
Signs and Symptoms of Human aging includes but are not limited to:
1. Increased body fat
2. Decreased energy
3. Decreased sexual performance
4. Decreased libido
5. Decreased skin elasticity
6. Decline in mental function
7. Decline in vision/eyesight
8. Joint pain
9. Decreased lean muscle
10. Decreased bone mass
11. Decline in memory
12. Diminished immune system
13. Wrinkles and cellulite
14. Decreased cardiac output
15. High blood pressure
16. undesirable cholesterol
17. Decreased exercise performance
18. Slower rate in healing
19. Decline in taste/smell
20. Frailty and others
In describing their work in an article entitled “Studies on age-Dependent Ozonide Changes in Human Cerebral Cortex,” (by Reichlmeier K., Ermini M., and Schlecth H. P.—Aktuellel Gerontl 1978 Aug. 8(8):44-8) the authors report that they investigated the activity of various enzymes of human brains obtained at autopsy and covering an age range of 19 to 91 years. Protein Kinase, which mediates the information carried by the second messenger, cyclic AMP (3′,5′-cyclic adenosine monophosphate), does not show age-related changes of basal activity. Cyclic AMP-dependent activation of protein kinase remains constant up to 60 years of life but it undergoes a distinct and progressive decline between 60 and 90 years. In the corpus striatum, no age related changes of cyclic AMP-dependent protein activity were observed. The activity of carbonic anhydrase exhibits, in both human cortex and corpus striatum, an age-dependent decrease that also begins after the sixth decade.
Aging is further divided into primary aging and secondary aging (accelerated). Primary Aging is caused mainly in the inherent progressive decrease activities of the genes that regulates the cell. While secondary aging (accelerated aging) is caused mainly by oxidative stress. Oxidative stress is mainly caused by external factors such as environmental factors, toxic materials, ionizing radiations, or any condition or disease that alters the vascular endothelium and the cell wall membrane. These altered conditions allows the entry of substances that will displace the zinc from cell specific carbonic anhydrase enzymes leading to the decreased level of cell specific carbonic anhydrase enzymes hence leading to cellular death.
In Aging there is an age-associated dysregulated inflammatory and immune response leading to an increase production of PGE2 and Cyclooxygenase. They inhibit the production of Cell Specific Carbonic Anhydrase Enzymes
IN Brain Behav Immun. 2004 November; 18(6):487-94 by Wu D, Meydani S N Mechanism of age-associated up-regulation in macrophage PGE2 synthesis Many physiological functions of the body change during the aging process. Dysregulated immune and inflammatory responses have been well documented in both humans and animals. The investigation into the cellular and molecular mechanism underlying these disorders has provided compelling evidence that up-regulated cyclooxygenase (COX2) and its product particularly prostaglandin (PGE2) lay a critical role in the age-associated dysregulation of the immune and inflammatory responses. Studies have shown that increase production of PGE2 by old macrophages contributes to the suppression of T cell function. Decreasing production of PGE2 have shown enhanced T mediated cell function. Upon stimulation old mice macrophages generate more ceramide which in turn augments stimulated COX2 expressions and PGE2 production.
Crit Rev Immunol. 2004; 24(5):349-62 by Trottein F, Faveeuw C, Gosset P, Angeli V
Role of the D prostanoid receptor 1 in modulation of immune and inflammatory responses.
Prostaglandins (PGS) are potent eicosanoid lipid mediators derived from phospholipase released arachidonic acid, which are involved in numerous homeostatic biological functions and inflammation. Along with their role in inflammatory responses evidence strongly suggest that PGS, including PGD2 are part of the complex regulatory network that modulates the immune system. PGE2 is the major prostaglandin activated by mast cells in allergic diseases.
In Arthritis Res. 1999; 1(1):63-70. Epub 1999 Oct. 14. by Tetlow L C, Wooley D E
The effects of alpha, 25-dihydrovitamin D3 on matrix metalloproteinase and prostaglandin E (2) production by cells of rheumatoid lesion. Vitamin D3 modulate the effect of Matrix metalloproteinase. Matrix metalloproteinase and PGE2 are chondrolyic enzymes which plays a major role in the breakdown in the rheumatoid joint.
Arthritis Rheum. 1999 December; 42(12):2561-8 by Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron D
Fluoxetine and aminitriptylline inhibit nitric oxide, Prostaglandin PGE2 and hyaluronic acid production in human synovial cells and synovial tissue cultures. Their conclusion; Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation.
In Cystic Fibrosis
Eur J Cell Biol. 2002 August; August; 81(8):437-47
Targeting of Carbonic Anhydrase IV to plasma membranes is altered in cultured human pancreatic duct cells expressing a mutated (deltaF508) CFTR—by Fanjul M, Salvador C, Alvarez L, Cantet S, Hollande E
Their studies showed that the level Carbonic Anhydrase IV is decreased resulting in the decreased secretion of Cl- and HCO3-ions as well as defective targeting of other proteins. This is due to a 6-10 fold fewer cells in the CFPAC-1 cell lines.
Antibodies to Cell Specific Carbonic Anhydrase Enymes are produced as a result of an immunologic response to defend themselves. This is in response to the progressive cell death as a result of the progressive decrease in the level of cell specific carbonic anhydrase enzymes in a subject due to oxidative stress and aging or conditions or diseases that decreases the level of cell specific carbonic anhydrase enzymes in the tissue of a subject as illustrated in FIG. 2
Antibodies to Carbonic anhydrase has been found in systemic lupus erythematosus and other rheumatic diseases; Arthritis Rheum. 1992 autoantibodies of CA I, CA II isoform, in Systemic Lupus
rythematosus, scleroderma, and polymyositis in their sera. January; 35(1):73-82 by Itoh Y, Reichlin M.
In Dermatol Sci. 1991 May; 2(3): 147-54 by Inagaki Y, Jinno-Yoshida Y, Hamasaki Y, Ueki H. they also found auto Antibodies to CA I, CA II isoform in patients sera in Syogren's Disease, Renal tubular acidosis and systemic Lupus Erythematosus.
Autoimmunity. 2003 March; 36(2):85-9 by Alessandri C, Bombardieri M, Scrivo R, Viganego F Conti F, deLuca N, Riccieri V, Valeseni G deals with the presence of anti-Carbonic anhydrase antibody as possible pathogenic role of anti-CA II in the development of lung damage in systemic sclerosis (SSC) disease.
In Clinical Chemistry. 2003; 49:1221-1223—Effect of Anti-Carbonic anhydrase antibodies on Carbonic anhydrase I and II by Francesco Botre, Claudio Botre, Elissabetta Podesta, Mauro Podda and Pietro Invernizzi. they isolated CA I, II isoform antibodies in patients with systemic lupus erythematosus, polymyositis, systemic sclerosis, endometriosis syogrens, disease, idiopathic chronic pancreatitis, primary biliary cirrhosis, and autoimmune cholangitis.
Int J Mol Med. 2002 May; 9(5):499-502 by Andoh A, Fujiyama Y, Yoshioka U, Sasaki M, Araki Y Tsugikawa T—discusses the presence of Anti-carbonic anhydrase II antibodies in patient with ulcerative colitis.
Growth Factors are useful in the enhancement maintenance proliferation and differentiation of stem cells to specific cells or tissues.
IN Proc Soc Exp Biol Med. 1987 January; 184(1):24-30 by Cavral A T R, Hewett-Emmett DWelty R J, Castor C W
Effects of human Carbonic anhydrase III on synovial and muscle fibroblastic glycosaminoglycanl metabolism
They investigated the ability of CA III, isolated from adult human skeletal muscle to regulate cell growth and glycosaminoglycan formation in connective tissue cells. Cell culture experiments showed that exposure to CA III by synovial connective tissue fibroblast, they were increased by 2 to 12 fold, also increased hyaluronic acid synthesis. Also exposure to CA III leads to an increase in muscle fibroblast by 20-45%, synovial fibroblasts by 16-70%.
Endocrinology. 1997 November; 138(11):4852-7. by Biskobing D M, Fan D, Fan X, Rubin J. Induction of carbonic anhydrase II expression in osteoclast progenitors requires physical contact with stromal cells. It tells that osteoclast progenitors requires the physical communication of Carbonic anhydrase II with stromal cells for them to differentiate to osteoclast.
j. Histochem Cytochem. 2004 August; 52(8):1057-62 by Kimoto M, Iwai S, Maeda T, Yura Y, Fernley R T, Ogawa Y
Tells us that CA VI plays A role in olfactory function as a growth factor in the maturation of the olfactory epithelial cells.
Am J Med Sci. 1999 December; 318(6):39-405—by Henkin R I, Martin E M, Agarwal R P
Efficacy of exogenous oral Zinc in treatment of patients with Carbonic Anhydrase VI deficiency.
Tells us about the use of oral Zinc in stimulating the production of CA VI which promotes the growth of taste buds.
In Transplantation. 2001 Jun. 27; 71(12):1735-40 by Nakano K, Migita M, Mochisuki H Shimada T Bone Marrow Transplantation was reported effective in preventing the progression of neurological deterioration of lysosomal disease. They concluded that the bone marrow contains cells capable of differentiating into oligodendrocytes and astrocytes.
and microglia when exposed to brain microenvironment.
J Histochem Cytochem. 2004 August; 52(8:1107-12 by Leinonem J S, Saari K A, Seppanem J m, Myllyla H M, Rajaniemi their studies shows that CA VI maybe a growth factor in the respiratory epithelium
Brain Res Dev Brain Res. 1992 Jun. 19; 67(2):257-63 by Cammer W, Zhang H shows that Carbonic anhydrase are distinct precursors of astrocytes and oligodendrocytes in the forebrains of neonatal and young rats.
The American Society for Biochemistry and Molecular Biology, Inc. Volume 271, Number 17, Issue of Apr. 26, 1996 pp. 10169-10174 Peter H. Frederikse, Donita Garland, J. Samuel Zigler Jr., Joram Piatigorsky In their studies, oxidative stress increases production of B-Amyloid Precursor Proteins and B amyloid (Ab) in mammalian lenses. Amyloid diseases are characterized by protein aggregations linked to oxidative stress.
Rinsho Byori. 2003 February; 51(2):140-5
Amyloidosis and Oxidative Stress-Nakamura M, Ando Y.
Their studies on oxidative stress have revealed that free radical injury Appears to be involved in either the amyloid formation process or in Post-fibrillar modification in several types of amyloidosis, the role of Oxidative stress in the pathogenesis of dialysis-related amyloidosis And familial amyloidotic polyneuropathy
Journal of Neuroinflammation 2004, 1:21 doi:10.1186/1742-2094-1-21 Yuemang Yao, Cinzia Chinnici, Hanguan Tang, John Q
Trajanowski, Virginia My Lee, Domenico Pratico
Brain Inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like Brain Amyloidosis
Their studies implicates an increasing body of evidence which implicates Both brain inflammation and oxidative stress in the pathogenesis of alzheimer's disease.
In Autism there are evidences that Mercury (HG), a neurotoxic metal causes Autism, Mercury displaces the Zinc ion found in the Carbonic Anhydrase Isozymes resulting in their decreased level.
In U.S. Pat. No. 6,297,212 and U.S. application Ser. No. 09/933,309-Gregory Fahy he used Growth hormone and dehydroepiandrosterone (DHEA) in regenerating the involuted thymus in restoring the immune system
Below are selected Patent References, other patent references published on diseases of oxidative stress are incorporated in this invention                1. U.S. Pat. No. 6,306,844—use of 2 alpha methyl-19-nor 20(s)1,25-dihydroxyvitamin D3 to increase bone strength        2. U.S. Pat. No. 6,150,346—Method & Composition for treating or preventing osteoporosis        3. U.S. Pat. No. 6,673,782—use of 1,25-dihydroxyvitamin D3-treatment of systemic lupus erythematosus        4. U.S. Pat. No. 7,078,059—treatment of bone disease        5. U.S. Pat. No. 6,828,331—growth hormone secretagogues        6. U.S. Pat. No. 5,895,652—metabolic adjuvanation and cellular repair        7. U.S. Pat. No. 6,297,212—Growth hormone therapy and related methods & Related methods pharmaceutical compositions        8. U.S. Pat. No. 5,763,429—Method for treating prostatic diseases using Vitamin D analogues        9. U.S. Pat. No. 5,763,428—method of treating skin disorders with Vitamin D4        10. U.S. Pat. No. 6,147,064 method for treating psoriasis        11. U.S. Pat. No. 5,700,790—Prevention and treatment of myocardial failure        12. U.S. Pat. No. 6,930,099—composition for the treatment and prevention of endothelial dysfunction        
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