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Skin Aging: A Generalization of the
Micro-inflammatory Hypothesis
Paolo U. Giacomoni
, Glen Rein
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Abstract
The micro-inflammatory hypothesis of skin aging can be represented as a cyclic phenomenon as follows. A
cell is damaged by endogenous or exogenous factors. The damaged cell releases proinflammatory signals
(prostaglandins, leukotrienes, etc.). Inflammatory signals bind to resident mast cells and induce the release
of histamine and TNF-α that diffuse to blood vessels lined by endothelial cells. Stimulated by histamine
and TNF-α, endothelial cells synthesize and mobilize ICAM-1. ICAM-1 synthesis can also be stimulated
by anoxia, glycated proteins, neuropeptides, hormonal imbalance, or other signals not originating from
damaged cells, which all are factors of skin aging. Circulating immune cells bind to ICAM-1, roll over,
release hydrogen peroxide, and perform diapedesis. In the presence of chemotactic signals from damaged
cell, immune cells fray a path across the dermis by releasing singlet oxygen and matrix metalloproteinases.
In the absence of chemotactic signals, immune cells damage the connective tissue surrounding the blood
vessels. When the damaged cell is reached, immune cells release an oxidative burst to destroy the damaged
cell, engulf the debris, and proceed to the lymphatic system. In these steps, innocent bystander cells can be
damaged, thus triggering another round of release of proinflammatory signals, and the cycle is repeated.
Keywords
Factors of aging ICAM-1 Cold stress Ethanol Neuromediators Physical exercise Sleep deprivation
Introduction
If “eternal youth” can be achieved by restoring, to the status quo ante, molecular changes as soon as they
occur, then aging can be defined as the accumulation of damage, where damage is understood as molecular
change [1]. This chapter describes how the micro-inflammatory hypothesis of skin aging has been induced
upon analyzing the clinical, biophysical, histological, electron microscopy, cellular, and macromolecular
aspects of skin aging. It points out environmental and lifestyle factors that accelerate the rate of aging. In
addition, it explores metabolic and genetic factors participating in the process of accumulating damage.
Factors of aging provoke physiological responses that share common mechanistic features. For an example,
let us consider the pathways to the onset of two visible signs of aging as diverse as solar elastosis and
varicose vein.
Ultraviolet (UV) radiation damages epidermal cells. Damaged cells trigger the arachidonic acid cascade
and the release of prostaglandins and leukotrienes. Upon binding these molecules, resident mast cells
release histamine and tumor necrosis factor α (TNF-α), which promote synthesis and mobilization of
intercellular adhesion molecule 1 (ICAM-1) in nearby endothelial cells. Circulating monocytes and
macrophages bind ICAM-1, roll over, enter the dermis, and chemotactically migrate to reach the UV-
damaged cell. Evidence for this phenomenon is provided by the histology-documented inflammatory
infiltration [2]. In so doing, immune cells release proteases and damage the extracellular matrix (ECM),
thus accelerating the rate of damage formation and accumulation, that is, aging process, which can be
defined as accumulation of damage versus time [1, 3, 4]. Damaged elastic fibers are slowly replaced by
new, disorganized ones [5, 6] and, with chronic exposure to solar radiation, the elastic properties of the skin
are lost and solar elastosis is observed.
Varicose veins are visible under the skin. They appear as if they were no longer maintained in the socket of
the vein-surrounding smooth muscle. When constrained to a static standing position over time, a person
develops anoxia in the veins of the lower legs. Anoxia provokes the synthesis and the mobilization of
ICAM-1 in the endothelial cells lining the vein walls [7], and monocytes and macrophage bind ICAM-1,
roll over, perform diapedesis, and infiltrate the surrounding extracellular matrix (ECM). Not having
chemotactic signals to follow, monocytes and macrophages release oxidative bursts and proteases in the
proximity of the smooth muscle cells surrounding the vein. With chronic exposure to anoxia, the
inflammatory infiltration persists, the smooth muscle cells are heavily damaged, the vein walls collapse,
and varicose veins appear as a sign of accelerated vascular aging.
It thus appears that two totally unrelated phenomena such as solar elastosis and varicose vein, which are the
effect of causes as different as ultraviolet radiation and anoxia, do result from the same mechanism, that is,
the synthesis and mobilization of ICAM-1. The comparison of the onset of solar elastosis and of varicose
vein led to the proposal of the micro-inflammatory model for skin aging [4]. Due to accumulating evidence
that environmental, lifestyle, and metabolic factors can also trigger the synthesis of ICAM-1 and the onset
of the inflammatory process, the micro-inflammatory model can be now considered more of a testable
hypothesis than a simple mechanistic model.
The Micro-inflammatory Hypothesis of Skin Aging
The aging of the skin is the consequence of the three oxidative steps subsequent to the synthesis and
mobilization of intercellular adhesion molecule 1 within the endothelium of cutaneous vessels. Agents able
to provoke this synthesis and mobilization contribute to skin aging [4].
First oxidative step. Vascular cell adhesion molecule-1 (VCAM-1) activates endothelial cell Nicotinamide
Adenosine Dinncletide Phosphate Reduced (NADPH) oxidase, which catalyzes the production of reactive
oxygen species (ROS). This activity is required for VCAM-1-dependent lymphocyte migration [8]. Upon
binding ICAM-1 and rolling over, circulating inflammatory cells release hydrogen peroxide [9], and
endothelial cells lose intercellular contact, round up, and allow monocytes and macrophages to perform
diapedesis across the vascular wall.
Second oxidative step. In the extracellular matrix, inflammatory cells can either follow chemotactic
signals to reach damaged somatic cells or agents of infection or just exert their lytic functions randomly. In
both cases, reactive oxygen species are released, together with specific matrix metalloproteinases.
Third oxidative step. In the presence of cells to destroy, engulf, and remove (such as damaged somatic
cells, foreign bacteria, or molds), inflammatory cells release H2O2. By-standing resident cells can be
damaged by this oxidative burst and trigger the arachidonic acid cascade and the release of prostaglandins
and leukotrienes which will be relayed by the secretion of histamine and TNF-α from resident mast cells,
and these cytokines and autacoids will induce synthesis and mobilization of ICAM-1, thus perpetuating the
inflammatory process.
The accumulation of oxidative and proteolytic damage experienced over time by the extracellular matrix,
together with the remodeling of fibers in a disorganized mode, leads to skin aging. The micro-inflammatory
hypothesis emphasizes the aging of the cutaneous connective tissue and of the extracellular matrix.
Macroscopic consequences of this hypothesis are verified by experiment. The recognition that post-UV
repair and wound healing share ECM remodeling as a common feature has allowed one to understand why
blood vessels are deeper down in aged skin than in young skin. The sagging of the dermis is the
consequence of a modified ECM and is accompanied by an overall increase in the surface area of the skin,
particularly of the face. With time, under the action of gravitational pull, the surface of the skin increases. It
can be surmised that in order to keep the skin around the skull, nerves and muscles act and pull the skin.
Facial wrinkles form along the sites of attachment of the skin to muscles. Wrinkles have a neuromuscular
cause and that is evidenced by their disappearance in hemiplegics, when the individual is under general
anesthesia, or when wrinkled skin is treated with Botox. The increase of skin surface area and the reduction
of total body volume can be invoked to explain the observation that, notwithstanding a nearly constant rate
of turnover of the keratinocytes through the life span, the thickness of the epidermis is diminished with
aging. This is more the consequence of the stretching of the skin than the consequence of a modification of
the turnover rate of the keratinocytes. Indeed, the turnover of the keratinocytes does not change with aging,
and this is confirmed by the fact that the thickness of the stratum corneum is, in fact, constant with aging
[10].
Early Justification of the Micro-inflammatory
Hypothesis
Environmental and lifestyle factors capable of accelerating skin aging were recognized by biomedical
investigations in the course of the twentieth century, and, as a consequence of the work of the European
Network for the Biology of Aging, it was pointed out in 1996 that several factors of skin aging share as a
common feature, the capability of inducing the synthesis and the mobilization of ICAM-1 in the
endothelium [4]. The factors first recognized as having this capability were ultraviolet radiation, tractions,
wounds, infections, trauma, anoxia, cigarette smoke, and specific hormonal imbalances. A cause–effect
relationship was later inferred between ICAM-1 synthesis and mobilization and protein glycation,
stretching, electromagnetic fields, psychological stressors, and neuropeptides [11].
Some of the factors of skin aging are also direct cell- or tissue-damaging factors. When damage to cells or
tissue is generated (e.g., by UV radiation, smoke-related free radicals, infectious agents, or wounds and
traumas), a number of modifications are provoked to the ECM, to resident cells, and to vessel walls by the
free radicals and lytic enzymes which are released in the course of the inflammatory response, consequent
to the diffusion of cytokines produced via the arachidonic acid cascade. What about other factors of aging
which are not directly damaging agents? Traction and gravitational forces provoke the activation of
phospholipase A2, an enzyme involved in the arachidonic acid cascade. Anoxia induces ICAM-1 synthesis
and diapedesis of macrophages, which start digesting the ECM around veins or other blood vessels.
Glucose binds to proteins in a nonenzymatic glycation process, and glycated proteins are inducers of
ICAM-1 synthesis. Electromagnetic fields associated with computers provoke the release of histamine, IL-
1, and IL-6. Neuropeptides regulate the expression of cell adhesion molecules on both leukocytes and
endothelial cells in a coordinated effort to control neurogenic inflammation. These phenomena trigger a
cycle of self-maintained inflammatory responses, which comprises the induction of mobilization and
neosynthesis of ICAM-1, and are summarized in [4, 5, 11].
Extension of the Validity of the Micro-inflammatory
Hypothesis
Recent investigations have generated further results indicating that other factors of skin aging, the mode of
action of which was not previously understood, induce physiological responses consistent with the micro-
inflammatory hypothesis. Exposure to low temperatures, consumption of specific nutritional elements,
neuromediators , physical exercise , and sleep deprivation are discussed.
Cold
Epidemiological evidence indicates that exposure to low temperatures is associated with visible signs of
skin aging, from type I and type II rosacea to the appearance of spider veins. Exposure to low temperatures
provokes a vasoconstriction, which is mediated by endothelin-1. Indeed, levels of circulating endothelin-1
increase sevenfold in venous plasma from a hand immersed in ice water and threefold in venous plasma
from the non-immersed, contralateral hand [12]. The levels of circulating adhesion soluble molecules, such
as sICAM-1, sVCAM-1, and sE-selectin, are indicators of an existing inflammatory reaction and were
found to increase within an hour after healthy individuals were subjected to a cold pressor test [13].
Remarkably enough, endothelin-1 increased the expression of E-selectin and ICAM-1 on Human Coronary
Artery Endothelial Cells (HCAEC) [14]. Endothelin-1 was also reported to mediate the induction of
ICAM-1 and VCAM-1 by C-reactive protein in human saphenous vein endothelial cells [15]. All these
results are consistent with the conclusion that endothelin-1 regulates cell surface adhesion molecules
including ICAM-1, which is key to cell–cell and cell–matrix adhesion and leukocyte infiltration [16].
From these studies one can expect that, upon chronic exposure to cold, the vasoconstriction provoked by
endothelin-1 will be associated with a moderate increase in the levels of adhesion molecules with
consequent diapedesis of circulating inflammatory cells. These could damage the smooth muscle cells
surrounding the cutaneous blood vessels, thus maintaining a mild vasodilation, which can provoke a
persistent erythema sometimes diagnosed as type I or type II rosacea. When the damage to smooth muscle
cells causes the collapse of the capillary walls, the erythema can become permanent and be accompanied by
broken capillaries, visible as spider veins.
Ethanol
The physiological effects of ethanol consumption are known to differ according to the dose and the
frequency of ingestion. Moderate drinkers, with an intake of 20–40 g ethanol/day, have lower serum
ICAM-1 and VCAM-1 levels than teetotalers, whereas heavy drinkers display much higher levels of
adhesion molecules than moderate drinkers or abstinent controls [17]. Furthermore, moderate consumption
of sparkling wine, red wine, or white wine in healthy individuals promotes the decrease of serum level of
circulating VCAM-1, E-selectin, and P-selectin [18, 19]. These results suggest that moderate alcohol intake
has anti-inflammatory effects on the cardiovascular system, but at higher doses ethanol can exert a
proinflammatory effect. Indeed, chronic alcoholics exhibit significantly higher serum levels of endothelial
adhesion molecules than abstainers or moderate drinkers [20]. It can therefore be surmised that the smooth
muscle surrounding the blood vessels of heavy drinkers is subjected to the persistent damaging effect of the
inflammatory infiltrate, which can cause the collapse of the walls of the vessels and the appearance of
spider veins.
Neuromediators
The skin is innervated by peripheral sensory nerves, which can form direct synapses with epidermal and
dermal cells. These sensory neurons contain and release a variety of neuropeptides and neurohormones,
which regulate a wide variety of biochemical processes and cell functions of keratinocytes, Langerhans
cells, mast cells, dermal microvascular endothelial cells, and infiltrating leukocytes under physiological and
pathological conditions. Furthermore, many of these cell types can act as a source of neuropeptides and in
turn affect the survival, regeneration, and functional capacity of sensory neurons.
Expression and regulation of receptors for neuromodulators that are synthesized on a variety of skin cells
determine the cellular responses mediated by these peptides. A majority of studies address diseased human
skin, but in most cases these phenomena are universal across most species and tissues and the results from
these studies can be extrapolated to normal skin. Of particular interest here are the vasoactive effects of
cutaneous neuropeptides resulting in inflammatory processes, previously proposed as a hallmark of skin
aging [11]. However, other proinflammatory neuromodulators are also discussed.
In addition to its well-known cardiovascular effects, serotonin can activate neuronal cells to release
Calcitonin gene Releated Peptide (CGRP) and endothelial cells to secrete NO [21]. Recent research has
focused on characterizing the different 5-HT receptor subtypes. Activation of nociceptor type 1D is
associated with inflammatory pain which is mediated by trigeminal neurons [22]. Serotonin receptor
agonists (including 1D) block neurogenic inflammation [23] by inhibiting the release of substance P and
CGRP from peptidergic afferents [24]. Some serotonin receptor agonists are currently being used in the
treatment of migraine pain [25].
Substance P and CGRP are co-localized in sensory cutaneous neurons and are released locally in response
to injury and induce neurogenic inflammation [26]. These neuropeptides increase microvascular
permeability, enhance leukocyte extravasation, and increase cellular migration [27] resulting in wheal and
flare [28] and pain [29].
There is strong evidence that cell adhesion molecules play a major role in neurogenic inflammation [11].
The role of substance P and CGRP in increasing the expression of ICAM-1, VCAM-1, and P- and E-
selectins is well established.
In patients with atopic eczema, a single intracutaneous injection of Vasoactive Intestinal Polypeptide (VIP)
increased local blood flow in a dose-dependent manner, induced a wheal-and-flare reaction, and increased
pruritus [30]. These results have been corroborated in in vivo animal studies where subcutaneous injections
of VIP caused concentration-dependent plasma extravasation in rat skin, although this was significantly less
effective than identical concentrations of substance P [31].
The proinflammatory activity of VIP in human skin is also mediated by a direct action on inflammatory
mediators: the addition of VIP to human keratinocytes in culture increases in the intracellular expressions
of IL-1α, IL-8, and TNF-α mRNA [32]. IL-1 and IL-8 protein levels were also increased in culture medium
of VIP-treated cells. A similar effect of VIP was observed on human mast cells where it induced the release
of IL-8, TNF-α, and monocyte chemoattractant protein-1 [33].
Bradykinin (BK) and other kinins are produced at sites of tissue injury and contribute to inflammatory
processes including edema formation, vasodilatation, and pain [34]. BK receptors have been found on
vascular endothelial cells, smooth muscles, mast cells, and sensory neurons [34]. In the case of sensory
nerve activation, BK causes the release of proinflammatory peptides including substance P and CGRP.
Thus, the response to BK is mediated indirectly by neuropeptides including substance P and CGRP [35].
Furthermore, at least with respect to edema, BK and CGRP are synergistic [36].
Furthermore, BK increases plasma extravasation in knee joints, although in this case no edema was
observed [37]. Its actions are mediated through BK receptors and indirectly by release or amplification of
inflammatory mediators including neuropeptides. More recently, the role of ectoenzymes kininase and
metalloendopeptidase, which metabolize BK, has been shown to regulate active BK receptors on peripheral
sensory neurons [38].
Physical Exercise
Psychological stress triggers the release of proinflammatory mediators [11]. In at least one study, similar
phenomena were observed with both psychological stress and physical exercise [39], suggesting that both
factors mediate age-accelerating inflammatory processes. Several studies indicate that moderate-intensity
exercise is associated with a reduction in inflammatory mediators (perhaps by reducing the risk of anoxia)
[40–42]. It has therefore been suggested that the health benefits associated with physical exercise are due to
this anti-inflammatory response. This conclusion is supported by a recent study measuring the expression
of hundreds of neutrophil genes before and after a single 30-min cycling exercise at 80 % peak oxygen
uptake. Both proinflammatory and anti-inflammatory genes showed increased expression immediately
following this exercise regime [43].
However, the beneficial anti-inflammatory effects of exercise are critically dependent on the type of
exercise, its duration and intensity, the level of fitness, and the time when the markers of inflammation are
measured after the exercise regime. Since these factors vary from one study to another, results reported in
the scientific literature are sometimes difficult to compare. Typically, studies which employ more intense
exercise regimes use more fit individuals. One interesting study measured the inflammatory response to 20
min of treadmill exercise (65–70 % VO2 maximum) in younger/fit versus older/unfit individuals. This
regime increased leukocyte adhesion to endothelial cells in vitro only in younger and fitter subjects [44].
Other studies, using different exercise programs, however, have shown proinflammatory changes
immediately after relatively intense resistive exercise. In an attempt to use real-life exercises, wrestling
matches are often used as an acute, intense, resistive form of exercise for adolescents, as they are known to
induce muscle injury. This form of exercise was used to study the change in the number and type of
circulating leukocytes. Using Fluorescence Activated Cell Sorter (FACS) flow cytometry, an increase in the
density of lymphocytes expressing ICAM-1 and LFA-1 was observed immediately after a single 1.5-h
wrestling practice session [45]. Furthermore, results from the redistribution of other lymphocyte subsets
indicate an increase in memory T cells. These lymphocytes are intimately involved with inflammation since
they preferentially adhere to endothelial cells and are selectively recruited into inflammatory sites [46] and
express IL-6 [47].
In addition to leukocyte cell numbers, other studies have measured circulating levels of proinflammatory
markers following physical exercise in healthy individuals using a variety of regimes. These studies report
increases in ICAM-1/VCAM [48], IL-6 [49], TNF-α [50], PGE2 and substance P [51], iNOS and NF-κβ
[52], and C-reactive protein [53]. The acute phase inflammatory response typically occurs within the first
48 h but can be maintained for several days [54], depending on which inflammatory marker is measured.
These inflammatory responses occur in both young and old healthy individuals.
Sleep Deprivation
A lifestyle factor known to promote apparent skin fatigue and perhaps to accelerate aging, and which has
been proven to trigger inflammatory responses in healthy individuals, is sleep deprivation. Like extensive
physical exercise, sleep deprivation is associated with poor quality of life, mood changes, higher
psychological stress levels, and increased susceptibility to a variety of diseases (notably cardiovascular
disease). Both sleep deprivation and extensive physical exercise increase serum concentrations of
proinflammatory cytokines, circulating leukocytes, and soluble cell adhesion molecules. In a study where
volunteers were subjected to both 7 days of semicontinuous strenuous exercise and sleep deprivation (1
h/night), plasma levels of IL-6, TNF-α, and IL-1β were increased and isolated leukocytes showed enhanced
release of these proinflammatory markers when stimulated with Lipo Poly saccharides (LPS) [55]. Similar
results were obtained by numerous other investigators examining sleep deprivation alone, although severe
sleep deprivation protocols often keep subjects awake for extended periods of time with no sleep at all. In
these studies, sleep is typically monitored using polysomnography, and sleep quality is usually assessed by
subjective reports using the Pittsburgh Sleep Quality Index (PSQI). Results from these studies reveal that in
addition to the proinflammatory cytokines [55], increased plasma levels of ICAM-1 and E-selectin [56],
endothelin-1 [57], and PGE2 [58] were observed in healthy individuals.
Results from these studies are often complicated by the fact that circadian fluctuations in levels of
proinflammatory cytokines are known to exist. However, several studies have taken these circadian
variations into account and reached the same conclusions. In the case of IL-6, for example, sleep
deprivation leads to daytime oversecretion and nighttime undersecretion [59]. In general, similar
proinflammatory changes are reported in both young and old subjects, although it is worth considering that
chronic sleep impairment can contribute to age-related changes in inflammatory responses [60].
Conclusion
The micro-inflammatory hypothesis of skin aging was proposed as a mechanistic model [4]. The original
model showed that skin aging is accelerated by agents or treatments able to induce the synthesis and
mobilization of ICAM-1 in endothelial cells. Other factors induce the synthesis and the mobilization of
ICAM-1 in endothelial cells and/or in circulating leukocytes. These factors are now believed to be
accelerators of skin aging.
Thus, the micro-inflammatory mechanistic model of skin aging is a testable hypothesis open for
experimental challenge and experimental confirmation.
In recent years further experimental evidence supported the micro-inflammatory hypothesis of skin aging,
and inflammatory contribution to the aging of organs as diverse as the brain and articular joints has been
pointed out [61, 62].
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Title
Skin Aging: A Generalization of the Micro-inflammatory Hypothesis
Reference Work Title
Textbook of Aging Skin
Pages
pp 1-10
Copyright
2015
DOI
10.1007/978-3-642-27814-3_76-2
Online ISBN
978-3-642-27814-3
Publisher
Springer Berlin Heidelberg
Copyright Holder
Springer-Verlag Berlin Heidelberg
Topics
Dermatology
Geriatrics/Gerontology
Gynecology
Keywords
Factors of aging
ICAM-1
Cold stress
Ethanol
Neuromediators
Physical exercise
Sleep deprivation
Industry Sectors
Health & Hospitals
Biotechnology
Consumer Packaged Goods
Pharma
eBook Packages
Medicine
Editors
Miranda A. Farage (1)
Kenneth W. Miller (2)
Howard I. Maibach (3)
Editor Affiliations
1. Procter & Gamble Co.
2. Procter & Gamble Co.
3. Department Dermatology, University of California, San Francisco School of Medicine
Authors
Paolo U. Giacomoni (4)
Glen Rein (5)
Author Affiliations
4. Elan Rose Int., 161 Fashion lane, Tustin, CA, USA
5. Innovative Biophysical Technologies, PO Box 428, Ridgway, CO, USA
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