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Page 2 of 6 Sparavigna. Plast Aesthet Res 2020;7:14 I http://dx.doi.org/10.20517/2347-9264.2019.73

permanent muscle tone is established to neutralize incorrect relaxation of the skin through compensating
[4]
mechanisms .

EXTRACELLULAR MATRIX AGING MECHANISMS
Over time, various body structures lose function in an unpredictable sequence. The aging process is
thus not gradual nor uniform, and aging of the facies becomes even more complex due to the presence
of mimetic muscles connected to the skin. Prevention and treatment strategies must therefore account
for the above. The extracellular matrix (ECM) provides a commonality amongst these intricate processes
and has emerged as an area of research focuse for the development of more effective strategies against the
[5]
cutaneous signs of aging .

There are several molecular mechanisms underlying the aging process. Although still not completely
undisclosed, such knowledge is very important clinically and is the focus of many current studies. The main
extrinsic factor responsible is still photodamage, which causes the release of collagenases and neutrophil
elastases that result in fragmentation of structural and tonic proteins. Additionally, the cellular responses
of autophagy and Ubiquitin Proteasome systems are slowed. Current strategies of ECM remodeling
are thus based on eliminating cellular debris and the stimulation of neocollagenesis, elastogenesis and
[6-8]
glycosaminoglycans production through the use of various peptides and other active agents . As far as we
know, the main mechanism involved in preventing ECM changes is to keep free radical (i.e., ROS, reactive
oxygen species) production under control. ROS are characterized by the presence of an unpaired electron,
which is responsible for their instability and reactivity towards chemical structures to which they bind to
capture another electron. In turn, this process generates unstable molecules and promotes chain reactions
that ultimately, lead to functional and structural damage both within cells and extracellularly. ROS are
produced in cellular structures such as membranes, lysosomes, and mitochondria. Their formation can
be exacerbated by external agents including ultraviolet (UV) light, tobacco, infections and chemicals.
The human body protects itself from ROS by utilizing antioxidant enzymes (SOD), such as catalases and
glutathione peroxidases, which neutralize radicals and produce less harmful substances. However, as one’s
[9]
body declines with age, levels of these antioxidant enzymes also decrease correspondingly .
[10]
Alteration of matrix metalloproteinase (MMP) levels can lead to dysregulation of skin homeostasis .
In the elderly, the levels of zinc-dependent proteases increase, causing degradation of ECM protein
components. Physiologically, MMPs ensure protein turnover by stimulating the renewal of elastic and
collagen fibers. MMP levels are regulated by tissue inhibitors, the expression of which can be disturbed
by UV light, smoke and ROS. Protein-degrading MMPs in contrast, render connective tissue less elastic.
Another critical point to be considered is protein glycation, namely the reaction of glucose and other sugars
such as fructose. This post translational protein modification is associated with increased levels of glucose,
affects protein structure and function through increased cross-linking, and results in the formation of
“Amadori” and advanced glycation end products. Glycated proteins increase the formation of free radicals
and release toxic products and pro-inflammatory components that cause protein damage, which ultimately
is the fundamental cause of aging [11,12] . In women, menopause is associated with reduced ovarian endocrine
activity leading to an increase in follicular stimulating hormone and decrease in estrogen and progesterone,
with downstream metabolic disturbances. Alterations start from sexual organs and involve all tissues
targeted by estrogen, in a multisystem framework that affects all connective tissues. Collagen atrophy is the
[13]
main factor associated with menopause-related skin aging, which contributes to reduced skin elasticity .
In menopause, skin thickness and collagen content are initially reduced by 1.13% and 2.1% per year
respectively; type I and III collagen decrease by 30%. The skin is not only a target for sex-hormones but
also produces and releases estrogen from the enzymatic conversion of estrogen precursors. Estrogen exerts
a number of functions on connective tissue such as counteracting the degradation of collagen by MMPs
induced by UV light and ROS through the activation of the TGF-b1 pathway. Skin and bone thickness