Free Radical Theory of Aging

The free radical theory of aging which was proposed in 1954 states that organisms age because cells accumulate free radical damage over time. In chemistry, free radicals are atoms, molecules, or ions with unpaired electrons. A free radical can be produced from almost any molecule when it loses an electron from one or more of its atoms. These unpaired electrons are highly reactive oxidizing agents (it gains electron in the redox reaction and oxidize the other molecule while itself become reduced) in an oxidation-reduction reaction (redox reaction). In general, oxidation refers to the loss of electrons, while reduction refers to the gain of electrons. The oxidizing agent itself is reduced by gaining electron from the reducing agents (reduction half reaction)  while the reducing agent is oxidized by losing the electron (oxidation reaction). Overall, there is/are electron(s) transferred from the reducing agent to the oxidizing agent. The whole chemical reaction is termed as redox reaction, each half reaction is termed as oxidation and reduction. Free radical would acquire electron from other molecules/atoms/ions to change itself into a stable form but leave the other molecule become a free radical and damage the function of those other molecules. Free radicals can involve (although not the only reaction) in electron chain reactions (chain redox reactions) where electrons are transferred in a sequence of redox chain reaction.

Free radicals normally exists in human body, and play important roles in biochemistry. Without free-radical activity, we would not be able to produce energy (by oxygen metabolism), maintain immunity, transmit nerve impulses, synthesize hormones or even contract our muscles. Examples of natural free radicals in our body include superoxide (O2-) and nitric oxide (NO) which regulate many biological processes. The immune system, for instance, uses free radicals to destroy bacteria and other pathogens. Nitric oxide, helps nerve cells in the brain communicate with each other.

The free radicals related to free radical theory of aging have 2 types of sources. One is the free radicals produced in our body by our normal energy metabolism – the oxygen metabolism occurred at Mitochondria, the subcellular organelle functions as our power house through production of energy molecule ATP. The other sources of free radicals related to aging and/or longevity is trigged and induced by environmental stress such as sunlight and other forms of ionizing radiation, ozone, industrial wastes, residues, pesticides and herbicides, hydrogen peroxide, heavy metal (aluminum), automobile exhaust, cigarette smoke as well as heat exposure. Even certain foods, particularly processed and preserved meats, and beverages, such as coffee and alcohol, are loaded with potent free radical generators. We will briefly introduce the mechanism of stress induced free radicals and aging here and will discuss this topic in more detail in our “stress induced premature aging” section together with other stress induced damage aging mechanisms. Here we will discuss the free radicals damage accumulated over time in aging from our normal energy metabolism and our body’s internal repair and replacement mechanism to counteract free radicals, and show how this repair mechanism become progressively deteriorated and declined while we age.

Our normal energy (oxygen) metabolism (cellular respiration) occurs as a chain redox reaction on the cell membrane of Mitochondrion through an electron transport chain by a cascade of enzyme systems. The whole reaction is as follows:

C6H12O6 (glucose) + 6O2 —-> 6CO2 + 6H2O + ~38 ATP (energy molecule)

One Glucose (C6H12O6) is broken down to 2 molecules of pyruvic acid. Pyruvic Acid is shuttled into the mitochondria, where it is converted to a molecule called Acetyl CoA — the common breakdown molecule from digested food protein (amino acids), fatty acid, and polysaccharides (sugar). Acetyl CoA enters citric acid cycle–the common central process leading to cellular respiration. NADH and succinate (sugar) are generated in the citric acid cycle which enters the electron transport chain.

Electron transport chains are used for extracting energy from redox reactions — the oxidation of sugars. This process results in the production of toxic by-product free radical superoxide(O2-). The electron transport chain couples the chemical reaction between the electron donor (NADH) and the terminal electron acceptor (O2) which is equivalent to the transfer of H+ ions across mitochondrial membrane, through a cascade of mediating biochemical reactions and enzyme complex. NADH and succinate generated in the citric acid cycle is oxidized. Oxygen is converted to water, and the sugar succinate converted to fumarate which eventually is converted to CO2, and NADH to NAD+ (recycled in citric acid cycle) and the reaction drives the transfer of H+ ions, creating the proton gradient across the Mitochondria membrane. This proton gradient (H+ ions) are used to produce adenosine triphosphate (ATP) from ADP and phosphate (called oxidative phosphorylation), the main energy intermediate.

This respiratory electron transport chains (ETC) on mitochondria membrane is the major sites of premature electron leakage to oxygen, thus being major sites of superoxide (O2-) production and drivers of oxidative stress, although electron transport occurs with great efficiency. The ETC releases energy into the cell, but it also shred electrons from oxygen leaving the oxygen atom with one unpaired electron. Free radicals generated in energy metabolism are also termed as Reactive Oxygen Species (ROS) i.e. oxygen free radical. Oxygen free radicals steal electrons from other molecules. These molecules, in turn, become unstable free radicals and combine readily with other molecules.

Reactive oxygen species (ROS) are ions or very small molecules that include oxygen ions (O2-), peroxides, perhydroxyl (HO2·) and hydroxyl (OH·) free radical, both inorganic and organic. A peroxide is a compound containing an oxygen-oxygen single bond. The simplest stable peroxide is hydrogen peroxide (H2O2). They are highly reactive free radicals. ROS form as a natural byproduct of the normal metabolism of oxygen as described above. One major contributor to oxidative damage is hydrogen peroxide (H2O2) which is converted from superoxide (O2-) that leaks from the mitochondria. Normally the oxygen is reduced to produce water; however, in about 0.1-2% of electrons passing through the chain, oxygen is instead prematurely and incompletely reduced to give the superoxide radical,·O2- Superoxide is not particularly reactive by itself, but can inactivate specific enzymes or initiate lipid peroxidation (see below for definition) in its perhydroxyl radical HO2· form. The pKa of the protonated superoxide (i.e. HO2·) is 4.8, thus at physiological pH the majority will exist as hydrogen peroxide (H2O2). Hydrogen peroxide is dangerous in the cell because it can easily be converted into hydroxyl radicals (OH·), one of the most destructive free radicals, by interacting with Fe2+ (this process is known as a Fenton reaction).

Fe2+ + H2O2 → Fe3+ + OH· + OH− (spontaneous reaction)

ROS can also be induced by environmental stress described above. However, during times of environmental stress, ROS levels can increase dramatically, which can result in significant damage to cell structures. All of these cumulates into a situation known as oxidative stress. (Read our “stress induced premature aging” section for more detailed discussion)

ROS and other free radicals can damage DNA and chromosome 3-D conformation, RNA, proteins (through cross-linking), lipids, cell membrane (consists of proteins and lipid-bilayer) which theoretically contributes to cellular damage/dysfunction and the physiology of ageing. They cause gene mutation, genomic instability, disturb DNA and RNA synthesis, interfere with synthesis of protein, lower our energy levels, prevent the body from building muscle mass and disrupt cell metabolism, destroy cellular enzymes, which are needed for vital chemical processes, cause apoptosis and other forms of cell havoc, etc. ROS and other free radical can steal electrons from lipids in cell membranes, a process called lipid peroxidation. A chain of damaging events can be triggered from a single ROS and other free radical molecule as unstable fatty acid radicals propagating in tissues and within cells produce other unstable radicals. Free radicals attack collagen and elastin, the structural protein that keep our skin moist, smooth, flexible and elastic. These vital tissues fray and break under the assaults of free radicals, a process particularly noticeable in the face, where folds of skin and deep-cut wrinkles are manifestation of the long-term effect of free-radical damage. Visit our “molecular mechanism of skin aging” part for more detailed discussion and for UV sun light induced free radical damage to our skin. The specific effects of free radicals on mitochondria damage will be discussed in “Mitochondria Damage Theory of Aging” section. Free radical concentration is the highest in mitochondria. Certain accumulation of metabolic waste products, including substances known as lipofuscins is caused by free radical. An excess of lipofuscins in the body is shown as “aging spots.” — the aging pigment. We will discuss more detail about lipfuscins and aging in our “biomarker of cellular senescence” section lipofuscins accumulation subsection.

Free radicals have been implicated not only in normal aging physiology but also in age-related degenerative disorders. The cellular damage inflicted by this uncontrolled oxidative stress inexorably spreads outward to the level of tissues and organs, where it eventually manifests itself as some form of degenerative disease. The damage can show up in many ways including skin erythema, hair loss, forms of vascular damage, internal bleeding, hypertension, weakened immune systems, sterility, premature aging and death. Over 80 degenerative diseases are now known to be linked to free radical-induced oxidative stress including cancer, atherosclerosis, Alzheimer’s disease, cataracts, type 2 diabetes and neurodegeneration. An estimated 80 to 90 percent of all degenerative diseases are now believed to involve free radical activity. Visit our “Pathologic and Physiological Age-Related Changes” — Age-Related Degenerative Diseases for more related information.

As has been mentioned in “Introduction”, our body has an internal “maintenance, repair and defense mechanism/system” that would repair and protect us from the various damaging effects. Usually this repair and defense system functions well while we are young, however when we progressively become more and more aged, this system itself also deteriorates and declines together with other body functions. The free radical is no exception. In our body, there is repair mechanism working to counteract the damage of free radical which will be discusses in more detail below. The groups of molecules that capable of counteracting and neutralizing free radical are called antioxidants.

The first line of defense against ROS consists of three protective antioxidant enzyme systems within the cell–superoxide dismutase (SOD), catalase and glutathione peroxidase. These natural defense mechanisms quench free radical damage by changing them to harmless substances, such as water, thereby preventing most oxidative damage. SOD converts the oxygen radical known as superoxide anion generated from ongoing energy metabolic reactions, into hydrogen peroxide. by combining with hydrogen ions (reaction 1 below). To rid itself of hydrogen peroxide, which is itself a toxic free radical generator, the cell then employs the two other antioxidant enzyme systems. Catalase, which is concentrated in peroxisomes located next to mitochondria, reacts with the hydrogen peroxide to catalyze the formation of water and oxygen (reaction 2). Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur containing protein called glutathione (reaction 3).

2 O2- (aq) → H2O2 (aq) (superoxide dismutase) 1

2 H2O2 → 2 H2O + O2 (catalase) 2

2GSH + H2O2 → GS–SG + 2H2O (glutathione peroxidase) 3

Superoxide dismutase (SOD) is present in three places naturally in the cell, i.e. the liver, kidney and adrenal gland. SOD that is present in the mitochondria contains manganese (MnSod). SOD that is present in the cytoplasm of the cell contains copper and zinc (CuZnSod). The genes that control the formation of SOD are located on chromosomes 21, 6, and 4. The less well known Peroxiredoxins also degrade H2O2, within the mitochondria, cytosol and nucleus.

The second line defense against other free radicals that was generated by ROS include Methionion sulfoxide reductase A (MSRA), the enzyme catalyzes the repair of protein-bound methionine radicals oxidized by ROS. Another enzyme that repairs oxidative damage is 8-oxo-dGTPase, which repairs 8-oxo-7,8-dihydroguanine, an abundant and mutagenic form of oxidative DNA damage.

The third line of defense against free radicals are accomplished by the natural antioxidants in our body they are not enzymes that catalyze neutralization reactions, but are free radical scavenger, seeking out free radicals and harmlessly bind them before they can attach themselves to other molecules and/or cause cross-linking. Many vitamins and minerals and other substances fight aging by acting as free-radical scavengers. One of the groups of antioxidant is vitamin C, vitamin E and beta carotene, the substance that our body uses to produce vitamin A.

It is now believed that as we discussed before, this repair and defense system itself will deteriorate and decline when people age. Their ability to make these important functional enzyme starts to falter. Once cells can no longer make sufficient amounts of these antioxidants enzymes, or produce faulty copies that don’t work very well (could be a result of oxidative damage to the genes that encode these proteins), then free radicals begin to accumulate and oxidative damage run out of control. Although we have now identified the genomic location of these antioxidant enzymes, but the underlying mechanism of how their gene and protein become dysfunctional when we age is not very clear.

Natural antioxidants include vitamin C, vitamin E and beta carotene, the substance that our body uses to produce vitamin A. Specialists in anti-aging medicine prescribe a host of natural and manufactured antioxidants to help combat the effects of aging. Visit our “active ingredients in anti-aging skin care creams” knowledge base and “anti-aging supplements” knowledge base for more detail about antioxidants used as active ingredients in skin care creams as well as in anti-aging supplements and anti-aging superfoods nutritional products.

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