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The Antioxidant Theory of Aging

Article

by Robin Koon -

In the scientific community, anti-aging research (also called life extension) refers to slowing, preventing or reversing the aging process. In the medical community, anti-aging medicine means the early detection, prevention and treatment of age-related diseases. Our understanding of aging is still quite limited because it is a complex biological process. The variation of average lifespan (aging) involves a variety of factors: pathological and physiological (biology, biochemistry, disease states, endocrinology, genetics, genomics, immunology and proteomics), environmental, nutrition (diet), etc. Aging is a complex process that leads to the gradual progression of deterioration in bodily functions. Most organisms actually die from age-related diseases rather than from aging itself (the weakest-link failing). Much research has been done to investigate the causes or methods of aging and in attempting to find interventions.

There are many different theories (and many cross over each other) of how and why we age, but none can singly explain or encompasses all the details of aging. The most well-known name linked to the search for the fountain of youth is the Spanish explorer Juan Ponce de Leon, who in 1513 thought it would be found in Florida. Nope, he didn’t find it either.

Various Key Aging Theories

Genetic Theory

The genetic theory of aging states that longevity is largely determined by the genes. Scientists estimate there may be variations or mutations in up to 7,000 genes involved in the aging process. As these are complex processes to understand, research is still being done to better understand the various human genes involved in aging.

Damage Theories

The general idea behind damage-based theories of aging is that a slow build-up of damage occurs over a lifetime. There are several examples of these theories:

  1. The wear and tear theory
  2. The oxidative stress theories

        a. The dna damage and repair theory

        b. The free radical theory

        c. Mitochondrial theory

        d. Telomere theory

        e. Glycation (crosslinking) theory

        f. The immunologic theory

        g. Protein damage theory

        h. Mitohormesis theory

        i. Inflammation (chronic) theory

This article cannot address all of these theories. The clear leader in this list (under oxidative stress theories) is the free radical theory, which is one of the most widely accepted aging mechanism hypotheses.

The Free-Radical Theory

The free radical theory of aging was conceived by the late Denham Harman, M.D., Ph.D., in 1954. The free radical theory states that aging is due to accumulation of oxidative damages to cells caused by free radicals.

Free radicals are produced in large quantities in cells by different mechanisms, such as exposure to oxygen (normal respiration), radiation or environmental toxins. Harman argued that oxygen-produced free radicals would cause cumulative damage that would lead to loss of functionality and, eventually, death.

We refer to these types of oxidative compounds as reactive oxygen species (ROS), which are chemically reactive molecules containing oxygen. These compounds include: oxygen free-radicals (O-), peroxides (H2O2), hydroxyl radical (·OH), hypochlorous acid (HClO), superoxide anion (O2-), etc. The biological production of ROS is the unavoidable byproduct produced during normal aerobic cellular metabolism.

An over-abundance of ROS can occur from exogenous exposure to drugs, excessive heat, pollutants (e.g. dioxins, heavy metals, organochlorines - PCBs, pesticides, smoke, volatile organic compounds (VOCs), , radiation and tobacco. This higher-than-normal ROS level can cause cellular damage, such as DNA and RNA damage, lipid oxidation (peroxidation), protein oxidation, other cell damage and inflammation. The inflammatory cascade is more active during aging and has been linked with many age-associated diseases.

The damage occurs when the free radical (which is an unbalanced molecule) wants to become balanced, and so it seeks to find another electron to match with its unpaired electron. The free radical often pulls an electron off a neighboring molecule (called oxidation), causing that molecule to be damaged or to become another free radical. The new free radical can then pull an electron off the next molecule, and so on. This can lead to a chemical chain reaction of radical production. The free radicals produced in such chain reactions eventually terminate. Such events cause damage to cells.

Free-radicals are integral to normal body function, so a redox paradox exists: On the one hand, oxygen is essential to aerobic organisms, and they do play key beneficial roles in situations including cell differentiation, proliferation, host defense response, the electron transfer chain in the mitochondria, the inflammation processes, etc. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS).

The body has evolved to control these aerobic oxidation-reductive processes to remain healthy. To control an excess of free radicals, the body has two main antioxidant systems, enzymatic and non-enzymatic antioxidants, which act (intra and extracellular) to control or remove the excess ROS.

The enzymatic antioxidant system consists of several endogenous enzymes: superoxide dismutases (3: Cu/Zn-SOD, Mn-SOD, and EC-SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) and Peroxiredoxin (Prx).

The non-enzymatic antioxidants system serves as another system for controlling the free radicals. Non-enzymatic antioxidants are exogenous, and directly scavenge free radicals while enhancing the enzymatic system protection against oxidative damage. Vitamins A, C and E are the most well-known antioxidants. In addition to vitamins, there are other compounds that work too, such as coenzyme Q10 (CoQ10), phenolic, flavonoid and carotenoid compounds, , α-lipoic acid, resveratrol, quercetine, EGCG, N-Acetyl Cysteine (NAC) and many more.

Antioxidant therapy

Harman believed the aging process could be slowed by reducing the free radical load with a healthy diet, regular exercise and dietary supplementation.

The free radical theory of aging holds that a progressive accumulation of oxidative damage caused by ROS impacts physiological function, increases incidence of disease and results in a potentially reduced life span. The theory also suggests that ingesting antioxidants (e.g., vitamins A, C, E, K and other antioxidant nutrients) can slow the process of aging by neutralizing these free radicals from oxidizing biological molecules or reducing the formation of free radicals.

Oxidative stress is due to the imbalance of the body’s scavenging ability to balance free radical species. Currently, several researchers claim the incidence of oxidative stress is related to the onset and development of more than 100 diseases and disease states. An example of this is chronic inflammatory response, which results in chronic oxidative stress. Many scientists consider antioxidant therapy, as a way to limit, prevent or treat various negative kinds of degenerative conditions.

The use of antioxidants to treat or prevent disease is controversial. While there is correlative data to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidative damage and aging has not been strongly established. There are clinical trials on both sides of this issue. Not all trials support the use of antioxidant supplements for primary or secondary prevention. We really do not know if their use can extend lifespan.

We do know their use appears to play an important role in protection against various disorders. Antioxidants have been used as therapies to decrease oxidative stress and fight onset of cardiovascular disease (CVD). In the 1970s, Linus Pauling suggested the intake of large amounts of vitamin C (the vitamin c theory) to improve health (stating that ascorbate deficiency was a significant factor for CVD).

There are many questions that science has yet to be able to answer: Is aging an inherent unstoppable progressive natural phenomenon? Will fighting aging process slow or improvement age related illness? Can we cure aging?

Strategies

During his later years, author Mark Twain noted "life would be infinitely happier if we could only be born at the age of 80 and gradually approach 18."   People expect  they can maximize life expectancy by using preventive measures: modern medicine, appropriate lifestyle and diet choices. Plus, they have access to physicians to treat age-related disease when it occurs.

Insufficient levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or destroy cells. But when it comes to ingesting antioxidants, don’t over compensate (mega doses)— more is not always better. It’s not about the marketing claims of “my ORAC is bigger than yours," rather, it’s about balance. Some scientists are concerned that the over-ingesting antioxidants can be damaging as well because some degree of oxidative stress is required for the body to function correctly, causing healthy changes in response to stresses, like exercise.

No one theory explains the aging process, as it may probably be too complex to be covered by just one theory. Just as there is probably no single mechanism that explains aging in all living organisms.

Robin Koon is executive vice-president at Best Formulations (bestformulations.com) and has more than 35 years of pharmaceutical experience in clinical pharmacy as a retail drug chain executive overseeing operations in managed-care and manufacturing.

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