© Whole Foods Magazine

November 2007

Antioxidants, Inflammation, Glycation and Skin Appearance

Part 2: An interview with Nicholas V. Perricone, M.D.

By Richard A. Passwater, Ph.D.


This month, we continue our chat with Dr. Perricone about how nutrition affects skin appearance and health. Last month, we traced Dr. Perricone’s research and his findings as they evolved and were presented in his earlier books. This month, we will chat with Dr. Perricone about the take-home messages in his latest published book and preview the teachings of his book to be published later this month.

 Nicholas Perricone, M.D., FACN, is a board-certified clinical and research dermatologist, and CEO of NV Perricone MD, Ltd. A brilliant scholar, Dr. Perricone completed medical school in just three years, graduating with distinction. He completed his internship in pediatrics at Yale Medical School and his dermatology residency at Ford Medical Center.

Dr. Perricone is an adjunct professor of medicine at Michigan State University’s College of Human Medicine. He is certified by the American Board of Dermatology, is a fellow of the New York Academy of Sciences, and is a fellow of the American College of Nutrition. He also is a fellow of the American Academy of Dermatology and the Society of Investigative Dermatology. Dr. Perricone has served as assistant clinical professor of dermatology at Yale School of Medicine and as chief of dermatology at the state of Connecticut’s Veterans Hospital.

Dr. Perricone’s latest book, AGE-less Face, AGE-less Mind (Ballantine Books), is scheduled to be released about November 15, 2007. This book expands upon his research and explains one of the cardinal processes of aging, apart from the inflammatory cascade initiated by free-radical damage. The “AGE-less” is in reference to the process that creates advanced glycation end products, appropriately known as AGEs.


Passwater: Your most recent book previous to your new book, AGE-less Face, AGE-less Mind, which will be released this month, was Dr. Perricone’s 7 Secrets to Beauty, Health, and Longevity: The Miracle of Cellular Rejuvenation. What is the science behind your approach to age-proofing from the inside out by stimulating cellular rejuvenation, a process that revives cells and helps us to grow new ones?


Perricone: Today, we can target the key parts of the cells such as the mitochondria to restore energy to the cell. As we age, energy levels decline in the cells—in fact, they eventually lose their ability to repair themselves altogether. With the use of a newly discovered class of mitochondrial rejuvenators, we can recharge the cells in all of our organ systems, including the skin, for total body rejuvenation. Being a dermatologist, I find this particularly exciting. Learning how to restore bone structure and muscle mass to the aging face is one of our greatest strategies in maintaining a youthful face.

However, the good news doesn’t stop there. Science has recently learned that brain cells can also be rejuvenated. It was a long and widely held belief that we were born with a genetically determined brain of fixed size and potential, for better or worse. This is far from the truth. We now know that the brain is a growing and changing organ. As we will learn in this book, we have many strategies to optimize this growth, including the essential fatty acid phosphatidylserine (PS), which is a powerful prevention for memory loss, Alzheimer’s disease and dementia. Other fatty acids such as the omega-3s and fish oils dramatically improve brain health, mood, attention span and more.

To rejuvenate our bodies on a cellular level, we need to protect the cells from inflammatory damage and recharge the mitochondrial “batteries” to keep them up and running with energy to spare. There are two ways to do this: through diet and through nutritional supplements. We’ll begin with diet.

The foods we eat are of critical importance because they either create or prevent the free radicals and inflammation implicated in aging and disease, meaning our diet can be either pro-inflammatory or anti-inflammatory. It is very exciting that scientific breakthroughs and discoveries now allow us to actually rejuvenate and revitalize our bodies on a cellular level—but if our diet is pro-inflammatory, we will undermine the effects of even the most powerful remedies. So, the first step in cellular rejuvenation is to establish a firm base, beginning with the foods we eat, thus ensuring the success of mitochondrial and other cellular rejuvenators.

Protein (for Cellular Rejuvenation). Protein plays a very important role in a successful health, beauty and anti-aging program. It is the basic material of life. In fact, the word “protein” comes from an ancient Greek root meaning “of first importance.” The body cannot grow or function without it.

As protein is digested, it breaks down into amino acids, which are then utilized by the cells to repair themselves. Since the human body can only manufacture 11 of the 20 amino acids that are essential for life, the remaining nine must be provided through the intake of dietary protein.

Without adequate protein, our bodies enter into an accelerated aging mode. Our muscles, organs, bones, cartilage, skin and the antibodies that protect us from disease are all made of protein. Even the enzymes that facilitate essential chemical reactions in the body—from digestion to building cells—are made of protein. If your cells do not have complete availability to all the essential amino acids, cellular repair will not only be incomplete; it will be much slower than it should be.

Carbohydrates (for Cellular Energy). Carbohydrates are sugars and starches, which are the most efficient source of food energy. They are stored in the muscle and liver as glycogen and in the blood as glucose. However, in order to make the most efficient use of this stored energy, sugar must be consumed in the form of complex carbohydrates like those found in whole fruits (preferably organic so we can eat the skin, which contains high levels of nutrients and fiber). Starches must be eaten in the form of beans, legumes and some whole grains, which break down slowly and won’t cause spikes in blood sugar and insulin. If the carbohydrate choices we make are fruits, vegetables, beans and legumes, along with whole grains such as old-fashioned oatmeal, we will reap great anti-aging benefits—from wrinkle protection to weight reduction.

In addition to choosing anti-inflammatory carbs, we must also learn how to avoid pro-inflammatory carbohydrates, which degrade cellular function. Pro-inflammatory carbohydrates are the “simple” sugars and starches as opposed to the “complex” carbohydrates described previously.

Essential Fatty Acids (for Cellular Stabilization). Our diets also must include anti-inflammatory fat sources. This is a topic that I have covered extensively over the years. In fact, because they cause increased inflammation in the brain, I hold extreme low-fat and fat-free diets culpable in the epidemic of depression sweeping this country during the past two decades. Ideally, our diets will be free of excess saturated fats and all transfatty acids—another reason to avoid all processed and pre-prepared foods.

The essential fatty acids found in fish (such as salmon, anchovies, sardines, sablefish, trout) nuts and seeds, avocados, are anti-inflammatory. They also have the unique ability to stabilize the cell plasma membrane, the outer portion of the cell. When we stabilize the cell plasma membrane, we decrease our risk of oxidative stress and its resultant production of the cascade of inflammatory chemicals that causes damage throughout the cell, especially the mitochondria.

The end result of following the anti-inflammatory diet will be the prevention of free radical-induced inflammation. There will be a great improvement in our physical appearance, decreased wrinkling and sagging of the skin, increased energy levels, elevated mood, better brain function, decreased body fat, greater muscle mass, stronger bones and a powerful immune system.

Carotenoids (for Cellular Growth and Repair). Carotenoids are fat-soluble pigments that give red–orange–yellow color to fruits, vegetables, egg yolks, wild salmon, steelhead trout, shellfish (e.g., shrimp and lobsters) and the feathers of birds, notably brilliant pink flamingos. Fish and fowl alike get their red–yellow–orange hues from eating large quantities of carotenoid-rich aquatic plants such as algae and plankton.

The deep, vibrant colors, such as those found in fruits, vegetables, beans, legumes, nuts, extra-virgin olive oil and seafood (such as wild salmon) signify the presence of antioxidants in foods, making them an essential part of this program. The carotenoid family of antioxidants offers very special and targeted properties for cellular rejuvenation—in fact, as you will see, they play a significant role in cellular growth and repair.

Dark, leafy greens like spinach, kale, chard and collards are also rich in carotenoids, but their red–yellow–orange colors are masked by green-hued chlorophyll, which is a more dominant pigment.

Because they are fat-soluble, carotenoids are able to enter both the cell plasma membrane and the mitochondria, where they protect these parts of the cell from oxidative stress, free-radical damage and pro-inflammatory chemicals. This is very important for protecting our immune systems because it is well known that immune cells are particularly sensitive to oxidative stress.


Passwater: The universal antioxidant, alpha lipoic acid plays a prominent role in your treatment. Why is alpha lipoic acid so important?


Perricone: Alpha lipoic acid is one of the most powerful anti-aging, antioxidants, anti-inflammatories available. Alpha lipoic acid boosts energy production in your cells, just as it helps the mitochondria portion of the cell change food to energy. The higher the energy level in the cell, the more youthful we remain. The importance of alpha lipoic acid—the metabolic antioxidant—is hard to overstate.

Features and benefits:

* Assists energy production in the cell,

* Fat- and water-soluble; works in both the fatty cell plasma membrane and the aqueous interior of the cell,

* Helps regenerate vitamins C and E,

* Protects DNA (the cells’ genetic instructions),

* Protects the mitochondria (the energy producing portion of cell),

* Inhibits the activation of transcription factor NF-κB , reducing cellular inflammation,

* Controls AP-1, helps to remodel collagen,

* Protects the skin from free-radical initiation of inflammation including sun exposure,

* Increases cellular energy and vitality,

* Inhibits one of the major causes of wrinkled skin, glycosylation, which is the abnormal attachment of sugar to protein. When this occurs, it results in cross-linking of collagen, making it stiff and inflexible,

* Acts synergistically with all antioxidant systems,

* Protects and elevates glutathione, an antioxidant inside the cells,

* Acts as a powerful anti-inflammatory agent,

* Accelerates the removal of glucose from the blood stream,

* Improves insulin function,

* Decreases insulin resistance,

* Inhibits replication of HIV virus in the test tube.


Intake Requirements and Supplement Recommendations. Alpha lipoic acid is called “the universal antioxidant” because it is both fat- and water-soluble. Further, it is 400 times stronger than vitamins E and C combined (both of which are renowned for their antioxidant properties). Alpha lipoic acid readily penetrates the cell plasma membrane and the plasma membranes that surround such key parts of the cell as the mitochondria and the nucleus. Since it is also water-soluble, it can get into the cytosol, the watery interior of the cell. By penetrating the inside and the outside of the cell, alpha lipoic acid brings protection wherever it is needed.

The body contains small amounts of alpha lipoic acid inside the mitochondria. It exists as part of an energy-producing enzyme system called the pyruvate dehydrogenase complex. This enzyme system helps convert food to energy, however it is important to note that lipoic acid remains locked with this system and does not float freely in the cell.

However, if you take alpha lipoic acid as a supplement in capsule form, or apply it topically in a lotion, it performs as an antioxidant as well as an aid to cellular metabolism. As you know, the higher the energy level in the cell, the more youthful you remain. The importance of alpha lipoic acid—the metabolic antioxidant—is hard to overstate.

Alpha lipoic acid also inhibits the action of transcription factor (proteins that participate in the synthesis of RNA using a DNA template), NF-kB, which enhances the production of inflammatory mediators. Alpha lipoic acid can “scoop up” free radicals before they attack the polyunsaturated fats in the cell plasma membrane, thus preventing the formation of dangerous oxidized fats called lipid peroxides. These toxic lipids trigger damage to DNA and the activation of NF-kB.

Under normal conditions, NF-kB is a harmless protein molecule that remains inert thanks to an inhibitor attachment. But, when a cell is in a state of oxidative stress, the inhibitor portion detaches, allowing NF-kB to migrate to the nucleus. There, NF-kB turns on transcription (it allows DNA to give instructions to the cell), causing the production of pro-inflammatory chemicals called cytokines (such as tumor necrosis factor alpha and interleukins).

The good news is that alpha lipoic acid inhibits the activation of NF-kB better than any other antioxidant. It blocks the production of enzymes that damage the collagen fibers, preserving a smooth skin surface. It is equally effective in preventing glycosylation, the harmful effects of sugar molecules on collagen fibers.

Alpha lipoic acid has a tremendous effect on the transcription factor, AP-1. When AP-1 is turned on by oxidative stress created by sunlight, it actually digests your collagen, causing micro-scars. But, when AP-1 is activated by alpha lipoic acid, it turns on the production of collagen-digesting enzymes that digest damaged rather than healthy collagen. That process helps to remodel scar tissue.

* Alpha lipoic acid is the only antioxidant that can boost cellular levels of glutathione, an antioxidant of tremendous importance in overall health and longevity and essential for the functioning of the immune system. People with chronic illnesses such as AIDS, cancer and autoimmune diseases generally have very low levels of glutathione. White blood cells are particularly sensitive to changes in glutathione levels, and even subtle changes may have profound effects on the immune response.

* Alpha lipoic acid helps regulate glucose metabolism. Sugar can be extremely damaging to our cells if it is not well controlled because it can react with molecules within the cell in a permanent bond called glycation. Once these bonds between sugar and protein are formed, they become mini-factories for the generation of free radicals that can attack our cells and their mitochondria and produce inflammation. Alpha lipoic acid helps prevent these damaging glycation reactions, while also increasing the cell’s ability to utilize glucose. When taken orally as a supplement, ALA can concentrate in both the cell and mitochondrial lipid membranes, where it protects both from free radical damage, thus preventing the commencement of an inflammatory cascade.

* Alpha lipoic acid is especially protective to the mitochondria in nerve cells, and can therefore help prevent the degeneration of the brain seen with aging and age-related diseases of the central nervous system. In addition, ALA has been used successfully to treat patients with diabetic neuropathy (nerve damage).

* Alpha lipoic acid works synergistically with other antioxidants in the skin to reduce the damaging inflammatory effects of ultraviolet radiation. Alpha lipoic acid’s capacity to regulate production of nitric oxide (which controls blood flow to the skin when applied topically) helps to transform the complexion from dull, pasty and pale to vibrant and glowing. Topical alpha lipoic acid also will reduce puffiness in the face and eye area, decrease wrinkles and pore size.


Passwater: Does alpha lipoic acid help when applied topically as well as orally?


Perricone: Alpha lipoic acid can increase energy levels in the cell. Oil glands that are energy-deficient produce abnormal ratios of oils secreted on the surface of the skin. When the proportion of these oils is off, the pores begin to clog. My theory is that alpha lipoic acid increases energy production in the oil gland, normalizing the oils secreted, which shrinks the pore size. Without abnormal oils clogging and stretching the pores, these tiny openings gradually normalize until they are invisible to the eye.


Alpha Lipoic Acid


* Powerful antioxidant, soluble in both water and fat.

* Alpha lipoic acid is called the “universal antioxidant” because of its dual solubility. Alpha lipoic acid also is called the “metabolic antioxidant” because it plays a vital role in the energy production of the cells.



* Gentle yet powerful—400 times more potent and antioxidant than vitamins C or E.

* Promotes optimum efficiency for production of energy and aids in exfoliation.



* Able to reach and protect both water and lipid portions of skin with potent antioxidant benefits.

* Protects levels of other antioxidants, like vitamins C and E, from depletion and works to increase their levels.

* Dual solubility enables ALA to be available rapidly to the skin.

* Skin develops a healthy, youthful, glowing appearance when treated with alpha lipoic acid.


Passwater: How important is the trace mineral silicon to skin health? What do you feel is the most effective supplemental form of silicon?


Perricone: Silicon is a trace mineral found in connective tissue. A form of silicon known as choline-stabilized orthosilicic acid (ch-OSA) improves the bone health benefits of both calcium and vitamin D. In addition, improvements in type I skin collagen after supplementation with ch-OSA have been noted in an animal study. Similarly, a clinical study presented at the 63rd American Academy of Dermatology Annual Meeting (2005) confirms ch-OSA also helps reduce the appearance of wrinkles and helps improve skin elasticity. The improvement in skin parameters is likely a result of the regeneration of damaged collagen fibers or the synthesis of new ones—all in all very exciting and encouraging results.

Passwater: What are some of your other favorite dietary supplements and why?

Perricone: In addition to those we have discussed, I stress Acetyl L-carnitine for cellular stabilization, coenzyme Q10 for cellular repair and niacin-bound chromium.


* Anti-Glycation Supplements

* Alpha lipoic acid

* Benfotiamine

* Carnosine


* Fat-Metabolizing Factors/Cellular Energy Boosters

* Conjugated linoleic acid

* Chromium polynicotinate

* Alpha lipoic acid

* Acetyl L-carnitine

* L-carnitine fumerate

* Essential fatty acids

* Coenzyme Q10


* Anti-Aging/Cellular Energy Boosters/Antioxidant/Anti-inflammatory

* Alpha lipoic acid

* Acetyl L-carnitine

* Coenzyme Q10

* Vitamin C

* Vitamin E

* Essential fatty acids


* Calcium

* Magnesium

* Manganese


* Wound Healing and Wrinkle Prevention

* Copper

* Thymic peptides


Many of the supplements that are listed in each category also possess significant cross-over activity into the other categories. This chart presents a snapshot of the properties of each supplement, based primarily on the current research, but also reflecting the results in my patients and myself.








Fat Burning and Weight Control

Cellular Energy Booster

General Anti-Aging


Alpha Lipoic Acid (ALA)






 cell protection and cellular energy

Acetyl L-carnitine (ACL)






 cellular energy, fat metabolizer















cellular energy








 anti-glycation; cell-protein protection


Conjugated Linoleic Acid (CLA)






 anti-cancer/ obesity effects

Coenzyme Q-10






 antioxidant and energy benefits







stabilized cell membranes

Gamma Linoleic Acid (GLA)






 anti-inflammatory benefits

Omega-3 Fatty Acids






 brain and heart benefits

Vitamin C (especially ester form)






 antioxidant effects

Vitamin E/






 antioxidant, heart and skin benefits

Thymic peptides






 nerve and endocrine benefits



Passwater: Your new book, AGE-less Face, AGE-less Mind (Ballantine Books, Oct. 30, 2007), to be released later this month, gives practical advice on reducing the damage from excess blood sugar (glucose) that results in glycosylation. It is interesting to note that your research with skin parallels my research with internal damage, only with a later timeframe. First, I concentrated on free radicals and antioxidants, the damage from oxygen. Then, I included the damage from AGEs, the damage from sugar.


Perricone: Yes, skin is affected from the inside out and our research has followed the same paths. My new book explains one of the cardinal processes of aging, apart from the inflammatory cascade initiated by free-radical damage. As you have written on before also, my new book examines the process that creates advanced glycation end products, appropriately known as AGEs.


Passwater: Yes, I have particularly discussed AGEs in this column in articles about lipoic acid and AGEs were a feature of my book, The Longevity Factor (Keats Publications,1993). The damage that high blood sugar (glucose) does to proteins is called glycation or glycosylation. The damaged proteins and complex derivatives of glucose themselves are called advanced glycation end products or advanced glycosylation end products (AGEs). The damage to skin proteins is like stapling the proteins together so they can’t move normally.


Perricone: AGEs exist at the very heart of the aging process and we have not had effective strategic interventions—at least not until very recently. And like chronic, sub-clinical inflammation, we can now both control and prevent their deleterious effects.

AGEs are the number one cause of accelerated physical and mental aging. AGEs are as detrimental to our health as trans fats, however, they’ve been far less well known to the public.

Fortunately, after decades of research, the mystery of how AGEs work—and how to halt and even reverse their devastating effects—has been solved. My book presents a three-part plan for effectively eliminating deep wrinkles and sagging skin, while also helping to prevent age-related conditions including Alzheimer’s disease, cataracts, cardiovascular disease, diabetes, impaired memory and cancer, which AGEs promote.

 In AGE-less Face, AGE-less Mind, I confront the revolutionary and introduce the ultimate in new technology—a technology that will help reverse the effects of AGEs in every organ system, as well as the vast majority of diseases long thought to be part of “normal” aging. I also have some really exciting new technology that will be of great benefit to the skin and the total body—the subtitle is “Erase Wrinkles and Rejuvenate the Brain.”

My strategies—including a nutritional program, targeted supplements and new topicals—result in rapid, noticeable improvements, while healing and strengthening all of the body's systems. I share secrets about which foods and cooking methods can minimize the AGEs threat, expose the presence of AGEs in processed foods and offer a practical shopping guide.

Passwater: Thank you, Dr. Perricone. Your research and books are widely appreciated. WF


© 2007 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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