Abstract

The signs and symptoms of aging are mostly a consequence of impaired antioxidant function in the body. Statins are drugs that have recently been discovered to counter these age-related changes. These drugs are typically prescribed for long-term control of plasma cholesterol levels in patients with atherosclerotic coronary artery disease. Statins have been found to enhance the enzyme paraoxonase, a potent antioxidant molecule; as a result, statins are able to alleviate manifestations of aging and effectively retard the aging process. Supplementing statins with dimercaprol and restriction of calorie consumption may also prove helpful in decelerating aging. However, use of statins frequency causes myopathy. In order to establish statins as an effective anti-aging medication, the exact pathophysiology of this side-effect must be determined.

Keywords: statins, anti-aging, HMG Co-A reductase, paraoxonase, antioxidant, ROS, sulfhydryl, dimercaprol, caloric restriction

Introduction

Statins decrease low-density lipoprotein (LDL) cholesterol while simultaneously elevating high-density lipoprotein (HDL) cholesterol levels.3 Rise in serum LDL level is correlated to increased cellular uptake of cholesterol, especially in the endothelia.2 During atherosclerosis, these LDL molecules undergo oxidation and amplify the inflammatory process through macrophage induced cytokine release. Cytokines then give rise to a prothrombotic state that leads to coronary artery thrombosis.3 HDL molecules, however, remove the excess cholesterol from body tissues and transport them to the liver for final degradation.2 Since statins reduce the serum LDL levels and increase serum HDL concentration, the risk of morbidity and mortality associated with coronary artery disease (CAD) can be significantly reduced by taking this drug.

However, recent research has revealed that the typical mechanism of action used by statins to control atherosclerosis might be useful in synthesizing future anti-aging medication.5 Aging brings about inevitable physiological changes. Among these, cardiopulmonary and renal disorders are the leading causes of death in the geriatric population, while aging skin spoils the beauty of an eternal youth. Aging imposes a significant health burden on the economy of a country, especially in developing nations. Degradation of beauty, although less important, possesses significant social implications. Hence, discovery of a drug to minimize age-related health complications and maintain external beauty can be a boon to health welfare authorities of every country and contribute to the economic prosperity of their nations.

The Mechanism of Statins in Opposing Atherosclerosis

The predominant mechanism of action of statins in preventing atherosclerotic CAD is by competitive inhibition of hexamethyl glutaryl Co-A (HMG Co-A) reductase enzyme, the key enzyme in the pathway of cholesterol biosynthesis. Statins also increase the expression of LDL receptors in the hepatocytes in order to clear plasma LDL molecules. In addition, the drugs increase the activity of paraoxonase-HDL enzyme complex.4 The functions of HDL and LDL molecules are exactly opposite to each other. LDL delivers cholesterol to the body tissues, while HDL removes the cellular cholesterol and presents them to the liver. Since low plasma cholesterol level is equivalent to low serum LDL concentration, LDL availability at the site of atherosclerosis is significantly decreased. As a result, LDL oxidation is reduced.

The alloenzyme PON 1 192 QQ of the paraoxonase-HDL complex is reported to possess the most prominent antioxidant action among all the enzymatic variants. It catalyzes the hydrolysis of phospholipid hydroperoxides in LDL.4 Paraoxonase plays an important role in preventing lipid peroxidation elsewhere in the body as well. Statins have been found to boost the activity of paraoxonase.5 Statins oppose atherosclerosis by using paraoxonase-HDL complex as the mediator.

Aging and Impaired Antioxidant Activity in the Body

Aging involves a significant deterioration in antioxidant activity of the body. There is a significant increase in mitochondrial activity as the body ages.6 As the site of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS) that are neutralized by superoxide dismutase (SOD), an important antioxidant molecule. With aging, the mitochondrial DNA may undergo mutations that amplify ROS generation.6 The free radicals alter the structure of mitochondrial membrane lipids and bring about undesirable changes in the organelle and other parts of the cell. This oxidative stress creates a functional deficiency of the SOD enzyme.6

ROS concentration has been found to rise in older age groups with unrestricted intake of calorie-rich foods (fats and carbohydrates). Metabolism of calorie-rich food increases the rate of transfer of electrons in oxidative phosphorylation, resulting in increased generation of ROS.7 Additionally, excessive calorie consumption leads to a dysregulation of cellular autophagy that, in turn, results in dolichol accumulation in the cells.8 Higher concentrations of dolichol lead to higher HMG Co-A reductase enzyme activity, thereby increasing serum cholesterol level in old age.8 Elevated serum cholesterol concentration increases rate of LDL oxidation and generates highly reactive LDL free radicals. Accumulation of free radicals and faulty SOD activity causes the loss of oxidant-antioxidant balance in the body tissues. The high level of oxidants then causes age-related changes in the different organ systems. Figure 1 below summarizes this relation between ROS production, excess calorie intake, and aging.

Statins as Possible Anti-aging Drugs

Their mechanism of action suggests that statins may be able to halt the natural process of aging by using HDL as a mediator. HDL downregulates LDL oxidation through paraoxonase;4 there is a time-regulated fall in the paraoxonase activity due to the accumulation of lipid peroxides, which are generated as byproducts of LDL oxidation.9 This decreased PON 1 192 QQ function is caused by interactions between its sulfhydryl groups and the metabolic by-products.9 Statins can reduce this interaction by decreasing the concentration of LDL molecules in the blood stream. If LDL levels are low, oxidation rate also drops, resulting in significantly reduced generation of oxidized byproducts that interact with paraoxonase.

Reduction of LDL oxidation, however, does not seem to be the definitive solution to this complex problem. Other non-high density lipoproteins such as intermediate-density lipoprotein (IDL) are independent risk factors for age-related CAD. Accumulation of IDL in high levels can bring about adverse effects despite low levels of LDL molecules. Nevertheless, new generations of statins have shown remarkable effects in reducing IDL levels in the blood stream.10

Statins can be combined with the drug dimercaprol to prevent decrease in paraoxonase activity. Dimercaprol is typically used as a chelating agent in heavy metal poisoning, such as arsenic poisoning. The drug possesses a large number of free sulfhydryl groups that attract metals; this unique property is used to free respiratory enzymes from inhibitory complexes with heavy metals (Figure 2). Because oxidized LDL products bind with the sulfhydryl radical of paraoxonase, dimercaprol can serve as a more attractive substrate for these oxidized products; this competition reduces paraoxonase inhibition (Figure 3). Unfortunately, dimercaprol is a nephrotoxic drug that can exacerbate the already-declining renal function of old age. Dimercaprol also leads to dose-related emesis, hypertension, and palpitation. To combat this, statins can be used in conjunction with dimercaprol to exert a synergistic effect in increasing paraoxonase activity. Therefore, the dose of dimercaprol can be decreased to a level where it will cause only minimal physiological distress.

In addition to these drug therapies, restricted calorie consumption can improve antioxidant effects in the body. Caloric restriction lowers both the HMG Co-A reductase activity and cholesterol biosynthesis. Low cholesterol production means a lower concentration of LDL and its subsequent oxidization, significantly enhancing paraoxonase activity and working with statin therapy to dampen generation of ROS.

Statins can be helpful in reducing incidence of atherosclerotic CAD, hypertension, hypertensive nephropathy, renal artery atherosclerosis, cerebral artery sclerosis, diabetic nephropathy, and dermatological changes. Slow progression of atherothrombotic changes in cerebral artery can lower incidences of cerebrovascular disease (stroke), improve cognition; the antioxidant activities of statins may also prevent cellular death, thus reducing development of skin wrinkles. Death of pancreatic beta cells due to ROS overproduction can be effectively limited and insulin sensitivity in the body tissues may be improved, which can decrease the risk of developing diabetic nephropathy and other micro and macrovascular changes.

A significant side effect, however, is the tendency of statins to cause myopathies.11 This adverse effect must be reduced or eliminated before statins can be introduced as an anti-aging pill in the global market. Drug trials have failed to establish any specific dose-response relationship for this pathological condition.12 However, lipophilic statins (simvastatin, lovastatin, atorvastatin) have been associated with a greater number of reported myopathy cases.13 As a result, statin-induced myopathy may be prevented by prescribing the lowest therapeutic dose of this group of drugs.

Conclusion

The antioxidant property of statins may be effective not only in treating dyslipidemia but also as a potential anti-aging medication. Although the combination of statins, dimercaprol, and caloric restriction seems promising towards reducing or even reversing the process of aging, the additive role of these therapies has not yet been studied fully. More intensive research is necessary to fill the gaps in our knowledge about aging mechanisms and to develop anti-aging drugs.

References

  1. Malloy, M. J.; Kane, J. P. Agents Used in Dyslipidemia. In Basic & Clinical Pharmacology, 11th ed.; Katzung, B. G. et al. Eds.; Tata McGraw-Hill: New Delhi, 2009; p 605-620.
  2. Botham, K. M.; Mayes, P. A. Lipid Transport and Storage. In Harper’s Illustrated Biochemistry, 27th ed.; Murray, R. K. et al. Eds.; McGraw-Hill: Singapore, 2006; p217-229.
  3. Mitchell, R. N.; Schoen, F. J. Blood Vessels. In Robbins and Cotran’s Pathological Basis of Disease, 8th ed.; Kumar, V. et al., Eds.; Elsevier: Haryana, 2010; p 487-528.
  4. Mahley, R. W.; Bersot, T.P. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.; Hardman, J. G. et al., Eds.; McGraw-Hill: New York, 2010; p 971-1002.
  5. Durrington, P. N. et al. Arterioscler. Thromb., Vasc. Biol. 2001, 21, 473-480.
  6. Pollack, M.; Leeuwenburgh, C. Molecular Mechanisms of Oxidative Stress in Aging: Free Radicals, Aging, Antioxidants and Disease. In Handbook of Oxidants and Antioxidants in Exercise; Sen, C. K. et al., Eds.; Elsevier Science: Amsterdam; p 881-923.
  7. de Grey, A. D. N. J. History of the Mitochondrial Free Radical Theory of Aging, 1954-1995. In The Mitochondrial Free Radical Theory of Aging; de Grey, A. D. N. J., Ed.; R. G. Landes: Austin, Texas; p 65-84.
  8. Cavallini, G. et al. Curr. Aging Sci. 1999, 1, 4-9.
  9. Aviram, M. et al. Free Radic. Biol. Med. 1999, 26, 892-904.
  10. Stein, D. T. et al. Arterioscler. Thromb. Vasc. Biol. 2001, 21, 2026-2031.
  11. Amato, A. A.; Brown Jr, R. H. Muscular Dystrophies and Other Muscle Diseases. In Harrison’s Principles of Internal Medicine, 18th ed.; Longo, D.L. et al., Eds.; McGraw-Hill: New York, 2012; p 3487-3508.
  12. Stewart, A. PLoS Curr. [Online] 2013, 1. http://currents.plos.org/genomictests/article/slco1b1-polymorphisms-and-statin-induced-myopathy/ (accessed March 14, 2013).
  13. Sathasivam, S; Lecky, B. Statin Induced Myopathy. BMJ [Online] 2008, 337:a2286. 

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