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Aging and Inflammation

Peter T. Pugliese, MD December 2009 issue of Skin Inc. magazine
older woman wringing hands

Editor’s note: Skin Inc. magazine recommends that all clients check with their physicians before incorporating any dietary changes.

A vast difference exists between chronological aging and physiological aging. Chronological aging is measured in years, while physiological aging is measured in decreased biological functionality. No hard and fast biological law states that after 80 years you must pack it in, yet experience tells you that maybe it is best not to make a 20-year plan.

Scientists throughout the world are studying the fundamental processes underlying aging changes, and although a great deal of progress has been made, there is much more yet to be learned. Using an analogy to farming, many fields still need to be plowed. One field that is yielding some early fruit, however, is that of inflammation and how it relates to aging. Just about every disease has some aspect of inflammation. For the esthetician to have a good understanding of aging and how it relates to acute and chronic conditions, a knowledge of the principles of inflammation is essential. Learning the basic concepts of immunology and inflammation will help the esthetician to appreciate the complexity of biological mechanisms and provide insight into the mysteries of aging.

Basic inflammatory reaction

Most texts illustrate inflammation by using a cut or break in the skin to show how the body first defends itself from potential invaders and then heals the wound. Actually, bacteria, viruses and even biochemicals, such as bee venom or pollen particles, can initiate an inflammatory reaction; in fact, just about any abnormal occurrence, trauma, infection or metabolic accident can do it. Let’s choose a cut with an accompanying bacteria to make a real gooey wound. If you do nothing about it in 24–48 hours, you will see and experience the four classic signs of inflammation: redness, swelling, heat and pain. Even a little pimple will produce these four reactions, and there are underlying basic processes that cause them.

Redness. Because the epidermis is transparent, the dilated capillaries at the site of the wound can be seen, but why would the blood vessels dilate first? Easy—they are the transport system that carries everything else to the wound site. The more vessels and the bigger the vessels, the more blood and the more goodies go to the wound. Depending on the type of wound and how much bleeding is associated with it, the blood vessels may first contract.

Swelling. Swelling is due to fluid in the tissues. It is a combination of interstitial fluid, plasma and white blood cells.

Heat. Heat is a combination of increased blood flow and tissue temperature due to fever-producing proteins.

Pain. Pain is due to the activation of the unmyelinated nerve endings in the skin. It can be mild or intense.

Processes of inflammation

Inflammation is the result of the body’s defense against a pathogenic antigen. There are two defense mechanisms the body uses to mount a response against these antigens. First is a rapid response known as the innate immune system. This system is able to detect many molecular patterns found on pathogenic organisms, but lacks specificity of recognition. The macrophage is a key cell in the initial response, along with other white blood cells such as neutrophils, basophils and eosinophils. Complement is a complex protein system that either destroys cells directly or marks them for destruction by other white blood cells. Phagocytosis is a major means of destroying cells by engulfing the bacteria and destroying it with enzymes (lysozymes). White blood cells release powerful proteins called cytokines that can coordinate and amplify the response.

The second response is launched by the adaptive immune system, which has a finely tuned antigen- recognition mechanism in lymphocytes known as T cells and B cells. These cells can produce massive amounts of antibodies, and T cells can differentiate into at least two subtypes of T helper (TH) cells.

The T helper 1 (TH1) cells produce a number of cytokines, including interferon-gamma (IFN-γ), reactive oxygen species (ROS), lipid species and other proinflammatory cytokines. The T helper 2 (TH2) cells stimulate long-term immunity through the production of a number of cytokines that induce B cell maturation resulting in antibody-producing special cells called plasma cells. TH2 cells can also call out more mast cells and contribute to chronic inflammation.

Chronic inflammation and aging

A key concept to understanding chronic inflammation is that signals from both the innate and adaptive immune systems combine, interact and affect two types of body cells: the epithelial cells and one or more mesenchymal cells of whatever organ is under attack. It is interesting that regardless of the disease that may result, ranging from arthritis to heart disease, the same inflammatory process is at work from the recruitment of leukocytes, extracellular matrix remodeling, proliferation of cells or cellular death, and even the building of new blood vessels, called angiogenesis. Both types of helper T cells are present in large numbers, which can create widespread tissue damage. Why? Why would the immune system attack its own body cells?

Normally the immune system would not attack a component such as blood vessels, and, in fact, the endothelial cells lining the interiors of blood vessels would resist any attack by white blood cells. After all, trillions of white blood cells are racing through blood vessels every minute of every day. However, if anything disrupts the integrity of these endothelial cells, such as bacteria, abnormal lipoprotein or even an active cytokine with a mind for destruction, the endothelial cell will respond by secreting a substance called vascular cell adhesion molecule-1 (VCAM-1).

Now the trouble begins. This type I membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and has been implicated in the development of artherosclerosis and rheumatoid arthritis. VCAM-1 promotes the adhesion of white blood cells such as lymphocytes, monocytes, eosinophils and basophils.

Cytokines. Two important subjects in immunology are cytokines and transcription factors. Cytokines are chemical compounds that get cells moving. They come in three flavors—proteins, peptides and glycoproteins—and they are powerful, actually 1,000 times more powerful than regular hormones. For example, while hormones are effective at levels of nanomoles, cytokines are effective at picomoles. A nanomole is one billionth of a molecular weight, while a picomole is one trillionth of a molecular weight. A mole is the weight of one molecule of a substance in grams.

The most common types of cytokines are interleukins, cytokines made by white blood cells for other white blood cells; lymphokines, made by lymphocytes; monokines, made by monocytes; and chemokines, which are cytokines that attract things, usually other cells. The function of cytokines is to regulate cell activity in immunity, inflammation and blood cell production, known as hematopoiesis.

All cytokines are made to order, act at very short distances and are never stored. They bind to specific cytokine receptors on the cell and trigger second messengers in the cell. These second messengers, and there are many of them, relay the cytokine signal to the nucleus and react with the DNA to do something that changes the cells in some manner. Most cytokines are made by T helper cells and macrophages.

Nuclear factor kappa B (NF-κB). Cytokines also activate transcription factors. One specific transcription factor is called NF-κB. When a cell receptor is bonded to a cytokine, it sends a message to biochemicals in the cytoplasm that translate the message, that is, what must then be done with this particular signal. The translation process itself is complicated, but is essentially one of activating the transcription factor to prepare it to enter the nucleus. According to Encyclopedia Britannica, a transcription factor is a “molecule that controls the activity of a gene by determining whether the gene’s deoxyribonucleic acid (DNA) is transcribed into ribonucleic acid (RNA). The enzyme RNA polymerase catalyzes the chemical reactions that synthesize RNA, using the gene’s DNA as a template. Transcription factors control when, where and how efficiently RNA polymerases function.”

NF-κB is an ubiquitous rapid-response transcription factor in cells involved in immune and inflammatory reactions, and exerts its effect by expressing cytokines, chemokines, cell adhesion molecules, growth factors and immunoreceptors.1

Inflammation and the aging process

The aging process may be described in many cases as prolonged inflammation associated with tissue destruction, active inflammation and attempts at healing, processes that are all present and active. Whatever the underlying cause, something initiates the process, and a sustained immune reaction results.

Tissue may not be destroyed, but it is definitely altered so that it does not function as well. Cells and cytokines of the innate immune system are the culprits, with the macrophages being the central cells in chronic inflammation. They interact with lymphocytes, secrete factors involved in tissue injury (ROS, proteases, inflammatory mediators), clean up debris and coordinate the granulation tissue response by inducing angiogenesis, the production of new blood vessels, by secreting fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).

It seems apparent that oxidative stress underlies the aging processes, but strong evidence indicates that calorie restriction (CR) reduces age-related oxidative stress and at the same time, produces anti-inflammatory properties.2 Exactly how all this ties together is not fully established, though the biochemical and molecular bases of the inflammatory effect in the aging process points to some key players. Investigators have identified the following biochemical reactions in aging: the upregulation of NF-κB and increased production of the cytokines interleukin-1 beta (IL-1 β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). In addition, two enzymes—cyclooxygenase-2, a major inflammation-producer, and inducible nitric oxide synthase (iNOS)—have been implicated as significant players in inflammatory reaction. It has been found the CR is able to attenuate all of these processes. The term “molecular inflammation” has been used to describe this process. See Figure 1.

Keep in mind that the inflammatory response is really the body’s defensive response via the immune system to combat injury or infection. Inflammation is now beginning to be seen as the root cause of most chronic diseases, from arthritis to cancer.3 See Diseases and Chronic Inflammation. Many factors have a role in inflammation, one of which is glycation, a process that directly stimulates NF-κB. This reaction results in a cascade of events, including mitochondrial energy depletion, calcification (mainly of blood vessels), fatty acid imbalance, marked immune dysfunction and oxidative stress. A serious complication of these processes is the appearance of autoimmune diseases, which are known to increase with age and are closely related to the aging process, with inflammation being the most significant factor. Rheumatoid arthritis is an autoimmune disorder in which high levels of the inflammatory cytokines, such as TNF-α and IL-6, are present, along with a new one, interleukin-8 (IL-8).


It’s pretty clear from all this information that by suppressing inflammation, aging can be slowed down or even prevented. How can you help correct this problem in clients when the immune system is so intricately bonded with the body’s life-saving defense system?

Obviously, diet plays a major role, not only for good health, but also as a major factor in the genesis of disease. First, however, consider the major changes that need to be made if your clients really want to counteract the insidious causes of aging. Clients can’t do much about their genetic background—they are stuck with that—but the right choices about what they do and what and how they eat can be made. Basic scientific studies appear to confirm that CR is the best bet.

After choosing to restrict calories, a decision must be made about what foods to consume and how to prepare them, because glycation is a real factor in the genesis of inflammation. Two other factors to consider include exercise and supplements. Exercise includes both mental and physical exertion. All of this can be done at home, without going to gym or buying expensive equipment. (Editor’s note: For more information about glycation from Dr. Pugliese, log on to

CR. CR has been shown as the most effective and reproducible means for increasing life span in many animal species, including mammals.4 It is an effective, wide-ranging cancer-prevention regimen based on experimental models. C-reactive protein (CRP) is a critical innate immune system molecule that is a potential predictive marker for the risk of heart disease and stroke. IL-6 is a cytokine with both anti- and pro-inflammatory effects on a variety of cell types, and IL-6 is able to induce the synthesis of all the acute phase proteins in the liver. In a rat study by Kalini et al., CRP, IL-6 and antioxidant levels in the plasma were measured in aging rats.5 There was an age-associated increase in CRP levels and a reduction in antioxidant status. Using a 40% CR diet, these values were reversed in as few as six months. Don’t be alarmed with the 40% CR, for as few as 8% CR was highly effective in reducing CRP, as well as the risk for arteriosclerosis. There was no effect on the level of IL-6.

More research must be done to apply the results of animal CR research to the prevention of human chronic disease, more so now since obesity, which is a risk factor for several chronic diseases and cancers, is increasing rapidly in the Western world.

Before recommending any dietary changes, make sure your client’s physician approves your suggestions. Begin by recommending a 10–20% reduction in caloric intake until the ideal weight is attained. It may take more time, but remember a lifetime habit is being formed. A good regimen is an antiglycation diet, consisting of no cheese and no fried, baked, broiled or roasted foods.

Here, in a nut shell, is why glycation is bad for you. Advanced glycation end (AGE) products are formed both within and outside the body. A major source of AGE is obtained from food cooked at high temperatures, such as frying and roasting. Chemically, AGE products are formed when a sugar such as glucose is combined with a protein to form a nonphysiological compound that the body cannot break down.

The AGE products are reactive and combine with normal proteins, such as collagen and enzymes. This combination results in either a poorly functional collagen or a nonfunctional enzyme. AGE products that circulate in the body combine with a specific receptor on many cells known as receptor advanced glycation end (RAGE) product. When activated, RAGE signals the cell to turn all NF-κB, which initiated a cascade of inflammatory cytokines. Lesson: Avoid foods cooked at high temperatures.

Exercise and supplements

The body is made to move. Even the most well-conditioned athletes will become extremely weak if they are bedridden for as few as two weeks. The fundamental law of nature “Use it or lose it,” is never more applicable than when related to muscle and brain cells. Nursing home residents confined to wheelchairs who are fed and dressed and bathed by attendants deteriorate rather rapidly. A simple exercise of walking, without a cane or walker, coupled with moderate resistance exercise, such as weight lifting, will have a remarkable effect on sedentary individuals in as few as two weeks. Set up a routine that you walk every day and lift weights, start with five pounds and go up to 10–20 pounds. If you can lift 20 pounds with each arm and do this three times week, you will be truly amazed at how well you feel.

I am a firm believer in supplements. See Supplements for Slowing Inflammatory Damage for a partial list of what I believe is essential to slow the inflammatory damage in aging. They are not listed by any ranking order. Multiple vitamins and calcium (600 mg) daily is also recommended, and you need not take all of these at one time. Divide them with your three meals a day. I take all of these … and a few more. In all cases, check with your physician if you are taking prescription medication to be sure there are no contraindications for specific supplements, especially if you are on blood-thinning medications.

Play an expanded role

A major cause of aging is chronic inflammation, and the defensive response of the immune system. Understanding these processes and explaining them to your clients will help them pay more attention to the damaging behaviors they may be practicing that help to spur on inflammation in the body. The three known means to combat aging and inflammation are reduction in diet, moderate exercise and the use of supplements. By helping clients understand this, you can play an expanded role in their anti-aging efforts.


1. JI Lee and GJ Burckart, Nuclear factor kappa B: important transcription factor and therapeutic target, J Clin Pharmacol 38(11) 981–993 (Nov 1998)

2. SN Meydani and D Wu, Nutrition and age-associated inflammation: implications for disease prevention, J Parenter Enteral Nutr 342 626 (2008)

3. H Bruunsgaar and BK Pedersen, Age-related inflammatory cytokines and disease, Immunol Allergy Clin N Am 23 15–39 (2003)

4. SD Hursting, et al., Calorie Restriction, Aging, and Cancer Prevention: Mechanisms of Action and Applicability to Humans, Annual Review of Medicine 54 131–152 (2003)

5. R Kalani, et al., Effects of caloric restriction and exercise on age-related, chronic inflammation assessed by C-reactive protein and interleukin-6, J of Ger Series A: Biological Sciences and Medical Sciences 61 211–217 (2006)

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Figure 1: How AGE Affects Cells and Inflammation

Figure 1

Figure 1: How AGE Affects Cells and Inflammation

Diseases and Chronic Inflammation

Many diseases are associated or linked to chronic inflammation, including the following.

Allergies. Allergies are associated with an increase in inflammatory cytokines, inducing autoimmune reactions.

Alzheimer’s disease. This is a complex disease marked by the destruction of brain cells due to inflammation.

Arthritis. Arthritis is characterized by elevated cytokines that destroy joint cartilage and synovial fluid.

Cancer. Cancer is known to be linked to chronic inflammation as well as many other causes.

Kidney failure. During this, inflammatory cytokines damage blood vessels and nephrons, tiny kidney tubules that excrete urine.

Psoriasis. Although psoriasis is fundamentally genetic in origin, it has a strong association with inflammatory cytokines that induce flareups of the dermatitis.

Supplements for Slowing Inflammatory Damage

Vitamin E: 400–800 mg daily

Ellagic acid: 500 mg daily

Vitamin C: 500 mg daily

Vitamin D: 1,000 IU daily

Curcumin: 500 mg daily

Alpha lipoic acid: 100–200 mgs daily

Carnosine: 500 mg daily

Acetyl carnitine: 500 mg daily

Krill oil : 500–1,000 mg daily

CoQ-10: 200 mg daily

Benfotiamine: 100 mg daily (glycation prevention)

Pyridoxamine: 100 mg daily (glycation prevention)

Beta glucan: 500 mg daily

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