Inflammation, Aging and Age-Related Diseases

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Inflammation, Aging and Age-Related Diseases

VOLUME: 10 PUBLICATION DATE: Dec 15 2002

Issue Number:

Volume 10 - Issue 12 - December 2002

author:

By Nicholas V. Perricone, M.D.

A ging and age-associated diseases such as Alzheimer’s, Parkinson’s, cardiovascular disease, arthritis and cancer are seemingly diverse processes and are mediated by free radical-induced cellular changes. Dietary antioxidants can boost our endogenous defenses and decrease the incidence of age-associated disease in all organ systems. This simple, inexpensive, non-toxic approach to treatment of the aging patient should be considered before signs of disease are evident. Much of the research is in the preliminary stages; however, due to the large safety margin, this option should be presented to all of our patients. In this article, I’ll review the focus of the latest research.

At the Mitochondrial Level
In 1954, Denham Harman proposed the free radical theory of aging.1 Today, a huge body of evidence confirms that oxidative stress promotes aging and these seemingly diverse age-associated diseases.2,3

Recently, there has been a shift of focus to the mitochondria where free radicals lead to mitochondrial DNA mutations and a progressive reduction in cellular energy output, which results in cellular senescence.4

In 1977, the Hungarian physician Imre Nagy proposed the membrane hypothesis of aging, which posited the cell membrane as the key target of free radical activity and which has been confirmed in experiments.5-8 Also, my research indicates that cellular membranes’ higher levels of oxygen tension predispose membranes to produce reactive oxygen species. These attack and easily oxidize the polyunsaturated fatty acids (PUFAs) in the lipid bi-layers, producing an inflammatory cascade that goes on for hours and days causing cellular damage and senescence.9,10

Also well accepted is the understanding that inflammatory cytokines can further free radical production in the cell, resulting in activation of transcription factors such as nuclear factor kappa B and AP-1. This in turn negatively affects gene expression.11,12 Inflammatory cytokines (for example, tumor necrosis factor alpha, interleukin-6, cytokine antagonists, and acute phase proteins) are seen at higher levels in older individuals.

So, Imre Nagy was correct that the membrane is a key component in the aging process. From my studies, it emerges that short-lived free radicals trigger inflammatory events beginning in the cell plasma membrane, resulting in altered energy production in the mitochondria, destruction of important organelles, further generation of free radicals in the nuclear membrane, activation of transcription factors, and pro-inflammatory gene expression.13,14

The Inflammation-Sugar-Aging Connection
The average American diet is pro-inflammatory, accelerating aging and increasing the incidence of age-related diseases. High levels of blood sugar from high-glycemic carbohydrates result in a burst of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6.15

In addition, this elevation of blood sugar results in a non-enzymatic reaction with long-lived proteins such as collagen, producing advanced glycosylated end products (AGEs).16 This reaction causes protein cross-linking in collagen, making it stiff and inflexible and resulting in arterial changes as well as visible changes in the skin such as sagging and wrinkling.17 Glycation of proteins can also take place in the cell’s plasma membrane surface, and it’s associated with a whole series of age-related problems.18-23

Anti-inflammatory, Anti-Aging Strategies
Damage from membrane-inflammation and excess sugar indicates a three-level therapeutic approach to age-related diseases.

1. The anti-inflammatory diet. The first stage is a protein-adequate anti-inflammatory diet that excludes trans fatty acids and is rich in low-glycemic, antioxidant foods and essential fatty acids (EFAs), especially the Omega-3 series. The powerful anti-inflammatory properties of EFAs decrease the risk for many age-associated diseases. Incorporated into the cell plasma membrane, EFAs increase membrane fluidity, resulting in a better nutrient exchange and an increase in hormone receptor sensitivity for insulin. Dietary Omega-3s and Omega-6s consumed in the correct ratio promote preferential production of prostaglandin E-1 levels and a marked positive effect on serum lipids, including both cholesterol and trigylcerides.24-30 Essential fatty acids are also beneficial to nervous system function, reducing stress, depression, and dementia scores.31-33

Essential fatty acids also have a profound effect on the health and appearance of skin. An increased intake of gamma linoleic acid has been shown to improve the course of inflammatory disorders such as atopic dermatitis.34 In addition, it has been my clinical observation that Omega-3 fatty acids such as those found in cold water fish, also improve skin radiance and pore size while reducing skin inflammation. Patients should avoid foods with a high glycemic index, which can lead to glycation of proteins, insulin insensitivity, obesity, high blood pressure, and wrinkling, sagging and discoloration of the skin.

2. Antioxidants and other natural anti-inflammatories. The following agents have been found to be helpful in helping the body fight oxidative and inflammatory processes.

• Alpha lipoic acid. The second therapeutic approach is to supplement vitamins or nutrient-like substances that protect against free radical damage and subsequent inflammation.

Studies indicate that vitamin supplements provide benefits beyond those of a nutritious diet.35 It’s important to provide water-soluble and fat-soluble antioxidants to all parts of the cell. Lipoic acid has been estimated to be 400 times more effective as an antioxidant than Vitamins C and E combined.36,37 Alpha lipoic acid is also a powerful anti-inflammatory.

When free radicals are created on a cellular level, endogenous defense mechanisms are overwhelmed. This condition, called oxidative stress, activates transcription factors, such as NfkB and AP-1. Lipoic acid prevents activation of NfkB better than any other antioxidant tested.38,39

Alpha lipoic acid has been shown to be cardio-protective and neuro-protective and has been used successfully to treat patients with diabetic neuropathy, among other benefits.40-45 Alpha lipoic acid works synergistically with other antioxidants in skin against the inflammatory effects of ultraviolet radiation.46

• Vitamin E. The benefits of ingesting vitamin E (improving cardiovascular disease, Alzheimer’s, oxidative stress, and inflammation) are believed to derive from the anti-inflammatory effects of vitamin E in the arterial wall and the protection of low-density lipoprotein from oxidation.47-51

• Vitamin C and its fatty acid esters.Vitamin C, L-ascorbic acid, and its fatty acid esters, such as ascorbyl palmitate, function as powerful antioxidants and anti-inflammatories. Combining fatty acid esters of vitamin C and ascorbate can be advantageous because fat-soluble esters can reside in the cell plasma membrane along with vitamin E and thus regenerate it at a much higher rate.52 Vitamin C is also a necessary co-factor for several key enzyme systems called dehydrogenases.53 Vitamin C may play a critical role in the prevention of coronary heart disease, cancer, and cataracts in addition to other beneficial effects.54-56

• Co-Enzyme Q10. Co-enzyme Q10 protects the mitochondrial DNA and membrane proteins from free radical-induced oxidative damage in the cell plasma membrane, and maintains the reduced forms of exogenous antioxidants such as vitamin E and vitamin C. At high levels, Co-Enzyme Q10 is protective against cardiovascular disease and breast cancer.57-61

• DMAE. Dimethylaminoethanol (DMAE) is an endogenous metabolic factor — fish are the primary dietary source. DMAE can intersperse in the lipid bi-layers of the cell plasma membrane and prevent disruption and subsequent production of arachidonic acid and biologically active polyunsaturated fatty acid fragments.62 DMAE was tested successfully as a treatment for Attention Deficit Hyperactivity Disorder and, far less successfully, as a cognitive enhancer.63-67

• Plant flavonoids. Flavonoids such as quercetin, proanthocyanidins, and catechins are phenolic antioxidants found in fruits, vegetables, herbs, nuts, seeds, cocoa, coffee, tea and wine. High intakes can decrease oxidative DNA damage and may also support endogenous antioxidants. Epidemiological studies and experiments indicate reduction of deleterious effects of oxidative stress.68-70

3. Antioxidants in degenerative disease. Use of antioxidants constitutes the third of our recommended therapeutic approaches. Here’s a look at different diseases and organs in the body and the effects antioxidants can have.

• Cardiovascular disease.The markers of inflammation are emerging as powerful new risk and prognostic factors in cardiovascular disease.71-74 The statin drugs produce clinical improvements via strong anti-inflammatory action.75 It has become clear that cardiovascular disease provides the strongest evidence of the protective role of antioxidants.76

• Neurodegenerative diseases. Advanced glycation end products (AGEs), protein-bound oxidation products of sugars, are involved in the pathologic process of Alzheimer’s disease and age-related cognitive decline.77-79

Elevated levels of NfkB, dependent production of cytokines, tumor necrosis factor alpha, and interleukin beta have been detected in the normal aging brain, as well as Alzheimer’s patients.80-82 Recent research details treatments by alpha lipoic acid as well as dietary antioxidants and plant-derived phenols.83,84

• Liver dysfunction. Recent clinical studies using alpha lipoic acid, silymarins (milk thistle flavonoids), and selenium produced rapid recovery from medication-induced liver ailments and improved laboratory values, rendering liver transplant unnecessary.85 Alpha lipoic acid antioxidant therapy has been tried successful in conditions including alcohol-induced cirrhosis, as well as mushroom, metal, and carbon tetrachloride poisoning.86

• The eyes. Cataractogenesis in elderly patients derives from oxidative damage to lens proteins, low antioxidant protection, and the accumulation of glycation end products.87,88 A generous intake of the antioxidants lutein and zeaxanthin can reduce risks for cataracts and age-related macular degeneration.89 Risks of cataracts and macular degeneration have been reduced by foods rich in the antioxidants lutein and zeaxanthin and from antioxidant vitamins.89,90

• Diabetes. Oxidative stress plays a key role in the development of vascular complications seen in type II diabetes and promotes complication in all forms of diabetes. Formation of advanced glycation end products is accompanied by oxidative radical generating reactions, and a subsequent increase in the pro-inflammatory cytokines.91,92 Type II diabetics have elevated markers of an acute phase inflammatory response.93 Lipoic acid blocks glycation of proteins, stabilizes the cell plasma membrane, and prevents activation of transcription factor nuclear factor kappa B.94-96

• Cancer. Oxidative DNA modifications can be important in cancer.97 Inhibition of tumor angiogenesis is also a mechanism by which antioxidant nutrients can act selectively on cancer cells.98 Antioxidants can quell inflammatory mediators in cancer, down regulate free serum IGF-1, modulate arachidonic acid metabolism and decrease activation of AP-1 and NfkB transcription factors.99 Certain antioxidant selenium compounds and polyphenols modify reactive cystines, decreasing tumor promoting cellular activity.100 Use caution because of certain dangerous effects of antioxidant activity.101,102

Topical Anti-Inflammatories for Aging Skin
Human skin is highly subject to oxidative stress from many sources, such as ultraviolet radiation, air pollution, harsh chemicals, infections and others. Ultraviolet radiation generates free radicals, especially in the cell plasma membrane, causing release of arachidonic acid, producing pro-inflammatory prostaglandins and other chemicals. 103

In addition the oxidized polyunsaturated fatty acid fragments enter the cell, causing a change in redox status which then activates nuclear factor kappa B, resulting in production of inflammatory cytokines such as tumor necrosis factor alpha, interleukins-1 and 6. Also, oxidative stress activates transcription factor AP-1, producing collagen-digesting enzymes such as the metalloproteinases. The metalloproteinases then attack collagen in the healthy dermis, causing micro-scarring, which eventually leads to macro-scarring and wrinkles.104-106

Some preliminary clinical studies show that increased dietary intake of antioxidants as well as antioxidants and nutrients in oral supplement form can reduce the incidence of wrinkles and cancer.107

The chief antioxidant defenses in skin are vitamin C, vitamin E, coenzyme Q10, and glutathione. These endogenous defenses drop rapidly with exposure to sun, even if large supplemental antioxidants are provided through dietary means.108 A large reservoir of antioxidant protection can be achieved by applying antioxidants that act as topical anti-inflammatories.109

Alpha lipoic acid has profound effects on skin, blocking erythema associated with ultraviolet radiation and inhibiting the activation of NfkB.110 Alpha lipoic acid also affects activation of transcription factor AP-1.

When AP-1 is activated by a strong reducing agent like alpha lipoic acid, metalloproteinases that are specific for digestion of damaged collagen are activated and subsequent scars and wrinkles improve.111 Use of a fat-soluble form of vitamin C (ascorbyl palmitate) rapidly replaces depleted stores of vitamin C under conditions of oxidative stress.

Ascorbyl palmitate is superior over L-ascorbic acid for topical application. When L-ascorbic acid is placed on skin, it interacts with free iron in an inflammatory Fenton reaction that produces the toxic hydroxyl radical. Vitamin C esters do not produce a Fenton reaction, yet provide all the benefits of vitamin C.112,113

The metabolic factor DMAE (dimethylaminoethanol), discussed earlier, has powerful anti-inflammatory effects when applied to skin.114 And, in a proper carrier, DMAE increase underlying muscle tone, yielding visible effects in as few as 30 minutes, and cumulative effects with long-term application. (It may produce muscle tone by acting as a precursor to acetylcholine, although this remains unproved.)

Recent studies indicate after double-blind placebo-controlled studies of use of topical DMAE over a period of 2 weeks to 1 year, a dramatic reduction in sagging on the aging face.115,116 While the use of topical anti-inflammatories has just begun, the results of this preliminary research look very promising.

Helping Patients Prevent Disease
Clearly, aging and age-associated diseases are promoted by free radicals and inflammation. We can help our patients a great deal by recommending they take dietary antioxidants, which can boost endogenous defenses and decrease the incidence of age-associated disease in all organ systems.

This material is adapted from the forthcoming publication, Skin Diseases in the Elderly by Nall, Cauwenbergh, and Jacobs. Permission granted from the publisher, Marcel Dekker, Inc.

References:

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