Inflamm’aging: a Unifying Theory of Life, Death, Aging, and Beauty

Inflammation (Latin, īnflammō, “I ignite, set alight”) is part of the complex biological response within tissues to harmful things, such as infectious agents (bacteria, viruses, etc), damaged cells, or irritants such as chemicals and sunlight (solar radiation).  It involves a cascade of events involving the local vascular system, the immune system (e.g. white blood cells), and various cells within the injured tissue, as well as stem cells (both locally resident and the 911 mobile emergency system of mesenchymal stem cells housed in the bone marrow).

inflammationInflammation is one of those phenomena of nature that is a good thing to have if and when you need it, but can be a bad thing when you don’t or if it just hangs around too long. Acute inflammation can be lifesaving. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. But healing in the presence of repeated cycles of inflammation is abnormal – leading to fibrosis (scar tissue, either internal or external) and poorly functioning, compromised tissues. A vicious cycle that will diminish quality of life, and lead to death.  Persistent inflammation is responsible for many of the most common diseases such as hay fever, periodontitis, atherosclerosis, heart attacks, stroke, diabetes, rheumatoid arthritis, and cancer.

The term ‘inflammaging’ is used to characterize a widely accepted paradigm that aging is accompanied by a low- grade inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is a (a) low-grade, (b) controlled, (c) asymptomatic, and (d) persistent or chronic.

Chronic inflammation is of prolonged duration and manifests microscopically by the presence of two different types of white white cellsblood cells, known as lymphocytes and macrophages. Lymphocytes function as “killer” cells, disabling and destroying infected tissue, such as tumors or infected cells, while macrophages literally consume cellular debris and pathogens. Together, these aggressive forms of white blood cells can result in the scarring of connective tissue and tissue death.

Furthermore, an excessive inflammatory response can also lead to systemic complications due to overproduction of inflammatory cytokines such as TNF-alpha and IL-1. This is believed to be a factor in mortality arising from severe influenza, severe acute respiratory syndrome, and sepsis.

Cytokines are chemical signals produced by all cells that modulate inflammation.

Inflammaging is mediated by increased levels inflamm cytokine balanceof pro-inflammatory cytokines, and decreased levels of anti-inflammatory cytokines.

Growth factors are a type of cytokine or signaling molecule that leads to tissue growth, whether for purposes or development (e.g. embryogenesis) or healing (regeneration). A damaged tissue needs to be rebuilt. But rebuilding cannot occur in the presence of inflammation – newly minted cells just get gobbled up along with the old & dying cells. Thus, in a wise conservation strategy, inflammatory cytokines tend to depress levels of growth factors while anti-inflammatory cytokines tend to increase their activity.

Most of you are familiar with the concept of oxidation occurring within cells, which if prolonged can lead to death, or may antioxidantdamage the DNA present within the cell nucleus leading to genetic mutations and thereby potentially to cancer. Reactive Oxygen Species (ROS) are released during inflammation, which cause both oxidative damage and elicit the release of additional inflammaging cytokines. This may lead to a vicious cycle, accumulating over decades, whereby the persistently pro- inflammatory state leads to pathophysiological changes in the tissue and a vicious cycle of inflammation, an immune “healing” response in response, and the “aging” of the tissue as evidenced by fibrosis, scarring, degeneration, and e.g. (skin being the most visible) things like wrinkles and discoloration, skin laxity, or possibly cancers and other lesions related to chronic oxidative stress.

Aging is also associated with a complex remodeling of the immune system, often in the direction of apparently decreased immune competence, and is therefore associated with the paradoxical co-existence of chronic inflammation and immunodeficiency.

A variety of life-threatening acute disorders also involve dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver, or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns, and anaphylaxis. Many complications of infectious diseases also involve dysregulation of inflammatory responses. Although an inflammatory response can kill invading pathogens, an excessive inflammatory response can also be quite destructive and in some cases can be a primary source of damage in infected tissues.

skin-wrinkles-800x800Inflammaging is the most widely accepted theory of aging amongst scientists today. The key pathways underlying inflammation involve cytokines.  There is abundant research going on worldwide to better understand these relationships, and to discover ways of staving off diseases, and slow aging, by altering cytokine networks with tissues.  We will discuss some of this in future posts.

DrGeorge and I, and our university colleagues, occupy the deep space outpost that might be described as the nexus between inflammation, cytokines, and aging skin.  We are not alone here, but there are not yet great numbers of us. In the next article in this series we will introduce you to the concept of skinflammaging. This is exactly what it sounds like – inflammaging theory as applied to skin, and the therapeutic concepts that derive from it.  Our work actually takes a very direct approach – altering the network of cytokines present within skin directly, in order to move them from an inflammatory to an anti-inflammatory balance.  We accomplish this not through weird voodoo concoctions or algae found only in a deep ocean thermal jet stream, but rather through the magic of stem cells. Human stem cells, not fruity ones (which are rather beside the point since their cytokines are indecipherable by human cells). And not just any human just any stem cells, but those that nature designed specifically for the task of maintaining cytokine balances favorable to the task at hand, whether it be healing, or regeneration (the core agenda of anti-aging therapeutics).


We’ll talk more about this soon.  Stay tuned.





G Makoto, Inflammaging (inflammation + aging): A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory?, Biosci Trends 2 6 218–30 (Dec 2008)

C Franceschi, et al., Inflamm-aging. An evolutionary perspective on  immunosenescence, Ann NY Acad Sci 908 244–54 (Jun 2000)

C Franceschi and M Bonafé, Centenarians as a model for healthy aging, Biochem Soc Trans 31 457–461 (Apr 2003)

C Franceschi, et al., Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007 Jan;128(1):92-105

JM Schroder, Cytokine Networks in the Skin. J Invest Dermatol 105:20S-24S, 1995



  1. Lina Jacobson says:

    Thank you for your time and attention on one aspect that damages DNA. Since this first aspect of your series focuses on the physiological damage to the entire body because of inflammation, I wanted to chime in on the effects of curcumin the active ingredient in turmeric on inflammation. The following reference plays nicely to the aspects you outlined for the damage of inflammation.

    From: Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets.

    Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry powder), has been used for centuries as a treatment for inflammatory diseases. Extensive research within the past two decades has shown that curcumin mediates its anti-inflammatory effects through the downregulation of inflammatory transcription factors (such as nuclear factor kappaB), enzymes (such as cyclooxygenase 2 and 5 lipoxygenase) and cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6). Because of the crucial role of inflammation in most chronic diseases, the potential of curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases. The pharmacodynamics and pharmacokinetics of curcumin have been examined in animals and in humans. Various pharmacological aspects of curcumin in vitro and in vivo are discussed in detail here.

    Since inflammation is an inside/outside demon I’ve always felt whatever proven modalities that are available should be considered, supplements such curcumin with countless research, etc.

    Now when it comes to topical, the stem cytokines derived from bone marrow; no contest as probably the best now known anti-inflammatory. But I won’t get ahead of your series, I’ll patiently await your next post as my enthusiasm knows no bounds.

    • drjohn says:

      Thanks, Lina. I am fascinated by curcumin. If it wasn’t for the color issue we would probably see a lot more use in dermatologics. here is a review paper from JDD for interested readers. Tuyet A. Nguyen BA BS and Adam J. Friedman MD Curcumin: A Novel Treatment for Skin-Related Disorders J Drugs Dermatol. 2013;12(10):1131-1137.

      Curcumin, or diferuloylmethane, is a crystalline compound which gives the East Asian spice turmeric its bright yellow color. The medicinal properties of this spice have been referenced in numerous countries and cultures throughout the world. Today, there is growing scientific evidence suggesting curcumin’s utility in the treatment of chronic pain, inflammatory dermatoses, acceleration of wound closure, skin infections, as well as cosmetic ailments such as dyspigmentation. In addition, curcumin may have a protective role against various pollutants and cytotoxic agents, indicating that it may be beneficial in a mitigational or prophylaxis role. Although turmeric has been used for thousands of years in alternative medicine, curcumin has yet to emerge as a component of our mainstream dermatologic therapeutic armamentarium. Interestingly, curcumin provides an ideal alternative to current therapies because of its relative safety profile even at high doses. Although the advantageous properties of curcumin in medicine are well established, its therapeutic potential thus far has been limited because of its poor oral bioavailablity. Topical administration of curcumin can directly deliver it to the affected tissue making it useful in treating skin-related disorders. However, limitations still exist such as the cosmetically unpleasing bright yellow-orange color, its poor solubility, and its poor stability at a high pH. Here the current literature detailing the potential and current use of curcumin in dermatology is reviewed.

  2. Lina Jacobson says:

    Thank you for the reference article. The current limitation for topical use due to its bright yellow-orange color reminds me of the early formulations of VitaminA/Retin A. Perhaps in the future…

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