The document discusses the micro-inflammatory theory of skin aging. It proposes that various factors of skin aging like UV radiation, stress, smoking, etc. trigger an inflammatory response through a common mechanism. Specifically, damaged skin cells release signals that cause mast cells to secrete histamine and TNF-α, stimulating endothelial cells to synthesize ICAM-1. This recruits immune cells from the bloodstream to the dermis where they release oxidative bursts, damaging the extracellular matrix and nearby cells. Over time, this micro-inflammatory cycle causes disorganization of the dermis and visible signs of aging. The theory suggests topical anti-oxidants and protease inhibitors may help by mitigating oxidative damage and inflammation at the dermal-epider

1. 3H&PC Today - Household and Personal Care Today, vol. 11(3) May/June 2016
THE RELEVANCE OF THE MICRO-INFLAMMATORY THEORY
OF SKIN AGING
The crucial aspect of the micro-inflammatory mechanism is
that, upon the binding I-CAM 1, the immune cells release a
firs oxidative burst in order to exit the blood vessel, then they
release a second oxidative burst associated with the release
of proteolytic enzymes (matrix metallo-proteinases etc) when
they fray a path in the extracellular matrix to migrate across
the dermis, and finally they release a third oxidative burst
when they dismantle the damaged cells before engulfing
the debris and remove them to the lymphatic system. Each
one of these oxidative bursts has the potential to damage
the extracellular matrix as well as cells nearby, the so-called
innocent bystanders cells, which can trigger a second micro-
inflammatory cycle and so on. In the long run, since the
renewal of the protein fibers in the dermis is quite slow (half-life
for collagen turnover is 15 years)(14) the net result will be a
totally disorganized extracellular matrix with the consequent
thinning, sagging, loss of elasticity and wrinkle formation.
The take home message of the micro-inflammatory theory
of skin aging is that it points out the paramount damaging
consequences of the response to an initial cell damage and
its potential of increasing the rate of skin aging.
The importance of the understanding of the micro-
inflammatory mechanism is that it points out the relevance
of anti-oxidants and of protease-inhibitors in skin care
products. As a matter of fact the dermal-epidermal junction
is digested by proteolytic enzymes from poly-morpho-nuclear
lymphocytes (15) and the topical application of protease
inhibitors can be expected to have a preventative effect
against inflammation-induced damage. In a similar way,
the oxidative burst associated to the inflammatory infiltration
provoked by UV radiation (9) and occurring in the epidermis,
for instance, can be mitigated by the topical application
of anti-oxidants such as vitamin E (16, 17). Oxidative stress
can produce nicks (single strand breaks) into DNA with the
consequent activation of poly ADP-ribosylation, drop of NAD
level and inhibition of energy production and the triggering
of a further round of an age-accelerating, inflammatory
response. This can be avoided by topical application of
vitamin B3 (18, 19).
Endothelial cells are the cells lining the interior of veins and
blood vessels. When they synthesize I-CAM 1, they induce
neutrophils and macrophages circulating in the blood
flow to attach to it, and to perform diapedesis (i.e. exit the
blood vessel) to enter the surrounding tissue where they
can exert their immune action by destroying their targets.
Remacle’s observation prompted Giacomoni and D’
Alessio to propose the micro-inflammatory model of Skin
Aging (3), stating that all the factors of skin aging share
as a common mechanism the capability of inducing the
synthesis of I-CAM 1.
As a matter of fact, when a skin cell is damaged by an
external aggression (such as solar exposure, wounds,
infections etc) it triggers the cascade of the arachidonic
acid, the release of prostaglandins, leukotriens and
thromboxane which stimulate the release of histamine and of
TNF-α from mast cells. These two molecules signal endothelial
cells to synthesize I-CAM 1. Circulating immune cells such as
neutrophils and macrophages attach to it, roll over and cross
the wall of the blood vessel to be recruited in the dermis where
they migrate to reach and remove the damaged cell.
Cigarette smoking is vaso-constrictive and reduces the flux
of nutrients to skin cells, and carries high concentrations of
Reactive Oxygen Species, with the consequent cell damage
and inflammatory response (11).
When the skin is subjected to mechanical strain (gravitational
forces, tractions such as the ones induced by inserting wooden
plates in the lips of women in some African tribes) even in
the absence of cell damage, skin cells release inflammatory
cytokines. Cytokines provoke the synthesis of I-CAM 1 and the
recruitment of immune cells into the dermis (12).
Protein glycation too, is a factor of skin aging and when cultured
human endothelial cells are incubated in the presence of
glycated bovine serum albumin, they synthetize I-CAM 1 (13).
Inhibitors of glycation can be found, such as Aminoguanidine
which is generally used as benchmark. A seven-fold more potent
inhibitor of glycation is found in an extract of the fruit Terminalia
chebula which is currently commercalized.
When one individual is exposed to psychological stress,
neuropeptides released by the neural endings in the skin
trigger the so-called neurogenic inflammation, the synthesis of
I-CAM 1 and the recruitment of immune cells into the dermis.
For detailed references cfrt (6, 8).
When one individual chronically absorbs high levels of ethanol, it
is easy to observe in specific anatomical regions (cheeks, nose)
the appearance of spider veins, i.e. of permanently dilated blood
vessel. The ethiology of spider veins has been recently elucidated
when it was observed that ethanol induces the increase of
circulating I-CAM 1 in blood and therefore the recruitment of
immune cells in the dermis. For details, see reference (4).
When the immune cells are in the dermis in the absence
of a chemotactic signal to follow, as it is the case for the
stress- or ethanol- or anoxia- or glycation-induced synthesis
of I-CAM, they exert their activity by digesting the smooth
muscle cells surrounding the vein or the blood vessel, with
their consequent macroscopic and permanent vaso-dilation,
provoking the so-called spider veins.
KEYWORDS: Skin aging, inflammation, I-CAM 1 (Inter-Cellular Adhesion Molecule 1), factors of skin aging, anti-aging.
Abstract Fighting skin aging can be considered in the frame of the micro-inflammatory hypothesis, a cyclic
mechanism, which can be tackled step by step. Damaged cells release pro-inflammatory signals inducing
mast cells to secrete histamine and TNF-α (Tumor Necrosis Factor α). Endothelial cells in blood vessels synthesize I-CAM 1 (Inter-cellular
Adhesion Molecule 1), a signal for immune cells to release H2O2 and exit the vessels. Immune cells follow chemotactic signals and fray
a path damaging the dermis. In the absence of chemotactic signals, immune cells damage the connective tissue surrounding the
blood vessels. When damaged cells are reached, immune cells release an oxidative burst, engulf cellular debris and proceed to the
lymphatic system. Innocent bystander cells can be damaged, thus triggering another round of release of pro-inflammatory signals. The
accumulation of damage provoked by this process can be hindered by the appropriate topical application of anti-oxidants such as
Vitamins C and E, of stimulators of DNA repair and booster of ATP synthesis such as nicotinamide. Aminoguannidine and T. chebula
extracts prevent pro-inflammatory glycation and other interventions against dry skin or age spots are discussed.
The Micro-inflammatory theory
of Skin Aging:
Mechanisms and Possible and Interventions
2
INTRODUCTION
The expression “damage of aging” is a very evocative yet
a very misleading expression. As a matter of fact, it was
pointed out by the collective work of the European Network
for the Biology of Aging in the late 1990s (1), that aging is
essentially the consequence, not the cause, of damage.
From a biochemical, quantitative point of view, aging can
be defined as the accumulation of molecular damage
(2). Molecular damage and remodeling can impair the
organization of molecules in the extracellular matrix, or the
basic physiology of a cell, with unwanted consequences.
Macroscopic signs of skin aging such as sagging, wrinkles,
age spots, varicose veins, spider veins, loss of elasticity,
elastotic skin, cutis rhomboidalis, dullness, loss of radiance
and of luminosity are the consequence of causes as diverse
as solar exposure, anoxia, wounds, infections, physical strain,
psychological stress, cigarette smoking, protein glycation and
the drinking of alcoholic beverages.
One of the questions tackled by the European Network for
the Biology of Aging was “Do these factors of skin aging
share common mechanistic features?” and the answer was
“Yes they do”, and papers were published to provide the
justification to this claim (3- 8).
THE MICRO-INFLAMMATORY THEORY OF SKIN AGING
It was known that ultraviolet radiation, the major factor of
skin aging, elicits an inflammatory response (9). It was also
known that some of the so-called “factors of aging” do elicit
an inflammatory response, but the observation which lead to
postulating the existence of a common, inflammatory step
in the general mechanism of action of the diverse factors
of aging was the observation by Remacle and coworkers
on the genesis of varicose veins (10). Indeed, whereas in
general, as it is the case with UV, the inflammatory process is
the consequence of cellular damage induced by the “factor
of aging”, this observation by Remacle pointed out that it is
possible for tissues to undergo an inflammatory reaction without
the presence of cellular damage in the epithelium or in the
conjunctive tissue. Varicose veins are visible under the skin. They
appear as enlarged veins, as if they were no longer constraint
within the vessel-surrounding sock of smooth muscle cells. They
are observed in individuals who have been subjected over
time, to a prolonged, motionless standing position. This position
hinders blood flow in the veins of the lower legs and provokes
local anoxia. Remacle and coworkers noticed that when
cultured endothelial cells are subjected to anoxia, there is a
strong synthesis of secondary messengers accompanied by the
adherence of neutrophils, via the synthesis of the Inter-cellular
Adhesion Molecule I-CAM 1 on the surface of endothelial cells.
FOCUS ON ANTIAGEING:
actives, formulation delivery, testing
PAOLO GIACOMONI
Élan Rose International - Tustin, CA
Insight Analysis Consulting - 115 Murry Drive, Madison, AL-35758 USA
H&PC Today - Household and Personal Care Today, vol. 11(3) May/June 2016
Paolo Giacomoni
3

2. 4 5H&PC Today - Household and Personal Care Today, vol. 11(3) May/June 20164
A remarkable molecule, which beats hydroquinone in preventing
and removing facultative pigmentation is 4-hexylresorcinol (24, 25).
Dry skin is the consequence of the dramatic reduction of
sebum secretion and the modification of its composition
occurring after menopause (26), as well as of the loss of water
retention capability associated with the reduction of estrogen
production in postmenopausal women (27). To these factors,
one should add the age-related changes in the composition
of the cornified envelope in the stratum corneum where,
after the age of 60, the content of filaggrin is reduced (and
therefore there is less Natural Moisturizing Factor) thus reducing
the flexibility of the stratum corneum itself (28). Another factor
responsible for increased skin dryness with age is the decrease
of the level of Aquaporin 3-b (29, 30). These observations
make it possible to design topical moisturizers to provide
ingredients appropriate for the age window of the targeted
consumer, adding the lipids or moisturizing factors present in
young skin and slowly disappearing from the skin of women of
increasing age. Some ingredients are reported to be capable
of stimulating the internal hydration network by stimulating
Aquaporin 3-b, e.g. Isosorbide dicaprylate (31).
Dull, non-radiant skin lacking luminosity is the result of the
sub-epidermal blood-vessels being “pushed down” as a
consequence of the dermal remodeling induced by the micro-
inflammation subsequent to the chronic exposure of the skin to
damaging environmental factors. Dull skin can be re-established
in a glowing, luminous status by topical application of exfoliating
agent (possibly non-acidic ones) such as activators of Stratum
Corneum Tryptic and Chemotryptic enzymes, and of substances
able to restore the production of energy within epidermal cells
such as vitamin B3 as evoked above.
CONCLUSION
Aging is not a pre-programmed curse. Skin aging occurs at a
rate, which is dictated by the individual’s behavior. Avoiding
the causes of age-inducing damage is a good rule of the
thumb to slow down the rate of aging. Topical treatments can
be of help in avoiding molecular damage, for instance those
containing sunscreens and anti-oxidants, or inducers of anti-
stress proteins. Sometimes it is also possible to boost the action
of endogenous systems able to remove molecular damage,
by providing appropriate ingredients able to increase energy
production, stimulate DNA repair, protect the immune system
etc. The macroscopic, visible signs of aging are more difficult
to remove, and at any rate, can be removed only transiently.
Wrinkles can be transiently “removed” by the topical
application of tightening film formers, or made less visible by
surface exfoliators. Dry skin can be transiently mitigated by
the addition of those lipids and natural factors, which happen
to be no longer present in older skin. Dull skin and skin with
discoloration can be treated with ingredients able to transiently
restore glow and homogenous skin tone. In general, the best
therapy to reduce the rate of skin aging is prevention.
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The technological advantage
afforded by the micro-inflammatory
model is that it allows one to identify
the factors that increase the rate of
aging by inducing a conspicuous
accumulation of damage, to
select the appropriate anti-aging
ingredients for topical application
and to design the formulas for
cutaneous delivery of these
ingredients. The micro-inflammatory
model also points out the anatomical
regions where topical anti-oxidants and
protease inhibitors have a chance to exert a
beneficial anti-aging action, i.e. on epidermal
cells and on the dermal-epidermal junction.
THE ONSET OF THE VISIBLE SIGNS OF AGING
Other factors contribute to the onset of the visible
signs of skin aging, but the damage inflicted
to the skin by the inflammatory response is of
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consider here, a few, major visible signs of aging
and possible interventions to minimize their aspect.
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correspondence of a wrinkle.
The age spot (lentigo senilis, not to be confused with freckels,
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