biomolecules

Review
Human Skin Aging and the Anti-Aging Properties of Retinol
Taihao Quan

Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
[email protected]

Abstract: The skin is the most-extensive and -abundant tissue in the human body. Like many organs,
as we age, human skin experiences gradual atrophy in both the epidermis and dermis. This can
be primarily attributed to the diminishing population of epidermal stem cells and the reduction
in collagen, which is the primary structural protein in the human body. The alterations occurring
in the epidermis and dermis due to the aging process result in disruptions to the structure and
functionality of the skin. This creates a microenvironment conducive to age-related skin conditions
such as a compromised skin barrier, slowed wound healing, and the onset of skin cancer. This
review emphasizes the recent molecular discoveries related to skin aging and evaluates preventive
approaches, such as the use of topical retinoids. Topical retinoids have demonstrated promise in
enhancing skin texture, diminishing fine lines, and augmenting the thickness of both the epidermal
and dermal layers.

Keywords: skin aging; retinol; collagen; MMPs; TGF-β

1. Introduction
The passage of time is an inevitable aspect of life, and with it comes the process of aging.
In humans, aging is a natural progression that involves both physical and psychological
changes. Physically, the human body undergoes numerous transformations over time.
Cells and tissues gradually deteriorate, leading to a decline in the body’s ability to function
optimally. Organs may become less efficient, and the body may experience a decrease in
Citation: Quan, T. Human Skin strength, flexibility, and overall vitality. The physical signs of aging primarily appear on
Aging and the Anti-Aging Properties the skin, such as wrinkles, gray hair, and changes in skin texture. These indications tend to
of Retinol. Biomolecules 2023, 13, 1614. become increasingly apparent with advancing age. The visible and conspicuous signs of
https://doi.org/10.3390/ aging that manifest on our skin hold considerable importance in our social interactions and
biom13111614 visual appearance. Consequently, the condition and appearance of our skin can profoundly
Academic Editors: Joshua T. Morgan
influence our emotional and psychological well-being, consequently affecting our overall
and Shantanu Pradhan quality of life.
The skin serves a critical role as the primary defense barrier against various envi-
Received: 22 September 2023 ronmental threats, including exposure to solar ultraviolet (UV) radiation, physical and
Revised: 1 November 2023
chemical injuries, infections from pathogens, and the prevention of water loss. Human skin
Accepted: 2 November 2023
comprises two primary layers: the outer layer, referred to as the epidermis, and the under-
Published: 4 November 2023
lying layer, known as the dermis. The epidermis is primarily composed of keratinocytes,
which produce keratins and form the stratum corneum, the outer protective layer of the
skin. In contrast, the dermis contains fewer cells and consists mainly of proteins such as
Copyright: © 2023 by the author. collagen, elastin, fibronectin, and proteoglycans, which constitute the extracellular matrix
Licensee MDPI, Basel, Switzerland. (ECM). Collagen, making up approximately 90% of the skin’s dry weight, stands as the
This article is an open access article predominant protein. Dermal fibroblasts play a crucial role in synthesizing, organizing,
distributed under the terms and and maintaining the collagen-rich ECM within human skin.
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Biomolecules 2023, 13, 1614. https://doi.org/10.3390/biom13111614 https://www.mdpi.com/journal/biomolecules

Biomolecules 2023, 13, 1614 2 of 16

Like all other organs, human skin undergoes a natural aging process as time passes.
However, unlike many other organs, human skin is continually exposed to environmental
stresses and damage, particularly from sources such as solar UV radiation [1]. The aging of
the skin can be categorized into two distinct types based on their underlying causes: intrin-
sic or chronological aging, which occurs as a natural consequence of the passage of time,
and extrinsic aging, often referred to as photoaging, which results from external factors,
most notably UV radiation exposure [1]. Chronological or intrinsic aging encompasses
changes that occur in everyone due to the natural passage of time, while photoaging or
extrinsic aging is linked to repeated exposure to UV radiation from the Sun. Both intrinsic
and extrinsic aging are linked to a reduction in collagen production and an elevation in
collagen breakdown, albeit with differing underlying mechanisms. Consequently, both
intrinsic and extrinsic aging share common molecular characteristics.
Over time, both forms of aging accumulate gradually, with photoaging exerting its
influence on the skin alongside the changes brought about by chronological aging. The
regions of the face, neck, forearms, and lower legs display the most-noticeable signs of aging,
as they undergo a combination of both chronological aging and photoaging [1]. These areas
are also where skin diseases related to aging are most commonly observed. Histological and
ultrastructural studies provide compelling evidence that the morphology of human skin
undergoes significant alterations during the aging process. A prominent feature of aging in
older individuals is the thinning of both the epidermal and dermal layers [2]. Multiple lines
of evidence strongly support the notion that the age-related thinning of the epidermis has a
substantial impact on skin function. This thinning notably compromises the skin’s ability
to function as an effective protective barrier against environmental aggressors and to retain
moisture, resulting in increased moisture loss. In addition to the epidermis, the dermal
layer of aged skin also experiences thinning, primarily attributed to the loss of collagen,
which serves as the skin’s primary structural protein. These age-related changes in the
epidermis and dermis directly contribute to various skin conditions, including heightened
fragility [3], compromised vascular support [4], delayed wound healing [5,6], and an
increased susceptibility to cancer development [7–9]. Consequently, skin aging extends
beyond mere cosmetic concerns, as it significantly contributes to age-related skin issues.

2. Molecular Mechanisms of Human Skin Aging

Intrinsic skin aging is triggered by a variety of factors, which include genomic insta-
bility, cellular senescence, and the shortening of telomeres. On the other hand, extrinsic
aging is accelerated by external factors such as UV radiation, pollution, tobacco smoke,
and alcohol consumption. These external elements expedite the aging process, leading to
premature skin aging. As the aging process unfolds, the skin undergoes a series of changes,
often characterized by the thinning and flattening of the epidermis, along with damage
to the dermis due to the breakdown of collagen fibrils. Additionally, an inflammatory
environment referred to as “inflammaging” becomes apparent [2].

2.1. Epidermal Aging

The epidermis, primarily composed of keratinocytes, functions as a protective skin
layer that serves as a barrier between the body and the surrounding environment. With the
passage of time, a series of alterations transpire within the epidermis, collectively denoted
as epidermal aging. These modifications are characterized by the thinning of the epidermal
layer and the flattening of rete ridges (as depicted in Figure 1, on the right). The principal
cause of epidermal aging can be traced to a reduction in the proliferation and turnover of
keratinocytes, primarily linked to the depletion of interfollicular epidermal (IFE) stem cells.
Biomolecules2023,
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Figure
Figure 1.1. Human
Human skin
skin epidermal
epidermal andand dermal
dermal aging.
aging. Aging impacts human skin profoundly,profoundly, with
with
significant changes
significant changes inin its
its structure.
structure. Notable aspects of skin skin aging
aging encompass
encompass the the thinning
thinning of
of both
both
the
the epidermis and dermis, as well as the graying of hair and reduced hair density.
and dermis, as well as the graying of hair and reduced hair density. Epidermal Epidermal aging
is characterized
aging by diminished
is characterized expression
by diminished of COL17A1
expression in the skin
of COL17A1 stem
in the cell
skin niche,
stem cellaffecting various
niche, affecting
components such as the interfollicular epidermis (IFE), melanocyte stem cells
various components such as the interfollicular epidermis (IFE), melanocyte stem cells (McSCs), (McSCs), and hair
follicle stem cells (HFSCs). This reduction weakens the attachment of stem cells to the basement
and hair follicle stem cells (HFSCs). This reduction weakens the attachment of stem cells to the
membrane, ultimately contributing to epidermal aging. Meanwhile, dermal aging stems from dys-
basement membrane, ultimately contributing to epidermal aging. Meanwhile, dermal aging stems
function in dermal fibroblasts, including upregulation of CCN1, which drives elevated expression
from dysfunction
of MMPs, in collagen
leading to dermal fibroblasts,
degradation, including upregulation
an increased presence of ofproinflammatory
CCN1, which drives elevated
cytokines that
expression of MMPs, leading
foster an inflammatory to collagen degradation,
microenvironment (referred to asan“inflammaging”),
increased presence andofaproinflammatory
reduction in col-
cytokines that foster
lagen production an inflammatory
by impairing microenvironment (referred to as “inflammaging”), and a
TGF-β signaling.
reduction in collagen production by impairing TGF-β signaling.
Despite the broad recognition of epidermal aging, the mechanisms responsible for
Despite
this phenomenon the broad
remainrecognition of epidermal
elusive. COL17A1 hasaging,
been the mechanisms
of particular responsible
interest due to for this
its role
phenomenon remain elusive. COL17A1 has been of particular interest
in maintaining the homeostasis of the skin stem cells [2,10,11]. COL17A1 serves as a struc- due to its role in
maintaining the homeostasis of the skin stem cells [2,10,11]. COL17A1
tural element within the dermal–epidermal basement membrane [12], and it is synthe- serves as a structural
element
sized bywithin the dermal–epidermal
epidermal keratinocytes, not basement
fibroblastsmembrane
[13]. COL17A1 [12], and it is synthesized
exhibits its primary ex- by
epidermal keratinocytes, not fibroblasts [13]. COL17A1 exhibits its
pression in the uppermost extensions of the rete ridges area, where the niches for IFE stem primary expression
in theare
cells uppermost extensions
located (Figure of the rete
1). Research ridges
results have area, where athe
suggested niches for
reduction IFE expression
in the stem cells
are located (Figure
of COL17A1 1). Research
in human skin affectedresults haveintrinsic
by both suggested anda extrinsic
reduction in the expression
photoaging, as well of
as
COL17A1 in human skin affected by both intrinsic and extrinsic
in human skin exposed to acute UV radiation [13,14]. The decrease in COL17A1 levels photoaging, as well as in
human skin exposed to acute UV radiation [13,14]. The decrease in COL17A1 levels within
within the area specific to the rete ridges can potentially diminish the adherence of IFE
the area specific to the rete ridges can potentially diminish the adherence of IFE stem cells
stem cells to their designated locations, leading to their removal from the skin [13,15].
to their designated locations, leading to their removal from the skin [13,15]. Consequently,
Consequently, the deficiency of COL17A1 results in decreased rates of keratinocyte re-
the deficiency of COL17A1 results in decreased rates of keratinocyte renewal and the
newal and the development of thinner epidermal layers, which constitute the primary
development of thinner epidermal layers, which constitute the primary morphological
morphological characteristic of aging skin. Decreased COL17A1 expression also contrib-
characteristic of aging skin. Decreased COL17A1 expression also contributes significantly to
utes significantly to the aging process of hair [10,16], which is a natural and unavoidable
the aging process of hair [10,16], which is a natural and unavoidable process as individuals
process as individuals grow older. The most-prominent signs of hair aging are the graying
grow older. The most-prominent signs of hair aging are the graying of hair and a decrease
of hair and a decrease in hair density. Gray hair primarily occurs because of the depletion
in hair density. Gray hair primarily occurs because of the depletion of melanocyte stem
of melanocyte stem cells (McSCs), whereas hair loss is a consequence of diminished hair
cells (McSCs), whereas hair loss is a consequence of diminished hair follicle stem cells
follicle stem cells (HFSCs). COL17A1 is located in the basal membrane of hair follicles and
(HFSCs). COL17A1 is located in the basal membrane of hair follicles and can impact the
can impact the
maintenance maintenanceinofhair
of homeostasis homeostasis
follicle stemin hair
cells.follicle stem cells.
The age-related The age-related
decrease in COL17A1 de-
crease in COL17A1 expression directly affects the integrity of the
expression directly affects the integrity of the basement membrane, potentially disrupting basement membrane,
potentially
the homeostasisdisrupting
of hairthe homeostasis
follicle stem cells of and
haircontributing
follicle stem to cells
hair and contributing
aging. The absence to hair
of
COL17A1 can also weaken the junction between the epidermis and dermis, leadingand
aging. The absence of COL17A1 can also weaken the junction between the epidermis to
dermis, age-related
various leading to various age-related
skin changes, such skin changes, such
as heightened skin as heightened
fragility, skin fragility,
blistering, and delayed blis-
tering, and
wound delayed
healing. woundthe
Moreover, healing.
weakened Moreover,
junction the weakened
between junction between
the epidermis and dermis the epi-
can
dermis and dermis can result in the formation of wrinkles and sagging
result in the formation of wrinkles and sagging skin. Additionally, COL17A1 has been skin. Additionally,
COL17A1 has been linked to age-related skin conditions like bullous pemphigoid, an
Biomolecules 2023, 13, 1614 4 of 16

linked to age-related skin conditions like bullous pemphigoid, an autoimmune blistering

disease [12]. Ongoing research is examining the role of COL17A1 in epidermal aging, and
further investigations are necessary to fully understand the underlying mechanisms and to
explore potential interventions or treatments.

2.2. Dermal Aging

The largest portion of the skin’s volume is taken up by the dermis, and it has a crucial
function in supplying mechanical strength and physical durability. The dermis mainly con-
sists of tightly woven collections of collagen fibrils, creating an intricate three-dimensional
ECM. Dermal fibroblasts, residing within and around the collagen bundles, are responsi-
ble for producing this collagenous ECM. As we grow older, there are adverse alterations
that occur in both collagen bundles and fibroblasts. These alterations encompass the
fragmentation and disarray of collagen fibrils, decreased collagen synthesis, and the estab-
lishment of an inflammatory microenvironment within the dermis, commonly referred to
as “inflammaging” [2,17]. These age-related alterations in the dermal microenvironment
directly contribute to various skin conditions, including increased fragility [3], impaired
support for blood vessels [4], compromised wound healing [5,6], and the promotion of can-
cer development [2,7,8]. As outlined below, the aging process in the dermis can mainly be
attributed to three specific molecular events: (1) the breakdown of collagen fibers due to the
actions of matrix metalloproteinases (MMPs), (2) reduced collagen production caused by
compromised TGF-β signaling, and (3) the presence of an inflammatory microenvironment
known as “inflammaging” (Figure 1, right).

2.2.1. Dermis Damage Caused by the Age-Related Increase in MMPs Leading to

Collagen Fragmentation
The fragmentation, lack of organization, and reduction in the collagen-rich ECM are
distinctive features of aged human skin [1]. MMPs constitute a class of proteases that play
a specific role in breaking down ECM proteins. Presently, the human MMP gene family
comprises more than 20 members, each displaying unique structures and preferences
for substrates [18]. These MMPs are implicated in a variety of natural and pathological
processes linked to ECM degradation. In human skin, MMP1, also known as collagenase 1,
is predominantly synthesized by dermal fibroblasts [19]. MMP1 serves as a crucial enzyme
responsible for initiating the breakdown of the original collagen fibrils. In young skin,
the levels of MMP1 are minimal; however, a significant increase in aged skin dermis is
experienced [19,20]. Alongside MMP1, several other MMPs also show heightened levels
in the aged dermis [20]. The MMP-mediated fragmentation of the collagen-rich ECM
leads to irreversible disruption of the dermis’s structural and mechanical integrity. This
disruption has detrimental effects on the skin’s ability to resist bruising and impacts the
functional interactions between dermal cells and the ECM. These detrimental changes are
believed to significantly contribute to several noticeable clinical characteristics of aging
skin, such as thinning, increased fragility, compromised wound healing, and an elevated
risk of developing carcinoma.

2.2.2. Dermis Thinning Due to Age-Related Impairment of TGF-β Signaling, Leading to

Decreased Collagen Production
Collagen plays a crucial role in maintaining the skin’s structural integrity and strength.
The diminished synthesis of collagen stands as a key factor contributing to the thinning
of the dermis in aging skin [2]. Transforming growth factor-beta (TGF-β), a versatile
cytokine, controls various cellular activities such as cell growth and differentiation, and
serves as a primary regulator of ECM components like collagen and elastin [21]. In aged
human skin, there is a decrease in the expression of the TGF-β Type II receptor (TβRII)
within dermal fibroblasts, leading to impaired TGF-β signaling [22]. This impairment
in TGF-β signaling can significantly impact the aging process of the skin by inhibiting
collagen production. Diminished TGF-β signaling can result in the increased activity
of MMPs, which subsequently break down collagen and other ECM proteins. Aberrant
Biomolecules 2023, 13, 1614 5 of 16

TGF-β signaling can also play a part in inflammaging, a phenomenon recognized for
hastening the aging process. Overall, impaired TGF-β signaling can result in decreased skin
elasticity, firmness, and resilience. This can manifest as sagging, wrinkles, fine lines, and
an overall deterioration in skin quality, all of which are characteristic traits of skin dermal
aging. Strategies aimed at addressing impaired TGF-β signaling and its consequences on
skin aging may involve targeted therapies and interventions designed to boost collagen
production, regulate the ECM, and mitigate skin inflammation.

2.2.3. The Impact of CCN1 Protein on the Aging Process of Human Skin
The role of the CCN1 protein (also known as CYR61) in human skin aging has gained
significant attention in recent years [22]. CCN1 is the first member of the CCN protein
family, which has six members designated as CCN1 to CCN6 [23–25]. CCN1 has been re-
ported to regulate cell adhesion and migration, chemotaxis, the production of inflammatory
mediators, cell–matrix interactions, the synthesis of ECM proteins, and wound responses,
in a variety of cells in culture and animal models [23,26,27]. Elevated CCN1 expression can
lead to a cellular phenotype characterized by enhanced secretion of cytokines, chemokines,
growth factors, and proteases [28–31].
In human skin, CCN1 is predominantly expressed in dermal fibroblasts and signif-
icantly elevated in aged human skin [32]. Remarkably, increased CCN1 expression by
dermal fibroblasts has a detrimental impact on the dermal microenvironment by promoting
the senescence-associated secretory phenotype (SASP) [33,34]. The CCN1 protein is emerg-
ing as a pivotal player in human skin aging, influencing collagen production, oxidative
stress, and inflammation [22]. Elevated CCN1 contributes to skin dermal aging through sev-
eral distinct mechanisms [22,32]: it reduces the expression of dermal collagen by inhibiting
the TGF-β signaling pathway, resulting in a thinner dermis; it increases the expression of
multiple transcription factors via Activator Protein 1 (AP-1), leading to a damaged dermis;
it enhances proinflammatory cytokine expression by inducing the generation of reactive
oxygen species (ROSs), leading to inflammaged skin.
As such, CCN1-induced alterations of the dermal microenvironment account for many
of the characteristic features of tagged human skin. A comprehensive understanding of
CCN1’s functions in the skin offers valuable insights into the mechanisms of skin aging.
Further research is needed to explore the therapeutic potential of targeting CCN1, which
may provide innovative strategies for addressing age-related skin concerns and maintaining
healthier, more-youthful skin.

2.2.4. Inflammaging Due to Increased Expression of Multiple Cytokines in Aged

Human Skin
Inflammaging is a term coined by combining “inflammation” and “aging”, describ-
ing a persistent, low-grade inflammatory state, which tends to intensify as people grow
older [35]. This concept is rooted in the fields of gerontology and immunology, highlight-
ing the phenomenon where the immune system becomes increasingly active, resulting in
more-frequent and sustained inflammatory responses as individuals age. This inflamma-
tory state can affect various tissues and organs throughout the body, often manifesting as a
systemic condition with widespread impacts. Elevated levels of pro-inflammatory markers
like interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP)
are frequently observed in older individuals experiencing inflammaging. IL-6 has become
a widely adopted indicator of inflammaging and is considered a defining characteristic of
chronic illness [36].
Notably, studies have indicated an increase in these inflammaging-related cytokines in
the skin of aged individuals in vivo [33], which can contribute to skin aging. Inflammaging
accelerates skin aging by promoting inflammation, breaking down collagen, and inhibiting
collagen production in the skin. While the exact sources of these inflammaging-related
cytokines are not fully understood, they can originate from various cell types within the
body, including immune cells and various tissues. Considering that the skin is the body’s
Biomolecules 2023, 13, 1614 6 of 16

largest organ and is frequently subjected to stresses from both internal factors (oxidative
stress) and external factors (UV irradiation), it is conceivable that the skin plays a significant
role in producing inflammaging-related cytokines [37,38]. The activator protein-1 (AP-1)
transcription factor plays a pivotal role in the expression of numerous cytokines. The
activation and induction of the AP-1 transcription factor primarily occur through the
mitogen-activated protein kinase (MAPK) pathways. The activation of MAP kinases
triggers the expression of both c-Jun and c-Fos, which are the major components of the
AP-1 transcription factor. Interestingly, research has shown that c-Jun is upregulated in
aged human skin, while c-Fos is consistently expressed [39], suggesting that increased c-Jun
activity may be a key driver behind the heightened production of inflammaging-related
cytokines in the skin of elderly individuals.
Inflammaging negatively affects the age-related decline in skin barrier function [37,40].
Inflammaging disrupts the epidermal lipid structure, rendering it more vulnerable to de-
hydration and external stressors. Interestingly, a study by Hu et al. demonstrated that
disrupting the epidermal barrier function in young mice led to elevated levels of proinflam-
matory cytokines in both the skin and serum [38,41]. Conversely, restoring the epidermal
barrier function in aged mouse skin resulted in reduced circulating cytokine levels. These
findings imply that the epidermis could have a significant role in the age-related systemic
inflammation observed in inflammaging. As the source of systemic inflammatory cytokines
in inflammaging remains elusive, it is intriguing to explore whether enhancing epidermal
barrier function could similarly alleviate inflammaging in humans. The results of such
research could provide a potential pathway to mitigate inflammaging and, subsequently,
reduce the risk of age-related diseases. In this context, the study conducted by Hu et al.
serves as a proof of concept, indicating that preserving epidermal barrier function is an ef-
fective approach to reducing systemic inflammation as individuals age. Understanding the
mechanisms underlying this phenomenon is pivotal for developing strategies to counteract
its effects. Ongoing research in this field continually furnishes valuable insights into the
connections between inflammation and skin aging, offering novel possibilities for potential
interventions and treatments.

2.2.5. Autophagy and Skin Aging

Autophagy is a crucial cellular process that maintains homeostasis by eliminating
damaged organelles and protein aggregates or recycles cytoplasmic components through
lysosomes [42]. Three distinct types of autophagy exist: macroautophagy, microautophagy,
and chaperone-mediated autophagy. In the process of organismal aging, autophagy and
various other lysosomal transport pathways demonstrate diminished activity [43–45]. The
skin, being an organ with limited access to nutrients, relies on autophagy to preserve its
scarce resources and maintain homeostasis. Recent research has demonstrated the critical
role of autophagy in maintaining skin homeostasis, and the dysregulation of autophagic
processes have been associated with age-related skin conditions [46,47]. Skin stem cells,
melanocytes, Merkel cells, and sweat gland secretory cells all rely on autophagy to maintain
their homeostasis [48].
In the dermis, autophagy has been linked to age-related cellular senescence and
alterations in the collagenous ECM [48–50]. The role of autophagy in the process of dermal
aging is a subject of significant interest in the fields of skin biology and skin aging [51,52].
As skin undergoes the aging process, the effectiveness of autophagy tends to diminish.
Consequently, cells become less capable of efficiently removing damaged or malfunctioning
cellular components. This decline in autophagic activity results in the buildup of cellular
waste, including misfolded proteins and impaired mitochondria. This accumulation, in
turn, can trigger oxidative stress and inflammation, which are characteristic features of
aging skin. Autophagy also plays a pivotal role in the breakdown of collagen and elastic
fibers within the dermal layer of the skin. A reduction in autophagy can lead to the
accumulation of damaged collagen and elastin, contributing to the development of sagging
skin and wrinkles.
Biomolecules 2023, 13, 1614 7 of 16

The decline in proteostasis, which refers to the maintenance of protein quality control
and integrity, as a consequence of aging, has been reported [53]. When the ability to clear
oxidized and misfolded proteins diminishes, it can trigger the activation of DNA damage
repair (DDR) pathways, subsequently leading to the initiation of cellular senescence [54]
and the secretion of senescence-associated secretory phenotype (SASP) factors [55].
Autophagy in fibroblasts is essential for eliminating lipofuscin, which is an accu-
mulation of proteins and lipids that have become misfolded and modified [56]. The
compromised autophagic activity observed in senescent human fibroblasts [57] could be
linked to the abnormal buildup of lipofuscin, which is known to be the root cause of
age-related pigmentation irregularities.
Autophagy also plays a role in maintaining the integrity of the epidermal protective
barrier by regulating the regeneration of skin cells, especially those located in the outermost
layer of the epidermis [46,58]. The reduced autophagic activity associated with aging may
lead to a weakened skin barrier, rendering the skin more susceptible to environmental
stressors and greater moisture loss.
One of the most well-understood aspects of autophagy in skin aging is mitophagy [59],
a form of selective autophagy that targets damaged mitochondria. As we age, the efficiency
of mitophagy may decline, leading to the accumulation of dysfunctional mitochondria,
which further exacerbates skin aging.
Several key regulators of autophagy in skin cells have been identified, including the
mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and
autophagy-related (ATG) genes [43,60,61]. These molecules control the initiation and
progression of autophagy, making them attractive targets for potential interventions to
combat aging. Pharmaceutical agents targeting autophagy regulators like mTOR and
AMPK are under investigation for their potential to promote skin health and slow the aging
process [62].
Autophagy in the skin is a vital process that maintains skin homeostasis. Its decline
with age contributes to various aspects of skin aging, including the breakdown of structural
components, diminished barrier function, and increased susceptibility to environmental
damage. Exploring strategies to boost autophagy in the skin presents exciting possibilities
for mitigating the signs of aging and promoting overall skin health.

2.2.6. A Mouse Model of Dermal Aging Achieved through the Fibroblast-Specific

Expression of Human MMP1
Two mouse models of dermal aging were recently reported by the selective ex-
pression of human MMP1 [9] or human CCN1 [63] in dermal fibroblasts driven by the
fibroblast-specific collagen1A2 (Col1a2) promoter and upstream enhancer [64,65]. These
mouse models of dermal aging are based on the human skin in vivo observations that
both MMP1 and CCN1 are significantly elevated in dermal fibroblasts of aged human skin
and drive dermal aging by establishing an aberrant dermal ECM microenvironment [22].
At six months of age, both Col1a2;hMMP1 [9] and Col1a2;hCCN1 [63] mice displayed
many of the hallmarks of aged human skin dermis. Importantly, Col1a2;hMMP1 and
Col1a2-hCCN1 mice exhibit an enhanced preponderance of keratinocyte cancer in mouse
models of skin carcinogenesis: cutaneous two-stage chemical carcinogenesis and inducible
HRas-oncogene-driven tumors (Figure 2).
A noteworthy discovery in this dermal aging mouse model was the impaired spread-
ing and morphology of fibroblasts in an environment with fragmented collagen fibrils.
Dermal fibroblasts are naturally situated within the collagen-rich ECM microenvironment,
and their direct interactions with collagen fibrils allow them to generate mechanical forces
that govern their shape and function. In aging skin, the breakdown of collagen fibrils
does not offer sufficient support for fibroblast attachment, leading to decreased spreading
of fibroblasts and diminished mechanical strength. In this state, fibroblasts take on an
aged phenotype, perpetuating collagen degradation, reduced collagen production, and the
emergence of an inflammaging milieu [66]. These findings were substantiated in hMMP1
Biomolecules 2023, 13, 1614 8 of 16

transgenic mice, where the loss of fibroblast spreading and an altered morphology led to
decreased collagen production, downregulated TβRII expression, upregulated expression
of several MMPs, and an increase in inflammatory cytokines associated with inflammaging.
Additionally, hMMP1 transgenic mice showed a significantly higher susceptibility to devel-
oping skin papillomas, underscoring the pivotal role of MMP1 expression in fibroblasts in
Biomolecules 2023, 13, x FOR PEER REVIEW 8 of 17
dermal aging and the creation of a dermal environment conducive to keratinocyte tumor
development, a phenomenon often observed in the elderly population [67].

Figure2.
Figure Mousemodels
2.Mouse modelsofofdermal
dermalaging.
aging.Illustration
Illustration outlining
outlining thethe establishment
establishment of of mouse
mouse mod-
models
simulating dermal
els simulating aging
dermal through
aging fibroblast-specific
through expression
fibroblast-specific of (a)catalytically
expression active
of (a) catalytically human
active hu-
MMP1 (Col1a2;hMMP1)
man MMP1 and (b)
(Col1a2;hMMP1) andhuman CCN1CCN1
(b) human (h Col1a2;hCCN1) under under
(h Col1a2;hCCN1) the regulation of the fibro-
the regulation of the
blast-specific Col-1a2
fibroblast-specific promoter
Col-1a2 andand
promoter enhancer.
enhancer. TheThe
fibroblast-specific
fibroblast-specificexpression
expressionofofhMMP1
hMMP1or or
hCCN1
hCCN1leads
leadstotothe
thedegradation
degradationof ofcollagen
collagenfibrils,
fibrils,disrupting
disruptinginteractions
interactionsbetween
betweenfibroblasts
fibroblastsand
and
collagen. This disruption results in diminished cell spreading and subsequent adaptive functional
collagen. This disruption results in diminished cell spreading and subsequent adaptive functional
changes, contributing to the perpetuation of dermal collagen degradation through the induction of
changes, contributing to the perpetuation of dermal collagen degradation through the induction
multiple MMPs. Additionally, it inhibits collagen synthesis by interfering with TGF-β signaling and
of multiple
promotes MMPs. Additionally,
inflammaging it inhibits
by triggering collagen synthesis
the production of variousby interferingproinflammatory
age-related with TGF-β signaling
cyto-
kines. Consequently, dermal aging creates a microenvironment conducive to theproinflammatory
and promotes inflammaging by triggering the production of various age-related development of
cytokines.
skin tumors.Consequently, dermal aging creates a microenvironment conducive to the development of
skin tumors.
A noteworthy discovery in this dermal aging mouse model was the impaired spread-
ing and In essence, the collagen-rich
morphology of fibroblasts dermal
in anmicroenvironment
environment withplays a criticalcollagen
fragmented role in shaping
fibrils.
the phenotype and behavior of fibroblasts. The age-related decline
Dermal fibroblasts are naturally situated within the collagen-rich ECM microenviron- in fibroblast function
can largely
ment, be attributed
and their to their adaptation
direct interactions with collagento the degeneration
fibrils allow themoftothe collagen-rich
generate ECM
mechanical
microenvironment. These findings introduce a novel concept, suggesting
forces that govern their shape and function. In aging skin, the breakdown of collagen fi- that age-related
fibroblast
brils does dysfunction primarily
not offer sufficient reflectsfor
support adaptive
fibroblastresponses to theleading
attachment, deteriorating dermal
to decreased
spreading of fibroblasts and diminished mechanical strength. In this state, fibroblastsontake
ECM microenvironment, thus establishing an “outside-in adaptation” perspective the
mechanism of dermal aging. This perspective is rooted in the fundamental
on an aged phenotype, perpetuating collagen degradation, reduced collagen production, principle of cell
biology,
and emphasizing
the emergence theinflammaging
of an intrinsic connection
milieu between
[66]. Theseform and function.
findings The form and
were substantiated in
function of dermal fibroblasts are fundamentally dictated by the structure, composition,
hMMP1 transgenic mice, where the loss of fibroblast spreading and an altered morphol-
organization, and mechanical properties of the dermal ECM they inhabit. Therefore, the
ogy led to decreased collagen production, downregulated TβRII expression, upregulated
collagen-rich ECM microenvironment serves not only as a physical scaffold, but also as a
expression of several MMPs, and an increase in inflammatory cytokines associated with
critical regulator of fibroblast behavior.
inflammaging. Additionally, hMMP1 transgenic mice showed a significantly higher sus-
ceptibility to developing
3. The Molecular skin papillomas,
Foundation Underlyingunderscoring
the Anti-Aging the Properties
pivotal roleof ofRetinol
MMP1 expres-
sion in fibroblasts in dermal aging and the creation of a dermal environment conducive to
Numerous approaches have been proposed to hinder the aging process and revitalize
keratinocyte tumor development, a phenomenon often observed in the elderly population
aged skin, yet presently, there are no reliable and secure treatments available to counteract
[67].
skin atrophy in older individuals. Retinol, a derivative of vitamin A, has demonstrated its
In essence, the collagen-rich dermal microenvironment plays a critical role in shaping
effectiveness in promoting various anti-aging benefits for the skin and is predominantly
the phenotype and behavior of fibroblasts. The age-related decline in fibroblast function
favored within the category of retinoids [68,69]. It can stimulate collagen synthesis, inhibit
can largely be attributed to their adaptation to the degeneration of the collagen-rich ECM
MMP activity, reduce oxidative stress, and modulate gene expression [68,70,71]. Retinol has
microenvironment.
exhibited efficacy inThese findingsthe
ameliorating introduce a novel concept,
visual manifestations ofsuggesting thatand
both intrinsic age-related
extrinsic
fibroblast dysfunction primarily reflects adaptive responses to the deteriorating
aging, such as wrinkles, fine lines, and irregular pigmentation [68,72–74]. The mechanisms dermal
ECM microenvironment, thus establishing an “outside-in adaptation” perspective
of retinol action may involve the activation of retinoic acid receptors (RARs) and retinoid on theX
mechanism of dermal
receptors (RXRs), whichaging. Thisgene
regulate perspective is rooted
transcription andin the
cell fundamental principle
differentiation. Retinol mayof
cell biology, emphasizing the intrinsic connection between form and
also modulate the activity of growth factors and cytokines involved in ECM turnover and function. The form
and function of Retinoids,
inflammation. dermal fibroblasts are to
which refer fundamentally
a group of vitamindictatedA by the structure,
derivatives, composi-
are among the
tion, organization, and mechanical properties of the dermal ECM they inhabit. Therefore,
the collagen-rich ECM microenvironment serves not only as a physical scaffold, but also
as a critical regulator of fibroblast behavior.

3. The Molecular Foundation Underlying the Anti-Aging Properties of Retinol

Biomolecules 2023, 13, 1614 9 of 16

most-extensively studied ingredients in skincare for combatting aging and enhancing the
appearance of mature skin. Retinoic acid (RA) is the active form of vitamin A and is also
called retinol (ROL). ROL serves as a precursor to retinoic acid and can be converted into
its active metabolite within human skin. When retinol is applied topically to human skin,
it can penetrate the skin and undergo sequential conversion to retinaldehyde and then to
retinoic acid [75]. ROL undergoes a two-step conversion process to become retinoic acid.
In the first step, the enzyme alcohol dehydrogenase (ADH) catalyzes the conversion of
retinol to retinaldehyde, while in the second step, retinaldehyde dehydrogenase (RALDH)
converts retinaldehyde to retinoic acid. Studies have demonstrated that vitamin A and
its metabolites can enhance the condition of skin that has aged due to both chronological
factors and sun exposure by stimulating the formation of new collagen and preventing its
breakdown [68,71]. Topical ROL has shown remarkable anti-skin aging effects, suggesting
that ROL is a promising and safe anti-aging natural product.
The precise cellular and molecular mechanisms underlying the anti-aging benefits of
retinoic acid are still not entirely understood. Additionally, when compared to retinoic acid,
there is a scarcity of research investigating the molecular foundation of the anti-aging effects
of topical retinol in human skin in live subjects. Understanding the molecular mechanisms
through which retinoids enhance aging in human skin has been difficult because of the
lack of appropriate in vitro models. The binding of retinoic acid to the retinoid receptors
exerts its biological actions. Cells within both the epidermal and dermal layers possess the
complete complement of proteins and receptors essential for the physiological actions of
vitamin A metabolites in the skin. Nevertheless, when primary keratinocytes or dermal
fibroblasts are cultivated as monolayers, their reactivity to retinoic acid treatment is modest.
This restricted responsiveness can be attributed, in part, to the diminished presence of
nuclear retinoid receptors, which are instrumental in modulating the expression of genes
under the control of retinoids. Skin-equivalent cultures present a promising avenue for
investigating the regulatory role of retinoids in collagen homeostasis. These cultures feature
stratified and differentiated keratinocytes, representing the epidermal layer, layered atop a
collagen lattice primarily comprising Type I collagen. Dermal fibroblasts are embedded
within this lattice to mimic the dermal layer. When subjected to retinoic acid treatment,
these skin-equivalent cultures exhibit a substantial increase in the number of keratinocyte
layers and elicit a dermal response akin to the effects observed when retinoic acid is topically
applied to human skin in vivo [76]. Consequently, skin-equivalent cultures hold significant
potential as a valuable model for delving into the mechanisms by which retinoids enhance
the appearance of aging skin in humans.

3.1. Increasing the Thickness of the Epidermis and the Vascularity of the Dermis in Aged Human
Skin In Vivo Using Topical ROL: Stimulating the Growth of Epidermal Keratinocytes and Dermal
Endothelial Cells
The application of topical ROL to aged human skin in a live setting has been found
to significantly enhance the thickness of the epidermis by stimulating the proliferation of
epidermal keratinocytes [71,77]. Moreover, in addition to improving epidermal thickness,
topical ROL has shown a notable increase in the proliferation of endothelial cells and blood
vessels in the papillary dermis [71,78,79]. These findings suggest that the topical application
of ROL results in the thickening of the epidermal layer and the development of fresh blood
vessels within the dermis. This occurs through the stimulation of the growth of epidermal
keratinocytes and dermal endothelial cells in the context of aging human skin in vivo.
The AP-1 transcription factor is of paramount importance in fostering the proliferation of
keratinocytes in response to growth factors, cytokines, and various stimuli [1]. Since the
AP-1 complex consists of c-Jun and c-Fos, it has been observed that topical ROL significantly
increases the expression of the epidermal-specific c-Jun protein, leading to a substantial
increase in epidermal thickness. In contrast, there has been no observed change in the
expression of c-Fos protein with topical ROL treatment. These findings suggest that topical
ROL enhances the activity of the epidermal-specific c-Jun transcription factor, thereby
stimulating the proliferation of epidermal keratinocytes in aged human skin in vivo.
Biomolecules 2023, 13, 1614 10 of 16

3.2. Topical ROL Improves the Dermal ECM Microenvironment by Promoting the Production of
Collagenous ECM in Aged Human Skin In Vivo
Topical ROL treatment increases Type I collagen expression, the major structural
protein in the skin [71]. Besides the increase in Type I collagen, the application of topical
ROL significantly enhances the expression of fibronectin and tropoelastin. In aged human
skin in vivo, topical ROL effectively activates dermal fibroblasts, leading to the substantial
production of collagenous ECM through the activation of the TGF-β/Smad pathway,
which is the principal regulator of ECM production. Topical ROL administration causes a
significant increase in TGF-β1 mRNA expression and a decrease in inhibitory Smad7, while
other components of the TGF-β pathway remain unaffected. Additionally, topical ROL
leads to an increase in the expression of connective tissue growth factor (CTGF/CCN2),
which is substantially reduced in the dermis of aged individuals and contributes to the
decline in collagen production associated with aging. These findings indicate that topical
ROL stimulates the production of ECM by dermal fibroblasts through the upregulation of
the TGF-β/CTGF pathway in aged human skin.
In addition to the upregulation of TGF-β/CTGF pathway, retinoic acid significantly re-
duces CCN1 gene expression in both naturally aged and photoaged human skin in vivo [76].
CCN1 is a negative regulator of collagen homeostasis by inhibiting the TGF-β/CTGF path-
way and stimulating MMPs’ induction [22,32]. These data suggest that the mechanism
by which topical ROL improves aged skin, through increased collagen production and
inhibition of MMPs, may involve the downregulation of CCN1.
In aging skin, decreased vascularity and thinning of the epidermis are substantial
factors contributing to skin fragility and hindered wound healing. Therefore, topical ROL
not only enhances ECM production, but also improves the dermal microenvironment by
promoting the expansion of vasculature through endothelial cell proliferation in aged
human skin. An age-related reduction in cutaneous vasculature has been reported [80,81].
The increased vascularity of the dermis induced by topical ROL can improve skin blood
flow and create a more-favorable microenvironment for the homeostasis of the epidermis
and dermis. Furthermore, the promotion of epidermal keratinocyte proliferation and the
restoration of ECM production by topical ROL could create a supportive environment for
the growth of endothelial cells and the development of dermal blood vessels. Epidermal
keratinocytes are a significant source of vascular endothelial growth factor (VEGF), a
powerful factor in promoting angiogenesis [81]. Furthermore, increased production of
dermal ECM has been demonstrated to stimulate the proliferation of endothelial cells. As a
result, the augmented dermal vascularity facilitated by ROL may have a significant impact
on the homeostasis of both the epidermis and dermis.

3.3. Topical ROL Improves Hyperpigmentation

Hyperpigmentation is a common dermatological concern affecting individuals of all
skin types and backgrounds. Hyperpigmentation, characterized by the darkening of certain
areas of the skin due to excess melanin production, is a common cosmetic concern that
affects a wide range of individuals [82]. This condition is often associated with sun damage,
post-inflammatory hyperpigmentation, melasma, and age-related changes.
While there are numerous treatment options available, retinoic acid has emerged as
a potent and versatile agent in the fight against this aesthetic concern [83–85]. Retinoic
acid functions primarily through its influence on gene expression and cellular differen-
tiation, impacting melanogenesis and melanin distribution [86–88]. The mechanisms by
which retinoic acid improves hyperpigmentation include the following: the regulation of
melanin production: retinoic acid downregulates the activity of tyrosinase, a key enzyme
in melanin synthesis, reducing the production of melanin and its transfer to keratinocytes;
the acceleration of cellular turnover: by promoting skin cell turnover, retinoic acid helps
to exfoliate pigmented cells, revealing fresh, less-pigmented skin beneath; the inhibition
of inflammation: retinoic acid has anti-inflammatory properties, making it effective in
addressing post-inflammatory hyperpigmentation; collagen stimulation: retinoic acid can
Biomolecules 2023, 13, 1614 11 of 16

improve skin texture, helping to mitigate the appearance of pigmented lesions and fostering
an overall youthful complexion. As such, retinoic acid has emerged as a powerful ally in
the battle against hyperpigmentation.

3.4. Side Effects and Precautions

The retinoid family consists of both naturally occurring and synthetic analogues of
retinol [89]. While it can be highly effective, it is essential to be aware of potential side
effects and to take necessary precautions when using retinoic acid. Topical ROL offers a
significant advantage over retinoic acid in terms of a reduced occurrence of side effects,
including erythema, scaling, dryness, and itching [90,91]. While a significantly higher
concentration of ROL (0.4%) is required to attain similar outcomes as observed with topical
retinoic acid, ROL triggers identical histological alterations (epidermal thickening and
dermal ECM production) as retinoic acid, all without causing retinoid irritation, which is
the most-prevalent side effect associated with retinoids. On the other hand, inappropriate
or excessive use of topical ROL may also result in potential side effects. These commonly
include skin dryness, redness, and peeling, which can cause discomfort. However, these
side effects typically diminish over time as the skin adjusts to the product. Contrasted with
topical ROL treatment, the consumption of excessive amounts of oral retinol can lead to
detrimental health consequences, including symptoms like nausea, vomiting, headaches,
and dizziness (LD50 1.5 g/kg in mouse) [92]. There are several common retinol derivatives
used in skin topical treatments, including retinyl palmitate, retinol, retinaldehyde, adapa-
lene, tretinoin, and tazarotene [89]. Retinyl palmitate and retinol are considered milder
forms of retinoids, while retinaldehyde, adapalene, tretinoin, and tazarotene are stronger
and more effective in treating skin concerns such as acne, deep wrinkles, and hyperpigmen-
tation. It is important to note that retinol and tretinoin are among the most-well-known
topical applications with strong clinical evidence of their anti-aging properties [89].

3.5. Summary
Figure 3 presents the fundamental molecular mechanisms responsible for the anti-aging
effects of retinol in aging human skin. The topical application of ROL to aged human skin
leads to remarkable transformations in both the epidermis and dermis, predominantly
influencing three key categories of skin cells: epidermal keratinocytes, dermal fibroblasts,
and endothelial cells. Topical ROL exerts a substantial influence on the thickness of
the epidermis by activating IFE stem cells and fostering the proliferation of epidermal
keratinocytes. This process involves the activation of the c-Jun transcription factor, which
plays a crucial role in driving keratinocyte proliferation. In addition to the effects on
the epidermis, topical ROL significantly improves the microenvironment of the dermal
ECM by activating fibroblasts and stimulating the formation of dermal blood vessels
through endothelial cell proliferation. From a mechanistic perspective, the application of
topical ROL triggers the activation of the TGF-β/CTGF pathway, a pivotal regulator of
ECM equilibrium. This activation results in an increased deposition of mature collagen
within aging human skin. Moreover, the augmented dermal vascularization induced by
topical ROL fosters improved circulation in the skin, thereby establishing a more-conducive
microenvironment for both the proliferation of epidermal keratinocytes and the activation
of dermal fibroblasts. Furthermore, the proliferation of epidermal keratinocytes may also
contribute to the development of dermal blood vessels by promoting the expression of
VEGF. We propose that the interconnected relationships among keratinocyte proliferation,
endothelial cell growth, and dermal fibroblast activation create a mutually reinforcing
environment, which may account for the remarkable anti-aging effects of retinol in aging
human skin.
 vation of dermal fibroblasts. Furthermore, the proliferation of epidermal keratinocytes
may also contribute to the development of dermal blood vessels by promoting the expres-
sion of VEGF. We propose that the interconnected relationships among keratinocyte pro-
liferation, endothelial cell growth, and dermal fibroblast activation create a mutually re-
inforcing environment, which may account for the remarkable anti-aging effects of retinol
Biomolecules 2023, 13, 1614 12 of 16
in aging human skin.

Figure 3. Topical
Topical ROLROLexerts
exertsanti-aging
anti-agingeffects
effectsininaged
agedhuman
humanskin.
skin.Topical
TopicalROL
ROL triggers changes
triggers changes in
in
thethe epidermis
epidermis andand dermis,
dermis, impacting
impacting keykey
skinskin
cell cell types:
types: epidermal
epidermal keratinocytes,
keratinocytes, dermaldermal fibro-
fibroblasts,
blasts, and endothelial
and endothelial cells. cells. It boosts
It boosts epidermal
epidermal thickness
thickness by activating
by activating IFEIFE
stem stem cells
cells and and promot-
promoting
ing keratinocyte growth. ROL also enhances the dermal microenvironment by
keratinocyte growth. ROL also enhances the dermal microenvironment by activating fibroblasts, activating fibroblasts,
fostering
fostering dermal
dermal blood
blood vessel
vessel formation
formation through
through endothelial
endothelial cell
cell proliferation.
proliferation. This
This occurs
occurs via
via the
the
TGF-β/CTGF pathway, increasing mature collagen in aged skin. The improved vasculature from
TGF-β/CTGF pathway, increasing mature collagen in aged skin. The improved vasculature from
ROL enhances blood flow, benefiting keratinocyte growth and fibroblast activation. Keratinocyte
ROL enhances blood flow, benefiting keratinocyte growth and fibroblast activation. Keratinocyte
proliferation might further stimulate VEGF, possibly aiding vessel growth. This interplay between
proliferation might
keratinocytes, furthercells,
endothelial stimulate VEGF, possibly
and fibroblasts aiding
creates vessel growth.
a reinforcing This interplay
environment, between
potentially ex-
keratinocytes,
plaining ROL’sendothelial cells, and fibroblasts
impactful anti-aging effects in agedcreates a reinforcing
skin. Skin sections environment,
embedded in potentially
OCT (7 μm ex-
plaining ROL’s
thickness) were impactful
acquired fromanti-aging
healthyeffects
buttockin skin
agedofskin.
agedSkin sections(with
individuals embedded in OCT
an average age(7ofµm76
±thickness)
6 years), were
after aacquired
seven-day fromtopical treatment
healthy buttockwithskinboth a vehicle
of aged and 0.4%
individuals retinol.
(with Skin sections
an average age of
were
76 ± 6immunostained with Ki67
years), after a seven-day (upper,
topical proliferation
treatment with bothmarker),
a vehicleCD31 (middle,
and 0.4% endothelial
retinol. cell
Skin sections
marker), and Type I procollagen (lower, major collagen in the skin). Representative
were immunostained with Ki67 (upper, proliferation marker), CD31 (middle, endothelial cell marker), images of six
individuals. Bar = 100 μm.
and Type I procollagen (lower, major collagen in the skin). Representative images of six individuals.
Bar = 100 µm.
4. Future Perspective
4. Future Perspectivethese mechanisms is important for developing interventions to slow
Understanding
downUnderstanding
the aging process
theseand improve skin
mechanisms health. Numerous
is important strategies
for developing are available
interventions to
to slow
down thethe
mitigate aging process of
progression and improve
skin skin health. Numerous
aging, encompassing strategies
the application are available
of sunscreen for UVto
mitigate the
radiation progression
protection, of skin
adherence toaging, encompassing
a nutritious theutilization
diet, and the application of of sunscreen
topical for
products
UV radiation
infused protection, adherence
with antioxidants, to anatural
retinoids, and nutritious diet, and
ingredients to the utilization
enhance of topical
skin health and
productsits
enhance infused with antioxidants,
appearance. retinoids,
Several possible avenuesand
fornatural
future ingredients to enhance
research in the realm ofskin
de-
health and
veloping enhance
novel its appearance.
interventions for skinSeveral possible
aging exist: avenues compounds
(1) Natural for future research in the
like polyphe-
realmflavonoids,
nols, of developing
andnovel interventions
carotenoids for skin
have been aging exist:
proposed (1) Natural
as anti-aging compounds
agents like
for the skin.
polyphenols, flavonoids, and carotenoids have been proposed as anti-aging agents for the
skin. Further research could scrutinize these compounds to identify their mechanisms of
action, safety profiles, and potential effectiveness as anti-aging agents. (2) Using natural
compounds in conjunction with other interventions like sunscreens or retinoids could
amplify their effects. Future research should examine the synergies of natural compounds
with other interventions and identify optimal combinations for enhancing skin health.
Exploring the use of natural compounds in combination with other interventions: Natural
compounds may be used in combination with other interventions, such as sunscreens or
retinoids, to enhance their effects. Future studies could investigate the synergistic effects of
natural compounds in combination with other interventions and determine the optimal
combinations for improving skin health, (3) Research indicates that natural compounds
could influence the skin microbiome, which is critical to skin health. Further studies could
explore the impact of natural compounds on the microbiome and assess the potential of
targeting it with natural compounds to enhance skin health. (4) Developing innovative
Biomolecules 2023, 13, 1614 13 of 16

formulations and delivery systems for natural compounds is crucial to improve their
efficacy, as poor absorption or stability can limit their effectiveness. Future research should
explore novel approaches to enhance the stability, absorption, and efficacy of natural
compounds through new formulations and delivery systems. Overall, these are a few
potential directions for future research on natural compounds and their effects on the skin.
By continuing to investigate the potential of natural compounds for improving skin health,
we may be able to develop new and effective interventions for skin aging, photoprotection,
and other skin-related concerns.

Funding: This work was supported by the National Institute of Health (RO1ES014697 to T. Quan,
R01AG081805 and R01AG083378 to G.J. Fisher and T. Quan and U01AG077924 to A.A. Dlugosz, G.J.
Fisher, and T. Quan) and the Dermatology Foundation Research grant (to T. Quan).
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the University of Michigan Institutional Review Board (HUM00139214,
8/4/2022), and all volunteers provided written informed consent.
Acknowledgments: The author thanks Yuan Shao, Tianyuan He, Zhaoping Qin, Trupta Purohit, and
Chunfang Guo for technical assistance; Suzan Rehbine for the procurement of tissue specimens; and
John J. Voorhees and Gary J. Fisher and the Department of Dermatology University of Michigan for
their support.
Conflicts of Interest: The author declares no conflict of interest.

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