Antioxidants

Fran E. Cook-Bolden

Jocelyne Papacharalambous

Antioxidants have had a key position in the medical and scientific arena since the early 1900s. More recently, they are taking center stage in the dermatologic and aesthetic community, where they are reported to play a critical role in skin health and youthfulness. Another increasingly important role is that they are being used to augment the effects of cosmetic procedures.¹^,² The fuel that has ignited this unquenchable flame for knowledge of antioxidants includes the pursuit of optimal health and well-being, the desire for optimal skin care, the search for longevity and eternal beauty, and the anti-aging movement. Additionally, the increased life span of the population, the desire to align with nature by spending more time outdoors, and the trend toward the use of “natural products” have also contributed to this growing phenomenon.³ Research has demonstrated a wide range of potential benefits from antioxidants, including improved cognition, improved immune function, prevention of malignancy, overall disease prevention, and anti-aging. Despite the steadily growing popularity of antioxidants and the increase in research in this area, there remains a large gap in detailed information about them, including results demonstrating their direct benefit in the general population.⁴ There is an even greater deficit of specific benefits in skin of color (worldwide the majority of the population), as most studies of this nature are performed on skin types I through III.⁵

Antioxidants

Antioxidants have been touted as the premier anti-aging substances for scavenging of free oxygen radicals and other harmful agents that have deleterious effects in the body and to the skin. They are defined as oral, topical, or intrinsic substances that protect and possibly correct oxidative injury to the body and the skin caused by free radicals.⁶ It has been reported that antioxidants have the ability to actually reverse these and other damaging environmental assaults from sunlight, air pollution, alcohol, cigarette smoke, and stress. Some of these substances not only restrict blood flow to our skin and organs, but also generate potent, destructive free radicals. These free radicals ultimately cause massive internal destruction beyond the cellular layer in every organ system of our body, rapidly increasing the aging and disease process overall, both inside and out. Nonetheless, although there has been a preponderance of speculation and growing clinical investigation supporting the benefits of antioxidants, firm evidence is lacking as to the direct link or cause-and-effect relationship and consistent, reproducible scientific data to guide their usage.⁷

Understanding Free Radicals and Oxygen Reactive Species

The molecules that make up the cells of our bodies and skin are held intact and made stable by the bonding of paired electrons. When oxygen molecules are involved in reactions in the body and the skin, these electron pairs are disrupted and lose their partner (the bonds are split), and unstable free radicals are formed. Free radicals (e.g., superoxide, nitric oxide, hydroxyl radicals) and other reactive species (e.g., hydrogen peroxide, peroxynitrite, hypochlorous acid) are produced in the body, primarily as a result of aerobic metabolism. Antioxidants (e.g., glutathione, arginine, citrulline, taurine, creatine, selenium, zinc, vitamin E, vitamin C, vitamin A, and tea polyphenols) and antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidases) exert synergistic actions in scavenging free radicals.⁸

As part of an internal process that occurs naturally in the body to repair this state and regain stability, a reaction begins that can affect every cell in the body. These very unstable free radicals quickly react with other compounds in efforts to regain their stability. They do this by attacking the nearest stable molecule to “steal” a partner; this regains stability, but results in the formation of another free radical. The process continues, ultimately ending up with a “chain” of rapid free radical formation and cascading damage to the body and skin. In summary, free radicals
are formed from oxidative damage incurred normally through body metabolic processes; environmental factors, such as ultraviolet (UV) radiation, pollution, herbicides, and pesticides; or other chemical exposure and cigarette smoke.⁹ The free radicals that arise during normal metabolic processes in the body are purposefully generated in response to messages from the body’s immune system to help neutralize viruses, bacteria, and other entities that can be harmful to the body. Hence, this free radical formation serves a useful purpose to the body. The body’s natural antioxidative processes limit the activity of these free radicals. Excessive free radical formation that occurs as the result of negative environmental influences can cause extensive damage. Free radical damage can accumulate over time and has been implicated in a number of disease processes and aging. It is this excessive and cumulative damage that the body cannot handle alone.⁹^,¹⁰ Antioxidation is the process of correcting the imbalance, hence halting the continuous chain reaction or repairing and possibly reversing any damage caused over time. Antioxidants prevent the unstable oxygen molecules from interacting with other molecules, ultimately halting the chain reaction of free radicals. This is achieved as the antioxidants donate one of their electrons to reproduce the stable pair of electrons. These molecules do not, in turn, become unstable; they are stable with or without this electron. They are often referred to as scavengers because of their ability to help to prevent cell and tissue damage that could lead to disease and aging.⁹ They “neutralize” the free oxygen radicals, stopping them from breaking down cells and allowing the cells to function normally.

Research on the Antioxidation Process

Although there is no direct link or proof that antioxidants can effectively stop or reverse the aging and deterioration process, continued scientifically sound research has shown strong evidence of positive change and support of proposed benefits with the use of antioxidants when compared with placebo or nonuse groups. Early antioxidant supplementation studies indicate life-span extensions by antioxidant feeding in various experimental organisms. Data collected under tightly controlled conditions also show that the feeding of 2-mercaptoethanol (0.25%) effectively prolonged both the median and maximum life spans of mice.¹¹ Among the most widely publicized research trials on antioxidants was a 5-year study published in 1993 involving approximately 30,000 residents of north-central China. Participants were given either a placebo or a dietary supplement containing one of seven vitamin-mineral combinations. In this study, persons who received a daily dose of beta-carotene, vitamin E, and selenium had a reduced cancer rate of 13%. Although many questions remain as to the significance of these findings for other populations, the study represents the first large-scale, randomized, prospective, placebo-controlled study showing the benefits of dietary supplementation with antioxidant vitamins and minerals. Much of the previous evidence was based on epidemiological studies of populations that suggested an association between antioxidants and disease prevention but were not designed to reveal cause-and-effect relationships. There has been growing evidence over the past three decades showing that malnutrition (e.g., dietary deficiencies of protein, selenium, and zinc) or excess of certain nutrients (e.g., iron and vitamin C) give rise to the oxidation of biomolecules and cell injury.⁸ A large body of the literature supports the notion that dietary antioxidants can protect against the harmful effects of radiation and play an important role in preventing many human diseases (e.g., cancer, atherosclerosis, stroke, rheumatoid arthritis, neurodegeneration, diabetes, and aging). There are, however, other theories in place.

Theories of Aging

There are many theories that address the so-called pillars of aging. Most of these theories support the benefits of antioxidants in the treatment and prevention of aging, including aging skin, based on free radical damage. Many others provide alternate explanations and reasoning behind disease and aging processes, some which totally go against the free radical theory and dispute the use of antioxidants and supplements.

The free radical theory

The free radical theory was developed in 1956 by Denham Harman at the University of Nebraska.¹²^,¹³^,¹⁴ This theory describes the development of an unpaired electron—which is ultimately destructive to the cells—and its efforts to stabilize. Any reaction in the body that uses oxygen (even eating, drinking, and breathing) can result in free radical formation; however, under normal circumstances, the body has built-in mechanisms (intrinsic antioxidation mechanism) to neutralize this free radical formation. When other excessive use of oxygen and undesirable oxidation processes occur (i.e., via pollutant, cigarette smoke, chemicals, radiation), the body is unable to handle the rate of free radical formation, hence these destructive processes occur. Antioxidants such as beta-carotene, vitamins C and E, grape-seed extract, Hydergine, melatonin, and vinpocetine have shown significant free radical scavenging benefits.¹²^,¹³^,¹⁴

The mitochondrial decline theory

Mitochondria are found in every cell and function to create adenosine triphosphate (ATP). ATP is necessary for every function of life. Enhancement and protection of the mitochondria are essential not only to preserve life moment to moment, but also for the body’s regenerative
and repair processes. However, as we age, mitochondria become less efficient and fewer in number, hence producing overall less ATP. Idebenone (coenzyme Q10), pregnenolone, acetyl-L-carnitine, and Hydergine are felt to be helpful in the overall process of maintaining stable levels of ATP.¹²

The cross-linking theory

Also known as the glycosylation theory of aging, cross-linking occurs in the presence of oxygen and involves the binding of glucose to protein, which impairs the protein and limits its ability to function. Examples of disease processes in which this mechanism is at work include diabetes, cardiac enlargement, renal disorders, and the binding of DNA resulting in cellular damage and the development of cancer. Dietary modification (a reduction in simple sugars and other simple carbohydrates) and supplements have shown great promise in the battle to prevent, slow, and even break existing cross-links.¹²^,¹⁵

The DNA and genetic theory

This theory, developed by genealogist Don Kleinsek, focuses on the encoded programming within our DNA.¹² We are born with a unique code and a predetermined tendency to certain types of physical and mental functioning that regulate the rate at which we age. The timing of this rate can be influenced via the accumulation of damage from DNA oxidation as a result of diet, toxins, pollution, and radiation. Other theories related to DNA damage involve the process of glycosylation (see the previous section, “The Cross-Linking Theory”) and the cell division process. The cell division process results in the shortening of telomeres (the sequence of nucleic acids extending from the ends of chromosomes), which leads to cellular damage and the inability of DNA to repair itself correctly, ultimately leading to cellular dysfunction, aging, and death (the telomerase theory). Because oxidation does play a role in the process of DNA damage, theoretically, antioxidants may serve some use in this theory. However, Kleinsek and his team of researchers have indicated that certain hormones may be the key in this genetic repair process.¹²

The neuroendocrine theory

The neuroendocrine theory is an alternative theory focused on hormones and aging. First proposed by Ward Dean and Vladimir Dilman, this theory states that the loss of the ability of the hypothalamus over time to dictate precisely its regulatory functions of the body’s organs and glands, and the loss of sensitivity of the receptors that uptake the individual hormones, lead to cell death. It is proposed that cortisol levels, which increase with age, damage the hypothalamus. Substances that slow down the accumulation of cortisol (DHEA, gerovital-H3, phenytoin) are felt to slow down this cortisol accumulation. Hormone replacement therapy is also felt to positively alter this process.¹²^,¹⁶

The membrane theory of aging

This theory, first described in Hungary by Imre Zs-Navy of Debrechen University, focuses on the removal of toxins by antioxidants. With age, the cell membrane loses its lipid content. This loss impairs the ability of the cell to efficiently conduct normal cell functions such as chemical transfer, heat processes, and electrical processes. A cellular toxin, lipofuschin, is thought to accumulate in the brain, heart, lungs, and skin. Substances that have been touted to aid in the removal of the accumulated lipofuscin are the amino acids acetyl-L-carnitine, carnosine, and centrophenoxine.¹²

The Hayflick limit theory

Developed by Leonard Hayflick, this theory focuses on substances that slow down cell division. The Hayflick limit theory suggests simply that the number of times a human cell can divide is limited. Working with Paul Moorehead in 1961, the two theorized that after that limited number of cell divisions is reached, the cells stop dividing and die.¹² According to this theory, efforts to slow down cell division should be helpful in extending life. Suggested substances that may be helpful include carnosine and RNA supplements.¹²

Antioxidants and the Skin

Skin aging results in characteristic tissue alterations, such as the degradation of collagen and the formation of visible fine lines and wrinkles.¹⁷ One of the major and important contributions to skin aging, skin disorders, and skin disease results from reactive oxygen species (ROS) or free-oxygen radicals such as superoxide, hydrogen peroxide, and hydroxyl radicals.

As an organ constantly exposed to its milieu and biological targets, the skin is often a target for oxidative stress caused by endogenous sources, such as neutrophils or pathological processes linked to inflammatory skin diseases, chronic infections, and exogenous sources (UV light being a primary culprit). Over the course of evolution, the skin has developed a complex defense system to protect the organism from oxidative damage. An overload of this system seems to be responsible, at least partially, for serious skin diseases, including the formation of tumors and premature skin aging. Hence, it seems to be a reasonable strategy to support the natural defense system of the skin, using substances that appear to alter this damage.

The skin is an extremely metabolic tissue that has the largest surface area in the body and serves as the protective layer for internal organs. Because skin is exposed to a variety of damaging species that originate in the outer environment, in the skin itself, and in various endogenous sources, it is a key contender and target of oxidative stress. For these reasons, the skin possesses a large number of
specific defense mechanisms for both physical and biochemical protection. The organization of the skin is very sophisticated, composed of several layers, each of which play a specific role and carry out a different function. Each layer has its own defense system, and the various systems differ from each other based on the layer’s vulnerability to oxidative stress.¹⁸ For example, studies have demonstrated that vitamin E (alpha-tocopherol) is, relative to the respective levels in the epidermis, the major antioxidant in the human stratum corneum (SC); its depletion is a very early and sensitive biomarker of environmentally induced oxidation; and a physiological mechanism exists to transport alpha-tocopherol to the skin surface via sebaceous gland secretion. Furthermore, there is conclusive evidence that the introduction of carbonyl groups into human SC keratins is inducible by oxidants and that the levels of protein oxidation increase toward the outer SC layers.¹⁹

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