Chapter One

THE ICU:
A NEW ANTIAGING RESEARCH LABORATORY

The day had dawned cold and gray with a lowering sky on the morning of February 16. The dark, angry waves of the Long Island Sound dashed against the rocks, a harbinger of worse to come. Another snowstorm was scheduled for New York and Connecticut, making the winter of 2010 one for the record books from Florida to Maine. Escaping to the tropics was on my mind, but duty called.

This was the day I was turning in the manuscript for my new book, Forever Young. I was proud to have written a book that broke new ground yet apprehensive, because the science might be considered cumbersome. I knew that there was no other way to tell the story. People needed strategies to stop the deadly degenerating signs of aging, and I feel it is important to explain my recommendations, which are all scientifically based.

As I nursed a cup of green tea and read the news on the Internet, a 24-point-type headline from the United Kingdom’s Financial Times caught my eye: “Scientists discover the secret of ageing.” The article explained how one of the biggest puzzles in biology—how and why living cells age—had been solved by an international team based at the United Kingdom’s Newcastle University. Using a complex “systems biology” approach, the researchers, in conjunction with scientists from the University of Ulm in Germany, had set out to discover why cells become senescent, or, in other words, grow old. The research, published by the journal Molecular Systems Biology, showed that when an aging cell detects serious DNA damage, which may be the result of general wear and tear from daily living, it sends out internal signals. These distress signals trigger the cell’s mitochondria, the energy-producing part of the cell, to make free-radical molecules, which instruct the cell either to destroy itself or to stop dividing. The reason for this is to avoid the damaged DNA that results in cancer.

As you will discover in these pages, I am convinced that the damaging diseases and cellular destruction associated with aging begin with the mitochondria. I concur with the research findings from Newcastle University, as they validate my own research regarding how and why we age. The release of this study just as I was delivering my manuscript to my publisher was very exciting, because the researchers’ discovery echoes the underlying theme of this book.

I have gone beyond the science of why we age to search for practical ways to intervene in the process. In Forever Young you will learn new, effective, and safe strategies to protect the mitochondria, the mitochondrial DNA, and other parts of the cell from this programmed cell death, known as apoptosis, starting with the miraculous therapeutic powers of niacinamide (vitamin B3), which you will read about on page 107.

A New Model for Understanding Aging

My first experience with seriously ill patients occurred when I was a medical student at Michigan State University College of Medicine. During my rotation in internal medicine, particularly the weeks spent in the intensive care unit, I became intimately familiar with sepsis, one of the most common causes of death.

Also known as gram-negative bacteremia and gram-positive bacteremia, sepsis occurs when infectious agents like bacteria or fungi or products of infection like bacterial toxins enter the body, most often through a wound or incision. If this systemic infection goes unchecked, it leads to a condition known as septic shock, resulting in hypotension, or extremely low blood pressure; dysregulation of blood sugar; and the failure of such multiple organ systems as the heart, kidney, liver, and lungs.

The Sepsis/Inflammation/Aging Connection

In 1981 when I was in medical school, I was trying to understand what caused underlying damage to the vital organs during septic shock. The question was a huge challenge for both physicians and scientists. The research indicated that metabolic changes occurring on a cellular level were the primary cause of organ dysfunction and failure. The consensus was that these fundamental metabolic disturbances were the result of inadequate tissue oxygenation and a disruption of the body’s ability to control blood sugar levels. This combination of symptoms came to be known as multiple organ dysfunction syndrome, or MODS. It was widely hypothesized that multiple organ dysfunction syndrome resulted from tissue hypoxia, a condition in which vital organs do not get enough oxygen to meet their needs. Fast-forward to a new millennium: the concept of inadequate oxygen levels to vital organs as the fundamental cause of MODS is now being seriously questioned.

Today, scientists believe that adequate oxygen is delivered to the vital organs by the bloodstream during sepsis and septic shock. The problem is that the cells are unable to use that oxygen, even though it is being supplied at adequate levels. The inability of the vital organs to utilize oxygen is a cellular malfunction in the tiny organelles known as the mitochondria. This impaired cellular oxygen problem is termed cytopathic hypoxia. Just as cytopathic hypoxia is far more important in the generation of MODS than had ever been thought in the past, I propose that cytopathic hypoxia, as seen in the cellular changes of aging, is far more important to the degeneration of the organ systems than was previously believed.

Having come to that conclusion, I had to ask the next question: If cells cannot utilize the oxygen, where in the cell is the defect? The answer is the mitochondria.

The Mighty Mitochondria

The mitochondria are tiny energy-generating parts of the cell. They function as microscopic furnaces, converting food into fuel, and are responsible for all energy production in the body. The majority of the oxygen supplied to the cell is utilized by the mitochondria to make a chemical known as adenosine triphosphate, or ATP. ATP is the energy storage and transfer molecule that is essential to life. As I discussed in one of my previous books, Dr. Perricone’s 7 Secrets to Beauty, Health, and Longevity, functioning mitochondria are vital to maintaining a healthy body and beautiful skin.

A Closer Look at Mitochondrial Function

Although tiny, the mitochondria play a huge role in the body as the energy-producing portion of the cell. To accomplish this feat, they consume 90 percent of the oxygen that is needed by our bodies. As mentioned, this oxygen is used to oxidize fuel or burn food to synthesize ATP, which is the energy currency of the cell. This process of ATP production in the mitochondria is known as oxidative phosphorylation and takes place in the part of the mitochondria known as the electron transport chain. Within the electron transport chain, ATP is produced in five steps. If anything disrupts this chain, free radicals are created; this further disrupts the electron transport chain, causing irreparable damage to the mitochondria. Damage to the mitochondria and disruption of the electron transport chain are the first events seen in sepsis. Unchecked, this results in total systemic collapse, multiple organ failure, and death.

Although it may seem counterproductive, the energy produced by the mitochondria is the major source of free-radical production in the cells. This is a result of the metabolic process that converts food and oxygen to water and ATP. As energy production takes place in the electron transport chain, within the mitochondrial membrane, about 5 percent of the electrons escape. This creates free radicals that damage both the mitochondria and the cell.
Note
FREE-RADICAL CHEMISTRY

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 (see page 6) 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.

Therapeutic Strategies for the Mitochondria in Disease and Aging

Although the concept that free radicals are responsible for triggering an inflammatory response on a cellular and molecular level was considered with skepticism when I introduced it in The Wrinkle Cure, it is now dogma accepted by even the most conservative scientists. The idea that free radicals and inflammation cause cellular dysfunction and accelerate the aging process is now considered common knowledge as well.

Strategies for Mitochondrial Protection

If you want to slow down the aging process and keep your body functional at optimal health, you need to protect the mitochondria and your cells from free radicals. Mitochondrial antioxidants and free radical scavengers can counter the damaging effects of an inflammatory cascade.

Mitochondrial Antioxidants and Free-Radical Scavengers

Mitochondrial antioxidants are one therapeutic approach in treating acute sepsis as well as aging. This is of critical importance because any damage to the mitochondria results in the loss of energy production. A young cell is characterized by high energy production. Conversely, aged cells are characterized by low energy production and an inability to repair themselves.

Glutathione: The Master Antioxidant

Cells have evolved a defense system to protect against this damage by free radicals. It consists of antioxidants and enzymes that can neutralize oxygen-based free radicals. One of the key substances in cellular protection is glutathione. Glutathione is a tripeptide, a molecule composed of three amino acids, and is the most abundant and important antioxidant protective system in our cells. Critical in the cell’s defense against inflammation-generating free radicals and oxidative stress, glutathione comes to the rescue whenever a cell is under severe oxidative stress, as an excess of free radicals is called. The mitochondria depend upon cellular glutathione for protection. Produced in the cytosol, the watery portion of the cell, this glutathione must be transferred into the mitochondria to defend against the free radicals, also known as reactive oxygen species, or ROSs. It is difficult to overstate the importance of glutathione as the body’s primary antioxidant defense system.
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GLUTATHIONE BREAKTHROUGH

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-palmitoleoylglutathione (glutathione combined with a monounsaturated fatty acid found in palm oil known as palmitoleic 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 N-acetylcysteine (NAC). N-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, N-acetylcysteine promotes the synthesis of glutathione in the liver. Both N-acetylcysteine and alpha-lipoic acid, when administered together (see page 13), 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 mito-chondria 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.

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.

Alpha-Lipoic Acid:
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 2 I 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?B and AP-1. Once NF?B 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.

SS Peptides

Another class of novel mitochondrial antioxidants that play a key role in the treatment of cytopathic hypoxia is the amino acid peptide-based antioxidants. These peptides, which I consider to be one of the most exciting discoveries to date, have been designated the SS (Szeto-Schiller) peptides. As you have learned, protecting the mitochondria is critical in preventing death and disease. Unfortunately, the performance of standard antioxidants has been somewhat disappointing because they have not been able to penetrate the mitochondrial membrane effectively. Without adequate protection, free radicals, both oxygen-based and nitrogen-based, damage the mitochondrial membrane, resulting in impaired function and apoptosis, or cell death.

The discovery of the SS peptides has stimulated tremendous activity among researchers. Some of the research is focused on treating problems in the central nervous system. Thanks to the brain-beauty connection, these peptides are showing great promise for improving the appearance of skin. When applied topically, SS peptides demonstrate significant effectiveness in rejuvenating aging skin.

Beauty: It’s Skin Deep

These peptides cannot be administered orally, as the digestive enzymes destroy their therapeutic activity. When placed in my phospholipid carrier system, they rapidly penetrate the skin, greatly improving the clinical appearance of the skin. When they are topically applied, the results are cumulative and continue to accrue with each application. Just some of the benefits include a decrease in fine lines and wrinkles and increased radiance. These effects can be attributed to enhanced energy production in the cells. These visible improvements in the skin can be seen within just a few short weeks of application.

The SS peptides have more than a cosmetic effect. In this carrier system, they are able to penetrate all layers of the skin, reaching the subdermal vasculature, where they enter the bloodstream and circulate throughout the body. Once these peptides enter the cell, they pass through the mitochondrial membrane, giving protection against a variety of highly damaging free radicals. In addition, the SS peptides protect against lipid peroxidation, or fat destruction, providing significant protection to the cell plasma membrane as well as the fragile mitochondrial membrane. These dual actions prevent the cellular damage that occurs during acute sepsis and/or aging. The SS peptides are currently being tested as a treatment for cytopathic hypoxia in the ICU.

Carnitine: A Multifunctional Anti-Inflammatory

Carnitine and its derivative acetyl L-carnitine (ALCAR) are amino acids that are essential in transporting fatty acids into the mitochondria to be burned for energy. Carnitine and ALCAR play a key role in maintaining mitochondrial energy production, which is critical in combating sepsis, MODS, and aging. To ensure that fats will be utilized for energy production in the cell, carnitine levels must be adequate.

Carnitine and ALCAR also protect the mitochondria through an antioxidant mechanism. Carnitine can also decrease the production of pro-inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alpha. The depletion of carnitine results in a highly damaging, systemic inflammatory burst. Since the key to preventing accelerated aging and age-related diseases is controlling inflammation, carnitine and ALCAR are indispensable in achieving this goal.

Since both forms of carnitine aid in transportation of fats into the mitochondria to be used for energy production, they are important in my weight loss regimen described in chapter 3. Carnitine and ALCAR enhance the sensitivity of insulin receptors, helping to decrease blood sugar levels and levels of circulating insulin, necessary to any successful antiaging and weight loss program.

Co Q10

Another important antiaging nutrient that can be used to protect the mitochondria and treat MODS is coenzyme Q10, also known as ubiquinol. 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.

Summary

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.

© 2010 Dr. Nicholas Perricone