Just  about  all  good  books  on  Health,  Nutrition,  and  Exercise,  is  an  amplification  of  the  old  master  of  "Health  and  Strength"  -  Charles  Atlas.  HIS  course  is  still  available.  I  have  his  original  course  from  when  I  was  14.  Type  in  "Charles  Atlas"  into  your  web  browser  and…. up  it  will  come  -  Keith Hunt


by  Nicholas  Perricone., M.D.


It seems impossible that my first book, The Wrinkle Cure, was published well over ten years ago, but time has a way of doing that. In fact, time seems to go by faster with each passing year. Since the excitement generated by that first book, I have continued to devote myself to slowing down time, or at least the toll it takes on our bodies. In The Wrinkle Cure, I introduced the concept that inflammation is at the basis of aging and age-related disease. This inflammation exists over abroad spectrum that ranges from low to high. On the low side, it occurs on a cellular level and is invisible to the naked eye. It can be discerned only microscopically or submicroscopically on a molecular level. On the high end of the spectrum, the inflammation is visibly evident as redness and swelling, as seen in a wound or sunburn.

In The Wrinkle Cure, I explained that this low-grade, subclinical, cellular inflammation is ultimately responsible for cell dysfunction, leading to organ dysfunction, aging, and death. In addition, I identified this subclinical inflammation as being the basis of such diverse age-related diseases as atherosclerosis, diabetes, various forms of cancer, Alzheimer's disease, and other neurologic diseases, as well as wrinkling of the skin.

My colleagues and mainstream medicine in general vigorously resisted the concept of the inflammation/aging/disease conrvectioti. Fortunately, a great deal has changed in a decade, and in that time, numerous studies have validated this concept. Many therapeutic interventions are now being developed counteracting subclinical inflammation, thereby prolonging both our health and our life span.

The Diabetes/Aging Connection

One of the models I use as an accelerated aging prototype is the disease of diabetes. Studying diabetes has helped me to understand the effects of irregularities in blood sugar and their role in the production of free radicals, leading to glycation and inflammation. Glycation is an inflammatory biochemical process that occurs when a glucose (sugar) molecule binds to a protein molecule without the influence of enzymes. In scientific terms we refer to these sugar/protein bonds as AGEs, an appropriate acronym for advanced glycation end products. Glycation and AGEs are highly damaging to all organ systems, including the skin. AGEs can cause arterial stiffening, atherosclerosis, cataracts, neurological impairment, diabetic complications, wrinkled, sagging skin, and more. The inflammation and glycation that I observed in diabetics whose disease was poorly controlled resulted in those patients' aging one-third faster than the normal population.

The Forever Young Approach to Aging

Uncontrolled or poorly controlled diabetes is not the only model for accelerated aging. As we enter a new decade, I am looking at another accelerated aging model. This model has provided me with the information I need to develop novel therapeutic interventions to further slow the aging process and radically decrease the onset of age-related disease. The culprit is an acute, severe, systemic infection known as sepsis, which leads to septic shock, the onset and progression of which closely parallel the bodily changes seen during aging. Sepsis leads to disorders that take place on a cellular level and closely mimics, in an abbreviated period of time, what happens to our bodies over a period of years and decades in the normal aging process.

Understanding how we age on a cellular level gives us the information we need to retard or even reverse the process. In Forever Young you will learn about the science of nutrigenomics and how some very special foods and substances can alter the way you age, both mentally and physically. Nutrigenomics is the study of how nutrition affects gene expression and how certain nutrients can turn on the genes that block disease and turn off the genes that cause accelerated aging and disease. As I have often told my patients, readers, and viewers, the fountain of youth may be no further away than your next meal!

As I observed accelerated models of aging, like poorly controlled diabetes and sepsis, and studied and implemented nutrigenomics, I have developed strategies designed to keep you, if not Forever Young, at least looking and feeling your very best for many decades into the future.

Thank you for joining me on this life-changing journey.

Nicholas Perricone, M.D., F.A.C.N., C.N.S. Madison, Connecticut January 2010


Many people are confused about free radicals. They know that they are bad and that antioxidants combat them. Understanding the chemistry of free radicals will give you an important perspective on aging.

Atoms and molecules are most stable when there is a pair of electrons circulating in their outer orbit. When a molecule or atom loses one of the electrons, it becomes a free radical. Its mission in life has now become the quest for another atom or molecule to hook up with. Any substance that rips electrons away from another molecule is known as an oxidizing agent or electrophile. Free radicals can damage tissues, cell membranes, and DNA, disrupting our store of genetic information, which may lead to the initiation of certain cancers.

Free radicals can also oxidize the fats that make up the cell wall membrane and the membrane covering the mitochondria and the nucleus. This oxidation can lead to cellular dysfunction and serious damage to the immune system and major organs such as the brain, heart, kidneys, and pancreas. Free radicals contribute to at least fifty major diseases, including atherosclerosis, heart disease, rheumatoid arthritis, and lung disease, as well as accelerated aging. Although free radicals exist for only a fraction of a second, the inflammatory cascade that they generate goes on for hours or days.

Antioxidants, including vitamin C, alpha-lipoic acid, and Co Q10, are known as reducing agents. They neutralize free radicals and leave a much more benign antioxidant free radical in its place. Unfortunately, the mitochondria are a site of constant free-radical production and very susceptible to the damage that free radicals can cause. If we hope to preserve youthful function and prevent disease, it is critical to search for agents and antioxidants that will protect the mitochondria from free-radical damage.


A major breakthrough in the use of glutathione is a recently synthesized molecule that is proving to be extremely protective on a cellular level. This derivative of glutathione is known as S-acyl-glutathione. This new molecule is a combination of a fatty acid attached to the glutathione molecule. The combination of a fatty acid with the glutathione enables the glutathione to be easily transported into the cell and subsequently into the mitochondria. This process is similar to the results I have seen using the standard glutathione molecule in my phospholipid carrier system.

One of the new S-acyl-glutathione derivatives I have been working with is S-palmitoleic glutathione (glutathione combined with palm oil). In several studies, this molecule has been able to enter cells, where it neutralizes such free radicals as reactive oxygen species (ROS). The acyl derivatives of glutathione also provide protection to the cell plasma membrane, the outer fatty portion of the cell. Studies show that they are extremely protective to fibroblast cells, which are responsible for producing collagen and elastin in our skin. Protecting this important part of the cell can lead to more youthful-looking, healthier skin.

In other studies, the S-acyl-glutathione derivatives are proving to be protective to brain cells. You will see many examples of substances that are therapeutic to both skin and brain throughout this book. I refer to this phenomenon as the Brain/Beauty Connection.

The Brain/Beauty Connection

During medical school, I spent a good deal of time working with patients who were receiving pharmacological agents for the central nervous system. Each time these patients were given treatment, I observed a markedly improved appearance of their skin. This is understandable if you know the basics of embryology, the branch of biology that studies the growth of the fertilized egg to approximately four months of gestation. During this period, all of the body's organ systems are derived from three distinct and separate layers of tissue in the embryo. Both the skin and the brain are derived from the same embryonic tissue, which is known as the ectoderm. There is an important and powerful connection between the brain and the skin. It should not be surprising that therapeutic agents that affect the brain positively would also be beneficial to the skin.

One of the new S-acyl-glutathione derivatives I have been working with is S-palmitoIeoylglutathione (glutathione combined with a monounsaturated fatty acid found in palm oil known as palmi-toleic acid), which is an important discovery in the treatment of neurological problems associated with aging such as Alzheimer's disease. Thanks to the brain/beauty connection, they are also extremely efficacious in treating the skin.

Increasing Glutathione Production

Another strategy for providing glutathione to the cell and giving additional protection to the mitochondria is to provide precursors that are needed for the formation of glutathione. One very important precursor is a slightly modified amino acid known as acetylcysteine (NAC) - acetylcysteine is a derivative of the amino acid L-cysteine. NAC contains a sulfur group known as a thiol, and it is the thiol that gives this amino acid its antioxidant effects. The cysteine portion of NAC is one of the three peptides that make up the glutathione molecule, and because it provides this building block, more glutathione is produced.

In combination with two other amino acids, glutamine and glycine….. when administered together, are precursors or building blocks of glutathione and work synergistically to elevate glutathione levels in the cell.

Physicians have been administering NAC to patients suffering from acute sepsis to elevate levels of glutathione in the mitochondria and protect against organ failure. Oral supplementation is also an excellent strategy to protect the body as we age.

While I was interning in pediatrics at the Yale University Medical Center, I encountered a problem on more than one occasion in the ER involving children suffering from an acetaminophen (Tylenol) overdose. Acetaminophen is extremely toxic when taken in large doses because it causes liver failure. At the time, the Yale Pediatric ER therapeutic protocol was to have the patient drink a foul-smelling liquid called Mucomyst. Designed to be used in a nebulizer, Mucomyst was a therapy for patients with respiratory problems. It worked by breaking down thick mucus in the bronchials of patients with lung problems. Mucomyst is a solution of N-acetylcysteine. The thiol in it is responsible for its terrible rotten egg aroma, because it is a sulfur group. In the Tylenol overdoses, NAC works by elevating levels of glutathione in the liver cells, preventing free-radical damage and liver damage. Although we all pitied the poor children who were forced to drink this horrible-smelling solution, we surmised that after experiencing this drink, they would not go near a Tylenol tablet, unsupervised, for the rest of their lives……

It is difficult to overstate the importance of glutathione as the body's primary antioxidant defense system……

Scientists and physicians, myself included, have spent many years researching methods to increase glutathione within the mitochondria. Elevating glutathione levels and other substances that protect against free-radical damage in the mitochondria is the cornerstone of our quest to look and feel Forever Young.

One of the greatest challenges in working with glutathione is the fact that glutathione supplementation has not been viable. This is because oral ingestion of supplemental glutathione is rapidly digested by the gastrointestinal system. Fortunately, we are finding ways to circumvent this problem. One such method is the focal point of my own research: the development of a phospholipid carrier system that is capable of transferring glutathione into the cells. This transdermal delivery system allows the mitochondria to receive increased levels of this protective tripeptide. When applied to the skin, glutathione, via the phospholipid carrier, is able to penetrate various levels, reaching into the deep dermis and finally into the subdermal microvasculature, or the small blood vessels under the skin. From this point, glutathione begins circulating in our blood, providing protective glutathione molecules to all organ systems and cells. When delivered in this form, the glutathione is able to enter the cells and provide elevated levels for increased protection. Once in the cell, the higher levels of glutathione are available to the mitochondria, where they help to maintain health and prevent disease.

In Forever Young, you are going to learn how to adopt these therapeutic interventions as a means of keeping the mitochondria in a youthful state.

The Universal and Metabolic Antioxidant

Another important antioxidant that can help elevate levels of glutathione in the cell is alpha-lipoic acid (ALA), which has always been important in my research and was first introduced to my readers in The Wrinkle Cure. Alpha-lipoic acid is unique as an antioxidant because it is both fat-and-water-soluble. This means that it is able to protect all portions of the cell, including the mitochondria. ALA is also a metabolic booster that assists in energy production in the mitochondria. It is found naturally in our cells, locked in an enzyme system that is part of the energy-producing mechanism in the mitochondria.

Just say NO

Another mechanism by which ALA gives protection to the cell and mitochondria is by inhibiting the release of nitric oxide (NO). Free radicals are not alone in acting as a destructive force in the mitochondria; nitric oxide can also wreak havoc (more about this in chapter 2).

Nitric oxide has been studied by thousands of scientists in tens of thousands of laboratories for many years because it has a physiological function. It is a signaling molecule that is important in the central nervous system, arteries, and various cell systems. At elevated levels, NO can have negative effects, especially on mitochondrial function. In fact, nitric oxide plays a key role in the formation and perpetuation of various forms of cancer. Regulating nitric oxide release has become a new therapeutic strategy being used in the treatment of cancer. In chapter 21 will introduce additional substances that can block the production of NO and inflammatory transcription factors.

Increased concentrations of nitric oxide interact with oxygen-free radicals, resulting in the production of a superpotent free radical called peroxynitrite. During the metabolic stress seen during sepsis, there is a large release of nitric oxide, which disrupts the electron transport chain within the mitochondria. The powerful antioxidant properties of ALA can inhibit the release of nitric oxide, providing vital protection to the mitochondria. Since ALA is powerful enough to protect the cells during the extreme examples of sepsis and septic shock, it follows that this antioxidant can protect your cells from the changes seen during aging. All of the therapies that protect the mitochondria from damage suffered during sepsis can be implemented to prevent many diseases associated with aging.

ALA also helps with glucose metabolism, which becomes more important as we age. Insulin resistance and the elevated glucose levels of hyperglycemia are rampant in the aging population. Unfortunately, there is an epidemic of insulin resistance, elevated glucose levels, and type 2 diabetes in the young as well, due to poor diet and a sedentary lifestyle. It should come as no surprise that glucose dysregulation is also a hallmark finding in sepsis and in the multiple organ dysfunction system (MODS). ALA helps in the cell's uptake of glucose, independent of the action of insulin. It also sensitizes the insulin receptors in the cell plasma membrane, enabling the cell to utilize insulin and glucose more efficiently. ALA can help restore blood sugar control and prevent metabolic syndrome and diabetes.

ALA's powerful antioxidant and anti-inflammatory properties work through several mechanisms. One of the most important is its ability to prevent the activation of pro-inflammatory transcription factors such as NF-kB and AP-1. Once NF-kB is activated in the cytosol (watery portion of the cell) during oxidative stress (excess free radicals), it translocates to the nucleus, where it activates gene expression for the production of pro-inflammatory proteins called cytokines. These include tumor necrosis factor alpha and interleukin-2, -4, and -8. This immune response initiates a cascade of inflammation that interferes with cell function and disrupts mitochondrial energy production, generating even more free radicals.

When ALA is administered in conjunction with NAC, it protects glutathione from destruction and increases glutathione production. ALA is an important tool in preventing cytopathic hypoxia—impaired cellular oxygen use—either acutely in the ICU or chronically in the prevention of aging. When ALA is applied topically, its ability to prevent cell death results in visibly decreased lines and wrinkles, increased skin radiance, and an enhanced overall appearance of the skin.

Co Q10

Another important antiaging nutrient that can be used to protect the mitochondria and treat MODS is coenzyme Q10, also known as ubi-quinol. Co Q10 is found within the mitochondrial electron transport chain and assists in passing the electrons through the chain for the production of ATP, the energy storage and transfer molecule that is essential to life. Co Q10 is also a powerful antioxidant, used both topically and orally to prevent the clinical and physiological changes seen with aging and aging skin. It has been found effective in reducing the incidence of fine lines and wrinkles in the skin when used orally and/or topically.


Although extreme examples, cytopathic hypoxia and MODS can also be a model for aging. Aging is characterized by mitochondrial dysfunction, with a disruption in energy production that eventually leads to cell death by apoptosis. The aging cell is unable to use oxygen even when there is adequate oxygen being delivered to the tissue. Finding therapeutic agents that can protect the mitochondria is critical to all organ systems, including the skin. When these agents are taken orally, there is improved function in all vital organs, including the central nervous system or brain, where they can slow the loss of memory and the decline of problem-solving abilities. They are also critical in preventing the diseases of the cardiovascular system, the greatest cause of mortality in the aging population. When they are applied topically, the results are significant, reducing the classic signs of aging skin, including wrinkles, loss of contour and muscle tone, sagging, loss of radiance, enlarged pores, and discoloration.

You have learned that you can positively affect the way your cells function and you can intervene in the cell death associated with aging.

In chapter 2, I will introduce you to exciting research that will demonstrate that you can manipulate the expression of your genes, turning off disease- and age-accelerating transcription factors and turning on those that fight age and disease. With the tools you will read about in Forever Young, you will be able to preserve and restore your vitality and youthful appearance with strategies that are based on the most up-to-date science.





Keith Hunt