Aging is the seemingly inevitable decline in physiologic function that occurs over time. For all living organisms, the ultimate terminus of aging is the same: death. Dr. Denham Harman, the “father” of the free radical theory of aging, has defined “aging” as the increased probability of death as the age of an organism increases, and diverse adverse physiologic changes accumulate. At least four major theories of aging have been propounded that purport to explain much or all of the cause of biological aging:

  • The free radical theory of aging (FRTA).
  • The mitochondrial theory of aging.
  • The cross-link theory of aging (5).
  • The membrane hypothesis of aging (4).

The FRTA was first proposed by Harman almost 50 years ago in November 1954 (6), and his groundbreaking original paper on the FRTA was published in 1956 (7). It is perhaps a measure of the profound explanatory and causal power of free radicals – highly reactive, small oxygen-containing molecules – that they play key roles in the mitochondrial, membrane and cross-link theories, as well as the FRTA.


“A free radical is simply a molecule carrying an impaired electron…. All free radicals are extremely reactive and will seek out and acquire an electron in any way possible. In the process of acquiring an electron, the free radical… will attach itself to another molecule, thereby modifying it biochemically.” (8). However, as free radicals (FR) steal an electron from the other molecules, they convert these molecules into FRs, or break down or alter their chemical structure. Thus, FRs are capable of damaging virtually any biomolecule, including proteins, sugars, fatty acids and nucleic acids (9). Harman points out that FR damage occurs to long-lived biomolecules such as collagen, elastin and DNA; mucopolysaccharides; lipids that make up the membranes of cells and organelles such as mitochondria and lysosomes; components of blood vessel walls; and proteins and lipids that combine and accumulate as “age pigment” – lipofuscin (10).

The main FRs are superoxide radical (SOR), hydroxyl radical (OHR), hydroperoxyl radical (HPR), alkoxyl radical (AR), peroxyl radical (PR) and nitric oxide radical (NOR) (11). Other molecules that are technically not FRs, but act much like them, are singlet oxygen, hydrogen peroxide (H2O2), and hypochlorous acid (HOCl) (11). Collectively, the FRs and non-FR mimics are called “oxidants” or “reactive oxygen species” (ROS).

FRs are extremely short-lived because of their extreme reactivity. The longest half-life is 1-10 seconds for NOR; the shortest (and most deleterious) is only one nanosecond (10 -9 sec) for OHR (11). A broad range of the chief diseases of aging, including cancer, heart/artery disease, essential hypertension, Alzheimer’s dementia, aging immune deficiency, cataracts, diabetes, Parkinson’s disease, arthritis and inflammatory disease, as well as aging itself, are now believed to be caused in whole or part through FR damage (10,11,12,18).


There are four primary sources of oxidants formed within living organisms. The major source of FRs and oxidants is the mitochondrial generation of ATP energy using oxygen. A small percentage (2-3% or less) of oxygen in mitochondria is inadvertently converted to SOR, which can in turn generate H2O2, OHR, and all other FRs (2,12,18). A second source of oxidants, especially H2O2, are the peroxisomes, organelles that degrade fatty acids (2, 12). A third source of oxidants is cytochrome P450 enzymes. These enzymes help cells, especially in the lungs and liver, detoxify a broad range of potentially toxic food, drug and environmental pollutant molecules. SOR is a by-product of many of these detoxification reactions (2,12).

Finally, white blood cells (phagocytes) attack germs with a mixture of oxidants including SOR, H2O2, NOR, HOCl, and OHR. (2,9.12). This may create serious FR problems, especially in those suffering a chronic immune-activation condition, such as AIDS, chronic candidiasis, protozoal infections, chronic fatigue syndrome, etc. (2,12). Also, various biomolecules including hydroquinones, flavins, catecholamines, thiols, pterins and hemoglobin, may spontaneously auto-oxidise and produce SOR (9).

From outside the body, polluted urban air, cigarette smoke, iron and copper salts, some phenolic compounds found in many plant foods, and various drugs may all contribute FRs or provoke FR reactions (9,12).


The FRTA has generated a massive amount of research designed to support or refute the theory. In a major review of the FRTA in 1998, Beckman and Ames surveyed 14 areas of research which have offered varying degrees of support to the FRTA, including oxidative phenomenology, interspecies comparisons, dietary (calorific) restriction, manipulation of the rate of living, manipulation of oxygen concentration, dietary antioxidant supplementation, pharmacological antioxidant administration, in vitro senescence studies, classical and population genetics, molecular genetics, transgenic organisms, sporadic degenerative diseases, inherited degenerative diseases and epidemiology (2). In this brief article only a “snapshot” of some of the evidence can be presented. The interested reader is directed to references 2, 9,12 and 18 for more detail, in particular, reference 2 has over 350 literature references.

The university of antioxidant defences is a major clue to the anti-life/ pro-aging nature of FRs. Antioxidants are usually small molecules that inhibit or quench (halt) FR reactions. “Although the nature of these defences varies between species, the presence of some type of antioxidant defence is universal…. Clearly, an indifference to oxygen free radicals is inconsistent with life, underlining the centrality of oxidative [FR] damage.” (2)

Antioxidants exist in both enzymatic (e.g. SOD, catalase) and non-enzymatic forms. Some non-enzymatic antioxidants, (e.g. glutathione) are produced within cells, others (e.g. vitamins C and E) are diet-derived.

One of the most elegant demonstrations of the FRTA comes from transgenic experimentation. Extra genes for SOD (which neutralizes SOR) and catalase, (which neutralizes H2O2,) were inserted into fruit flies (Drosophila). As compared to their normal brethren, transgenic flies had up to 30% longer average and maximum life-spans; a reduction of age-related accumulation of oxidative damage to protein and DNA; reduced DNA damage when live flies were X-ray exposed, and many other improved indices of oxidant damage (2,16).

Interspecies comparison of FR production, oxidative damage, and antioxidant levels also supports the FRTA. The white-footed mouse, (Peromyscus leucopus) lives about twice as long as the house mouse, (Mus musculus): 8 years vs. 4 years. Their metabolic rates are similar. At age 3.5 years, the rates of mitochondrial SOR and H2O2 generation was 40% less in heart and 80% less in brain in Peromyscus, while catalase and glutathione peroxidase antioxidant activities were about twice as high in Peromyscus, and the level of FR-damaged protein was 80% higher in Mus m. (2,16). Pigeons and rats have similar body mass and metabolic rates, yet rates of heart, liver and brain mitochondrial SOR and H2O2 generation are 10 times less in pigeons, while their levels of catalase and glutathione peroxidase are higher. The pigeon lives 8-10 times longer than the rat (2,16). Beckman and Ames note that; “Together, interspecies comparisons of oxidative damage, antioxidant defences, and oxidant generation provide some of the most compelling evidence that oxidants are one of the most significant determinants of life span.” (2)

Human studies have also shown a strong connection between FR/oxidative damage and aging. A 1999 study reported that; “we examined markers of oxidative damage to DNA, lipids, and proteins in 66 muscle biopsy specimens from humans aged 25 to 93 years. There were age-dependent increases in 8-hydroxy-2-deoxyguanosine, (a marker of oxidative damage to DNA), in malondialdehyde (MDA), a marker of lipid peroxidation, and to a lesser extent in protein carbonyl groups, a marker of protein oxidation…. These results provide evidence for a role of oxidative damage in human aging….” (13)

A 1996 study examined 100 healthy people in their 80s and 90s, 62 disabled, unhealthy people of similar age, and 91 healthy adults, (age 54± 16 years). The researchers found the highest levels of lipid oxidation products in blood in the disabled elderly, and lowest levels of lipid oxidation products in blood in the disabled elderly, an intermediate level in the healthy elderly, and lowest levels in the healthy adults. They also noted that higher blood levels of antioxidant vitamins C and E were associated with lesser disability, and higher lipid peroxidation levels were associated with greater disability. They concluded that; “These findings suggest that aging associated with disability, i.e. unsuccessful aging, could somehow be related to a higher degree of oxidative stress [i.e. FR damage] compared with successful aging, which is characterized by the absence of significant pathological conditions.” (14)

After assessing the 14 years of evidence concerning the FRTA, Beckman and Ames conclude that; “…the momentum gathering behind the free radical theory is not due to any single experiment or approach, but rather derives from the extraordinary multidisciplinary nature of current research. Although no single line of reasoning alone permits definitive conclusions, together they present a compelling case…. In its broader sense (‘oxidants contribute significantly to the process of degenerative senescence [aging]’), the theory has clearly been validated. In the more strict sense of the theory, (‘oxidants determine maximum life span potential’), whilst the data are not yet conclusive, a large body of consistent data, [that tends to support the theory] has been generated.” (2)


The FR research of the past 50 years has proven beyond a reasonable doubt that FRs are at least a major factor in aging, illness and death. Fortunately, there are a variety of measures we can take to bolster antioxidant defences and also reduce oxidant generation and FR damage. One of the oldest known methods is dietary (calorific) restriction.


It has been known since 1936 that a decreased calorific intake in mice and rats, without malnutrition, extends the maximum life span (16). Calorific restriction (CR) increase in maximum life span has also been shown in fish, spiders, water-fleas, and some other non-rodent species (16). Although no studies have yet been completed on primates, ongoing studies (primarily with rhesus monkeys) have shown that important physiological effects of CR seen in rodents, (such as decreased blood glucose and insulin levels, improved insulin sensitivity and lowering of body temperature), are also seen in rhesus monkeys (16). Sohal and Weindruch point out that rodents subjected to CR show reduced age-associated increases in rates of mitochondrial SOR and H2O2 generation, slower accumulation of oxidative damage, decreased alkane production, (a measure of lipid peroxidation), and delayed age-associated loss of membrane fluidity (16). They report that CR in rodents elicits about 300 age-sensitive changes, with 80-90% of these changes exhibiting a “delayed aging” profile (16).

Gerald Reaven has identified “Syndrome X” in humans, which consists of the combined presence of insulin resistance and glucose intolerance, obesity, blood fat abnormalities (including FR-oxidized cholesterol), and hypertension (17). These in turn are associated with heart/artery disease, cancer, diabetes, and premature aging (17). The “Syndrome X” parameters are all reduced in animal CR experiments (16). A permanent 20-30% reduction in “normal” levels of caloric intake, combined with sugar/junk food reduction, might produce similar benefits in human as CR in animals. In his 1996 article “Aging and disease: extending the functional life span,” FRTA pioneer Harman recommends CR as a part of a FR-reducing life-extending lifestyle (19).


Iron and are trace minerals essential for mammalian life. Severe deficiency of iron or copper may cause red blood cell anemia, among other things. Yet iron and copper turn out to be the best promoters of OHR production, by the “Fenton reaction” (2). OHR is the most toxic free radical (2). Iron and copper also promote generation of toxic lipid (fatty acid) radicals (20, p.33). Human body iron content increases with age – throughout life in men, after menopause in women (2). Iron accumulation may increase risk of oxidative damage with aging (2,12), and too much dietary iron or copper is a risk factor for cancer and cardiovascular disease in men (12). It is therefore a prudent antioxidant measure to be moderate in (high iron), red meat consumption, take iron supplements only if careful medical testing proves it necessary, and to keep supplemental copper levels to at most 2mg daily. Do not take inorganic iron/copper salts (sulfate, oxide, pyrophosphate) with vitamin C – that would initiate the OHR-producing Fenton reaction in the gut. Also, in the U.S. (I don’t know about Europe or elsewhere) commercial “enriched” wheat flour is iron-fortified, so a diet high in bread, pasta, pizza and other baked goods is a high iron diet, best avoid. Harman also recommends minimizing iron and copper intake (19).


One of the biggest dietary revolutions of the 20th century was the shift away from saturated fats, (such as lard, coconut oil, meat and dairy fat, etc.) to polyunsaturated fat (primarily linoleic acid) – rich margarines and vegetable oils. While monosaturated fats (olive oil), cholesterol, and even saturated fats are subject to FR damage, it is polyunsaturated fatty acids (PUFA) that are most susceptible to FR damage (20, p.35). PUFA lipid peroxides “have toxicities comparable to the radical species produced by [X-ray] irradiation.” (20, p.37) Lipid peroxides and their breakdown products (e.g. MDA) can cross-link proteins, phospholipids, nucleic acids and cellular DNA (20, p.38). They can inactivate enzymes (20, p.38). While all cellular components are subject to FR attack, it is membranes, usually PUFA-rich, that are most susceptible to peroxidative FR damage (20, p.38). Also, more unsaturated PUFA (such as EPA and DHA) are more FR-damage prone than less unsaturated PUFA, (e.g. linoleic acid) (20, p.39). Thus a prudent antioxidant measure is to avoid all margarines and PUFA-rich vegetable oils, such as safflower, sunflower, corn, soy and canola oil. Foods fried in PUFA-rich oils are especially good sources of (unwanted) lipid peroxides (21). Harman also recommends low dietary intake of especially oxidation-prone molecules (19).


In humans the first line of antioxidant defence are the antioxidant enzymes, especially SOD, glutathione peroxidase (GPX), and to a lesser extent catalase, as well as the tripeptide glutathione (GSH) (11). These enzymes will help destroy SOR, H2O2 and lipid peroxides, while GSH protects against oxidized protein (20, p.48). There is no known direct enzymatic defence against the supertoxic OHR (20, p.48), although any antioxidant defence against SOR and H2O2 is indirectly a defence against OHR, since they can combine to generate OHR (8, p.66). A major antioxidant role is therefore left to a group of nutrients, including vitamins C and E, selenium, CoQ10 and lipoic acid (9,12,30). The pineal hormone melatonin also plays multiple antioxidant roles (18,22) and various drugs, including centrophenoxine (41) and pyritinol (40) have also shown serious antioxidant power.


Vitamin C (VC) may be the most versatile and important nutrient-antioxidant. It is a powerful scavenger of OHR (20, p.52). Vitamin C can regenerate vitamin E that has been “radicalized” by neutralizing lipid peroxides (20, p.52). Frei and colleagues found that plasma lipids subjected to oxidative stress were best protected by Vitamin C, and that loss of vitamin E did not begin until after all Vitamin C was consumed (11). Vitamin C can spare and regenerate the key antioxidant GSH, which reacts enzymatically (through GPX) and non-enzymatically with a broad range of oxidants (11). Red cell GSH rose 50% in healthy adults supplemented with Vitamin C, and an improvement in red cell oxidant defence was shown (11). Vitamin C neutralizes SOR, although about 3,000 times slower than SOD (9). However, cellular Vitamin C levels are 1,000 times higher than SOD, so Vitamin C may contribute significant defence against SOR, especially when intracellular Vitamin C levels are pushed higher than normal through “ascorbate loading.” Physician R. Cathcart has found, working with thousands of patients, that they can absorb 30-200 (!) grams of VC/day orally when subject to a broad range of medical conditions, (many infectious or inflammatory) where high SOR levels could be expected (23). He has found no evidence of toxicity in these patients, but instead generally significant, even amazing amelioration of the medical problems and symptoms (23). Although in test tube experiments Vitamin C can act as a pro-oxidant, especially in the presence of iron or copper ions, E. Niki points out that “under physiologic conditions urate prevent the pro-oxidant action of ascorbate [VC].” (24) Lutsenko and colleagues “found that c-loading resulted in substantially decreased mutations [in cellular DNA] induced by the H2O2.” (25) For these and many other reasons, Vitamin C is a key longevity-antioxidant. Superbly healthy adults may only need 250-500 mg daily, but those suffering chronic health problems probably require 1-10,000 mg daily in divided doses. Even more might be useful – see Cathcart’s paper for details (23). (Ed.- Our vitamin C unique contains only L-ascorbic acid, the most active form of vitamin C- “normal” vitamin C is made up of D-ascorbic acid and L-ascorbic acid, therefore dosages for the above in theory can be halved with this form.


Vitamin E (VE) is the chief fat-soluble antioxidant, and occurs prominently in all membranes (9). In mammals, an abnormally low ratio of VE/ dietary fatty acids is associated with a spontaneous increase in lipid peroxidation in fatty tissues (20, p.57). VE can quench SOR and lipid peroxide radicals (9). When VE quenches FRs, it becomes a VE radical, which then uses VC to return it to its antioxidant state (11). Thus VC and VE are key synergistic antioxidants. In a study with 30 elderly women taking 1000 mg VC and 200 mg VE daily for 16 weeks, serum MDA levels, (a measure of lipid peroxidation) dropped about 40% in the 10 healthy women, about 65% in the 10 women suffering from depression, and about 60% in the 10 women suffering from heart disease (26). In a mouse experiment, researchers found that a VC/VE combination provided significant protection against butyl hydroperoxide-induced brain lipid peroxidation. “We observed that prior supplementation of [VC/VE] – combination reduced lipid peroxidation induced… in every brain region.” (27) Peroxynitrite is a powerful neurodegenerative oxidant formed through the interaction of SOR and NOR. Peroxynitrite is generated through excitotoxic pathways in the brain (28). Gammatocopheral VE, but not alpha-tocopherol VE, neutralizes peroxynitrite (29). VC also neutralizes peroxynitrite, so once again synergizes with VE. 100-800 IU VE daily (preferably at least 20% as gamma VE) in natural, not synthetic form, is a generally safe and reasonable VE antioxidant dosage. VE may synergize with blood thinners (e.g. coumadin), so those on prescription drugs should check with a knowledgeable physician about any adverse interaction with VE.


Alpha-lipoic acid (ALA) is a quasi-vitamin anti-oxidant. It can be made by the body, but also absorbed from diet or supplements (30). Alpha-lipoic acid is the oxidised form of lipoic acid; dihydrolipoic acid (DHLA) is the reduced form. They can be inter-converted (30). As DHLA is converted to Alpha-lipoic acid, oxidized VC, CoQ10, and glutathione are regenerated (30). Alpha-Lipoic Acid and DHLA are both powerful antioxidants. Alpha-Lipoic Acid scavenges OHR, HOCl, NOR, peroxynitrite, and H2O2 (30). DHLA does also, but adds SOR and lipid peroxides to its quenching activity (30). Alpha-Lipoic Acid is extremely non-toxic, and has been used for decades in Germany to treat diabetic neuropathy (30). Packer and co-workers found that rats fed Alpha-Lipoic Acid had a 50% reduction in lipid peroxide products from induced lipid peroxidation in three different brain regions (30). In rats subjected to reperfusion injury, (which generates massive levels of FRs), pre-treatment with Alpha-Lipoic Acid reduced mortality from 78% to 26% in the 24 hours following reperfusion (30). When aged rats were compared to young rats, VC, VE and GSH brain levels were low, but lipid peroxidation was high. Treatment with Alpha-Lipoic Acid for 14 days reduced lipid peroxidation and elevated antioxidant levels (31). Aged mice fed Alpha-Lipoic Acid for 15 days “exhibited improved performance in an open-field memory test, and 24 hours after the first test [ALA]-treated animals performed better than young animals.” (30) The authors concluded Alpha-Lipoic Acid improves age-reduced NMDA receptor density, improving memory (30). Alpha-Lipoic Acid is a generally safe and useful antioxidant at levels of 50-200 mg, two or three times daily. A newly available form, (R)-lipoic acid, requires only half the dose.


“Ubiquinone (coenzyme Q), in addition to its function… in mitochondrial electron transport… ATP synthesis, acts in its reduced form (ubiquinol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and in serum [LDL]. According to recent evidence it can also protect mitochondrial inner membrane proteins and DNA against oxidative damage accompanying lipid peroxidation” (32). Tissue CoQ1O levels decrease during aging (32). Ubiquinol can regenerate oxidized VE (32), and oxidized CoQ1O can be reconverted to ubiquinol through DHLA (30). Stocker and colleagues found ubiquinol to be “much more efficient in inhibiting LDL oxidation than either lycopene, (-carotene, or (-tocopherol.” (33) Reduced LDL oxidation reduces heart disease risk (33).

A synthetic analogue of CoQ1O, idebenone (QSA-10), has been developed. In a study comparing QSA-10 to CoQ1O in protecting liver preserved in transplant solution, QSA-10 was found vastly superior to CoQ10 at protecting the preserved liver from the free radical damage that normally occurs in organ preservation solutions (34). Weiland and colleagues report that “QSA-10 (idebenone) … is known to have a greater antioxidative capacity than [Co]Q10, which is not restricted to the reduced form of the molecule [QSA-10].

In our experiments, QSA-10 was far more effective than Q10 in protecting oxygen radical-mediated damage…. QSA-10 is non-toxic to humans and has been used successfully in the therapy of patients suffering from a variety of neurological disorders.” (34) A supplement of 100 mg CoQ10 and 90 mg idebenone daily is a safe and useful addition to the antioxidant arsenal.


Selenium (Se) is an essential trace mineral, yet at levels over 1200 mcg (inorganic Se) or 3500 mcg (organic Se), it may be toxic (35). In Europe and America, dietary Se levels are frequently quite low – e.g. 55 mcg/day in Belgium (36). The American average is estimated at 100 mcg, but may range from 50-200 mcg (35). Se is a natural antioxidant synergist with VE (9). Ethane is a lipid peroxide breakdown product. “In combined vitamin E-selenium deficiencies in the rat, ethane production was .7.4 nanomoles…; supplementation of the deficient diet with vitamin E, selenium or both reduced ethane evolution to 0.4, 3.1, and 0.2 nanomoles … respectively.” (9) An essential role for Se is the activation of glutathione peroxidase (GPX), the most important enzyme antioxidant. A.L. Tappel found that GPX activity is proportional to the log of the dietary Se concentration (9). A supplement of 100-200 mcg Se/day, as selenomethionine, or sodium selenite/selenate, is a generally safe and useful antioxidant booster. (Ed.- Uniquely, the Melatonin designed by melatonin researcher and expert, Walter Pierpaoli MD, branded TI-MElatonin ®, also contains 50mcg of selenium per tablet).


Melatonin (MLT) is a pineal gland hormone that decreases with aging. Melatonin secretion peaks around age 10 and has usually dropped drastically by age 50 (22). During the 1990s Melatonin was discovered to be a powerful free radical scavenger. In a test system that generated OHR, Reiter found melatonin to be five times more efficient at scavenging OHR than glutathione (GSH) (22). The Melatonin metabolite then produced can scavenge SOR (22). Pieri and co-workers found Melatonin to be a very efficient scavenger of the peroxyl radical generated during lipid peroxidation, better than VC, VE and GSH (22). Melatonin protected mice from a normally lethal dose of FR-producing ionizing radiation (22). Melatonin powerfully protected human lymphocyte chromosomes from the damaging effects of ionizing radiation in culture (22). In cataract-induction experiments, Melatonin protected newborn rats from FR-induced protein damage (22). These are just highlights of the wide array of Melatonin antioxidant experiments. As Reiter and colleagues note, Melatonin is “available, readily absorbed and non-toxic.” (22) A supplement of 1-6 mg at bedtime may prove a powerful antioxidant addition, especially in those over 40.


Deprenyl (DPR) researcher, Joseph Knoll, has provided evidence that the current maximum human life span of 115 years is governed by the gradual yet relentless FR damage to the nigrostriatal, (Parkinson’s disease) brain region that occurs after age 45, on average. Knoll argues that by reducing the average 13% nigrostriatal cell death/decade that occurs after age 45, to a 10% death rate, average human life span could be increased 15 years, and maximum life span could be increased to 145 years (15).

Deprenyl protects dopaminergic brain cells against the powerful oxidant peroxynitrite (28). Deprenyl prevents FR-induced excitotoxic damage to nigrostriatal cells (28). Deprenyl has significantly increased SOD and catalase activity in rat nigrostriatal neurons (28). Deprenyl protected nigrostriatal neurons in-vivo from OHR damage induced by the neurotoxin MPTP (37). Deprenyl protected cultured rat nigral neurons from FR damage induced by GSH depletion at levels 40 times less than VC provided similar protection (38). Knoll believes that 10-15 mg Deprenyl weekly (1.5-2 mg/day) should provide serious antioxidant protection to nigrostriatal neurons, especially if started by age 40 or 50 (15).


Pyritinol is a vitamin B6 analogue with no B6 activity (39). Pyritinol has been used to treat dyslexia, post-stroke states, cerebral trauma, attention deficit disorder and other physical and mental conditions since 1961 (39). Pavilik and Pilar compared Pyritinol to other nootropic drugs, including the known nootropic antioxidants DMAE and centrophenoxine (CPX) (40). Their experiments “found that pyritinol exerts a pronounced scavenger action against hydroxyl radicals which was confirmed by the electron spin resonance spectroscopic technique in spin trapping experiments.” (40) Pyritinol protected both serum albumin and brain cytosol protein from OHR attack (40). Pyritinol provided OHR protection at levels 10 to 30 times less than the DMAE and CPX levels needed (40). Pavlik and Pilar note that Pyritnol’s protective action in rheumatoid arthritis, stroke and brain trauma may be explained by its OHR-scavenging action, since OHR production is abundant and damaging in these conditions (40). 100-300 mg Pyritinol daily is a generally useful and safe nootropic OHR scavenger. (Ed.- Those taking rheumatoid arthritis drugs should avoid pyritinol, unless under the supervision of a physician, for further details read the caution in reference 39).


Centrophenoxine is a “classic” nootropic drug, in use since 1959. Centrophenoxine is a compound of DMAE and PCPA (41), but Centrophenoxine produces higher brain DMAE levels than taking DMAE itself (41). Once inside brain cells, much of the DMAE is converted into phosphatidyl DMAE (PhDMAE) and incorporated into cell membranes (41). PhDMAE is a powerful OHR scavenger (41).

Centrophenoxine researcher Imre Zs.-Nagy has conducted many experiments showing the deleterious effects of OHRs on nerve cell membranes and membrane proteins, and the antioxidant benefits of Centrophenoxine/PhDMAE in combating these effects (41). Experiments with rats have shown that even when administered late in life, Centrophenoxine/PhDMAE can promote significant repair/regeneration of age /OHR-damaged neuronal cell membranes (41).

Centrophenoxine has also been shown to be a powerful inhibitor of lipofuscin (LPF) accumulation. LPF is a “garbage residue” in cells that may take up 50% of cell volume.

LPF is a product of FR damage to, and cross-linking of, membrane fatty acids and proteins (41). 250 mg Centrophenoxine, taken once or twice daily with breakfast/ lunch, is a generally safe and useful dose. (See reference 41 for some minor cautions).


Carnosine (CRs) is a dipeptide of beta-alanine and histidine that occurs naturally in mammalian tissue, especially muscle (42). Carnosine is a versatile antioxidant, preventing lipid peroxidation catalyzed by diverse agents, including iron, peroxyl radicals, and OHR (42). Carnosine complexes with copper in a manner that reduces copper’s FR-inducing activity (42). Carnosine is known to be actively absorbed in the small intestine, and transported to kidney, liver and muscle (42). Dietary supplementation of Carnosine can increase skeletal muscle Carnosine levels (42). In a small scale experiment with 12 healthy adults, Kyriazis found that 100 mg carnosine/day lowered urinary MDA levels about 25-30% (43). MDA is a toxic aldehyde produced by lipid peroxidation (20, p.37). MDA is a powerful, irreversible cross-linker of biomolecules, and enzyme in-activator (20, pp.37-8). Carnosine taken on an empty stomach, 100-200 mg daily is a safe and potentially important anti-cross-linking antioxidant, best used in combination with other antioxidants.


Laetrile, also called amygdalin, is a controversial anti-cancer substance, found naturally in a broad range of plant foods throughout the world (44). Cancer is known to be, at least in part, a FR disease (10,12). Heikkila and Cabbat discovered that Laetrile is a powerful OHR scavenger in tests with mice, using alloxan to induce diabetes through OHR damage to the pancreas (45). Dorfman used a pulse radiolysis technique to quantify the high rate of OHR scavenging by Laetrile (45). Heikkila and Cabbat noted that Laetrile is made of components that themselves are known to be highly reactive free radical OHR scavengers (45). They also reported that “amygdalin… can be tolerated by experimental animals at rather high doses” (45), providing yet another disproof of the orthodox medical establishment’s claim of Laetrile toxicity. Since 50-100 mg Laetrile daily may be a safe and effective cancer preventative (see reference 44 for more detail), its demonstrated effective OHR scavenging activity provides yet another rationale for its role in the anti-aging supplement program. Anyone using Laetrile should consult reference 44 for details of safe and optimal use. [Ed. – Laetrile is now available in a unique topical cream form, mixed with DMSO to enable easy and fast passage through the skin and into the blood. A topical Laetrile bypasses the side-effect issues of stomach acids.


The free radical theory of aging is not just one of the oldest and still current theories of aging – it is one of the best proven. Any serious long-term anti-aging program must be based upon practical knowledge of, and disciplined use of various techniques and supplements to cope with, the reality of FRs. And even if an antioxidant/ anti-FR program doesn’t ultimately lengthen one’s life, it should still seriously reduce the risk of heart attacks, strokes, cancer, Alzheimer’s disease, and many other of the “plagues” of the modern world.


Knoll, J. (1969) The theory of active reflexes. An analysis of some fundamental mechanisms of higher nervous activity. Pages 1-131, Publishing House of the Hungarian Academy of Sciences, Budapest, Hafner Publishing Company, New York. Knoll, J. (1994) Memories of my 45 years in research. Pharmacol Toxicol 75:65-72. Knoll, J. (1998) (-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain. Pharmacol Toxicol 82:57-66. Knoll, J. (2001) Antiaging compounds: (-)Deprenyl (Selegiline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, (-)BPAP, a selective highly potent enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. CNS Drug Reviews 7:317-345. Knoll, J. (2003) Enhancer regulation/Endogenous and Synthetic Enhancer Compounds: A Neurochemical Concept of the Innate and Acquired Drives. Neurochem Res 28:1187-1209. Knoll, J., Miklya, I. (1994) Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition. Arch int Pharmacodyn Thér 328:1-15. Knoll, J., Miklya, I. (1995) Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity: Rationale for prophylactic (-)deprenyl (selegiline) medication. Life Sci 56:611-620. Knoll, J., Yen, T.T., Miklya, I. (1994) Sexually low performing male rats die earlier than their high performing peers and (-) deprenyl treatment eliminates this difference. Life Sci 54:1047-1057. Knoll, J., Miklya, I., Knoll, B., Markó, R., Kelemen, K. (1996a) (-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons. Life Sci 58:817-827. Knoll, J., Knoll, B., Miklya, I. (1996b) High performing rats are more sensitive toward catecholaminergic activity enhancer (CAE) compounds than their low performing peers. Life Sci 58:945-952. Knoll, J., Miklya, I., Knoll, B., Markó, R., Rácz, D. (1996c) Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain. Life Sci 58:2101-2114. Knoll, J., Yoneda, F., Knoll, B., Ohde, H., Miklya, I. (1999) (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. Br J Pharmacol 128:1723-1732. Knoll, J., Miklya, I., Knoll, B., Dalló, J. (2000) Sexual hormones terminate in the rat the significantly enhanced catecholaminergic/serotoninergic tone in the brain characteristic to the post-weaning period. Life Sci 67:765-773. Miklya, I., Knoll, J. (2003) Analysis of the effect of (-)-BPAP, a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. Life Sci 72:2915-2921. Parkinson Study Group. (1989) Effect of (-)deprenyl on the progression disability in early Parkinson’s disease. New Engl J Med 321:1364-1371. Sano, M., Ernesto, C., Thomas, R.G., Klauber, M.R., Schafer, K., Grundman, M., Woodbury, P., Growdon, J., Cotman, C.W., Pfeiffer, E., Schneider, L.S., Thal, L.J. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. New Engl J Med 336:1216-1222. South, J. (2001) Deprenyl: The anti-aging psychoenergizer. Anti-Aging Bulletin 4:3-19. Tetrud, J.W., Langston, J.W. (1989) The effect of (-)deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 245:519-522.