Inflammation is a non-specific response of the skin to potential treats to its integrity. Because it is not specific, inflammation is not the perfect response. It is a little blind and can get excessive. It can be destructive to some extent, but it is fast and efficient. Typical triggers of inflammation include, but are not limited to:
- Pollutants, irritants, smoke: cytotoxic substances triggering the production of free radicals
- UV light: generates free radicals.
Inflammation is a reaction designed to fight aggressions such as bacterial infections and is also set in motion by the above-mentioned signals. The skin will fight them as if they were an infection and will not succeed because it isn’t.
When the inflammatory process is launched, it does not stop. It is a cascade of events which leads to the elimination of some of the treats, but also causes tissue damage and ultimately, aging. However, inflammation is a quick response, not a finely crafted one.
It could be compared to a carpet of bombs, destroying the enemy with a lot of certainty, but definitely damaging the sites on which it takes place. Even when the detected enemy is not properly eliminated by the inflammatory response, the damage is still done.
But for the most part, it does the job. Most times, the damage done as a result of the process of inflammation is in no way comparable to the damage that would be done by the aggressor it is fighting.
When these aggressors are detected, the skin cells (fibroblasts and keratinocyes as well as cells of the immune system such as neutrophils and mast cells) generate substances called inflammatory mediators. Immune cells, such as T cells and macrophages, are attracted to the site of the aggression by the mediators secreted in the first place: IL1 (Interleukine 1), and TNF for instance, are also called cytokines, and they trigger the migration of the cells (cyto, form the greek “kutos”, cell, and kine, from the greek “kinesis”,movement).
Other mediators include IL6 or IL10, or Prostaglandines such as the Prostaglandine E2 (PGE2). The PGE2 increases blood flow to help the migration of cells (see below) and the quick elimination of waste products generated by the reaction. The macrophages also produce Nitrous Oxide, which increases the blood flow further.
These inflammatory mediators will in turn activate the dermal fibroblasts, normally responsible for collagen production as well as cells of the immune system such as mast cells. These cells will produce collagenases and other metalloproteases.
These enzymes degrade the collagen and other constituents of the Extra Cellular Matrix (Elastin, Hyaluronic acid) to help the migration of immune cells coming fromn the lymph nodes towards the site of the inflammatory reaction.
Since the activation of the immune response is usually triggered by a bacterial invasion or other types of aggression (chemical pollutants, UV. etc.) the immune cells act to destroy and eliminate the factors which have activated the stress (remember, this is a non-specific response, pollutants and UV are perceived as invaders because they trigger the same kind of damage in a first phase as bacteria) The elimination of these factors is usually done by producing different types of free radicals which are highly toxic for bacteria. However the response activated by the immune cells is generally excessively strong inducing some severe damage to the healthy cells located nearby the site of injury (by baxteria, pollutants and UV light).
It is easy then to see how low-level irritants, such as pollutants, can trigger an almost ongoing inflammatory reaction that, in the long run, accelerates skin aging.
Recent research on a phenomenon called INFLAMM-AGING is interesting as it really points out chronic inflammation as a major culprit in aging, and brings a new dimension to our understanding of inflammation: that of endogenous inflammation.
Inflamm-aging is a phenomenon triggered by the conjunction of chronic repetitive and subclinical inflammation (from EXTERNAL aggressors) and INTERNAL inflammatory mechanisms due to the progressive degradation of systems such as the mitochondrial function.
As we age, there is also a lack in the elimination of oxidated proteins, due to the decay of the proteasome. These proteins will in turn transfer ROS to the cells, further adding to the oxidative damage triggering the inflammation.
In a recent article, a team of Italian scientists summarized state of the art on inflamm-aging and also reviewed new hypotheses on the role of mitochondria. The data favored the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity.
The energy theory of aging
The role played by the loss of efficiency in mitochondrial activity and most particularly by the progressive deterioration of the electron transport chain during the generation of energy – producing more and more free radicals for less and less energy – is one of the most promising avenues of research around inflamm’aging.
Production of ATP is reduced and the generation of ROS (in particular the hydroxyl radical) , increases. These are generated inside the very cell, and close the mitochondrial and nuclear DNA, and will have an even more damaging effect than exogenous ROS. These endogenous damages then add onto the exogenous damages created by the chronic inflammation triggered by pollutants and other environmental factors.
The increase in intracellular ROS also increases the level of oxidized proteins inside the cells. Because the proteasome, also a victim of aging, is less active, these damaged proteins stay around longer. Many of these being anti-oxidant enzymes, the cell then suffers a double damage: loss of efficacy of its normal antioxidative arsenal, and added oxidation phenomena due to the release of free radicals by these non eliminated oxidized proteins.
“What this shows us, is that inflamm’aging is a self worsening phenomenon which, if not addressed, can only lead to greater damage than it started with. Just like any chronic inflammation phenomenon it will not be very obvious, and creep into real damage that is then very difficult to fight once it is finally apparent”, says Daniel Maes, former Senior VP of R&D for Estée Lauder, and a specialist of the field.
In order to fight inflamm’aging, one needs to take care of both aspects of the phenomenon:
Fighting the external damage: by using anti-inflammatory compounds (antiPGE2, anti IL1, anti IL6, anti PGE2) and antioxidant compounds.
Fighting mitochondrial damage: protecting mtDNA, but also fighting the generation of ROS inside the mitochondria + (cumulating and SOD Like and catalase like effect), that help the primary anti-oxidant reactivation
Fighting protein oxidation: by the reactivation of proteasome.
 Inflamm-Aging, Cytokines and Aging: State of the Art, New Hypotheses on the Role of Mitochondria and New Perspectives from Systems Biology, Salvioli, S.; Capri, M.; Valensin, S.; Tieri, P.; Monti, D.; Ottaviani, E.; Franceschi, C.; Current Pharmaceutical Design, Volume 12, Number 24, August 2006 , pp. 3161-3171(11)
Marie Alice Dibon, PharmD
Posted: March 7, 2011, from the March 2011 issue of GCI Magazine.
Marie Alice Dibon, PharmD, is the principal at Alice Communications, Inc., helping companies in the life science sector to develop innovative technologies.
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