REVIEW

published: 30 July 2019

doi: 10.3389/fcell.2019.00143

Autophagic Control of Skin Aging

Leopold Eckhart 1* , Erwin Tschachler 1 and Florian Gruber 1,2
1
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna,
Vienna, Austria, 2 Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria

The skin forms the barrier to the environment. Maintenance of this barrier during aging
requires orchestrated responses to variable types of stress, the continuous renewal
of the epithelial compartment, and the homeostasis of long-lived cell types. Recent
experimental evidence suggests that autophagy is critically involved in skin homeostasis
and skin aging is associated with and partially caused by defects of autophagy.
In the outer skin epithelium, autophagy is constitutively active during cornification
of keratinocytes and increases the resistance to environmental stress. Experimental
suppression of autophagy in the absence of stress is tolerated by the rapidly renewing
epidermal epithelium, whereas long-lived skin cells such as melanocytes, Merkel cells
and secretory cells of sweat glands depend on autophagy for cellular homeostasis
and normal execution of their functions during aging. Yet other important roles of
autophagy have been identified in the dermis where senescence of mesenchymal cells
and alterations of the extracellular matrix (ECM) are hallmarks of aging. Here, we review
Edited by:
Tassula Proikas-Cezanne, the evidence for cell type-specific roles of autophagy in the skin and their differential
University of Tübingen, Germany contributions to aging.
Reviewed by:
Keywords: skin, autophagy, aging, epidermis, keratinocytes, hair, sweat gland, melanocytes
Ying Zhu,
Sun Yat-sen University, China
Yan Wu,
Sun Yat-sen University, China INTRODUCTION
*Correspondence:
Leopold Eckhart
Changes of the skin belong to the most recognizable signs of aging. Accordingly, skin aging is a
[email protected] major area of interest for cosmetic and skin care industries. From the medical viewpoint, aging
of the skin is associated with health problems including increased skin fragility, delayed wound
Specialty section: healing and the increased occurrence of skin cancers, the most abundant types of malignancies in
This article was submitted to humans. The prevention and management of skin aging depends on a thorough understanding
Cell Death and Survival, of the aging process in general, which can be defined as the time-dependent decline in tissue and
a section of the journal organismal functions (Leidal et al., 2018), and on the understanding of the function and interplay
Frontiers in Cell and Developmental
of the unique cell types that build the skin. For a long time it has been recognized that the rate
Biology
of skin aging is determined by intrinsic and extrinsic drivers, but only recent advances in skin
Received: 30 April 2019
gerontology have helped to dissect the molecular and cellular processes that underlie the aging
Accepted: 11 July 2019
of the skin (Gilchrest and Krutmann, 2006; Chang, 2016; Ghosh and Capell, 2016; Botchkarev,
Published: 30 July 2019
2017; Rinnerthaler and Richter, 2018; Wang and Dreesen, 2018). Several of the aging processes are
Citation:
triggered or enhanced by the presence of damaged molecules and organelles within cells, and their
Eckhart L, Tschachler E and
Gruber F (2019) Autophagic Control
turnover is controlled partly by autophagy. Besides proteostasis and organelle maintenance, other
of Skin Aging. factors that are accepted hallmarks of aging (López-Otín et al., 2013), such as nutrient sensing and
Front. Cell Dev. Biol. 7:143. genomic instability are under the control of or elicit the activation of autophagy, making autophagy
doi: 10.3389/fcell.2019.00143 a major counter-regulatory process that supports skin homeostasis and healthy aging.

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Eckhart et al. Autophagic Control of Skin Aging

Autophagy is a process of cellular self-digestion by delivering and nutrients to the skin, regulate the body temperature, and
cytoplasmic material to the lysosome for breakdown. Three serve as highways for immune cell trafficking. The vast web
pathways of autophagy can be distinguished mechanistically, of dermal nerve endings reaches as far as into the epidermis
i.e., macroautophagy, microautophagy, and chaperone-mediated and transmits sensorial perceptions such as temperature, touch,
autophagy. Macroautophagy is controlled by autophagy-related pain and itch to the central nervous system (McGlone and
proteins (ATGs) and depends on the sequestration of material Reilly, 2010). Adding to the complexity of this tissue, it harbors
within double-membraned vesicles (autophagosomes) in a multitude of resident immune cells including mast cells,
the cytoplasm. These vesicles fuse with lysosomes to form tissue macrophages and professional antigen presenting cells
autophagolysosomes in which the cargo is degraded by lysosomal (McGrath, 2005).
enzymes. Breakdown products are released from lysosomes Attached to the dermis by specialized proteins of the basement
and subsequently are utilized for catabolic processes or energy membrane, the epidermis forms the outermost skin layer. It is
production. Microautophagy is characterized by the invagination a stratified epithelium consisting mainly (95% of all epidermal
of the lysosomal membrane in yeast, whereas in mammals it cells) of keratinocytes, which undergo terminal differentiation
involves the invagination of the late endosomal membrane to and form the stratum corneum, which serves as the ultimate
trap cytoplasmic material which is then degraded either in late barrier against the environment (Eckhart and Zeeuwen, 2018).
endosomes or in lysosomes after endosomal-lysosomal fusion Besides keratinocytes, the epidermis contains regularly dispersed
(Tekirdag and Cuervo, 2018). Chaperone-mediated autophagy Langerhans cells, the remotest antigen presenting cells of the
relies on the cytosolic chaperone hsc70 for substrate targeting immune system, and melanocytes, which produce the UV
to the lysosome. Proteins that contain a consensus pentapeptide protective melanin and transfer it to the adjacent keratinocytes
motif are bound by hsc70, unfolded and translocated into the thereby determining also the color of the skin and hair
lysosomal lumen in a lysosome-associated membrane protein (McGrath, 2005).
type 2A (LAMP2A)-dependent manner (Tekirdag and Cuervo, In contrast to internal organs, the signs of skin aging
2018). For further details of the mechanisms of autophagy, are immediately recognizable also to non-medically trained
the reader is referred to many excellent reviews (Rubinsztein observers. Most obvious are the occurrence of facial wrinkles
et al., 2011; Boya et al., 2013; Galluzzi et al., 2017; Hansen et al., which are either the consequence of repeated activity of the
2018; Levine and Kroemer, 2019). In the present review of underlying muscles during facial expression, or tissue slackening
autophagy in the skin, the term “autophagy” is equivalent to as a consequence of loss of elastin and collagen fibers. Tissue
“macroautophagy” unless stated otherwise. slackening manifests with a loss of the facial oval and sagging
Here, we review the features of skin aging at the levels of of the upper eyelids. In addition, pigment irregularities of sun-
the tissue and the cells and then describe the contributions of exposed skin are a hallmark of aging skin (Guinot et al., 2002).
autophagy to the control of skin aging. We propose a concept in When analyzing skin aging, one has to take into account that
which aging is driven by changes in three categories of cells with apart from intrinsic aging which proceeds in all organs and is
different dependencies on autophagy. genetically determined, skin aging is also strongly modified by
extrinsic factors such as chronic sun exposure and life style habits
in particular cigarette smoking (Guinot et al., 2002). Intrinsic
SKIN AGING AT THE TISSUE LEVEL aging is characterized primarily by a progressive loss of skin
tissue, i.e., a thinning of all skin layers. The subcutaneous fat
The skin is a composite organ consisting of a layer of pad decreases with age and so do the components of the dermal
subcutaneous fat tissue, the mesenchymal dermis and the ECM. Functionally, the loss of the fat pad results in an increased
outermost epithelial layer, the epidermis (McGrath, 2005). sensitivity to both hot and cold temperature whereas the loss
In addition, there are skin appendages, i.e., hair, sebaceous of the dermal ECM makes the skin more fragile and prone to
glands, sweat glands and nails, which are derived through wounding. Within the epidermis the turnover of keratinocytes
the differentiation of epithelial cells in cooperation with is reduced resulting in a thinning of the epidermis and a
mesenchymal cells. These skin appendages are anchored mainly reduced capacity to rapidly restore the skin barrier after barrier
within the dermis (McGrath, 2005; Figure 1, left panel). breaks. As to the skin appendages, hair becomes thinner and
The subcutaneous fat tissue functions both as insulation on the scalp terminal hair follicles are gradually miniaturized
against temperature fluctuations and as energy storage, and is (Fernandez-Flores et al., 2019). Most obvious, the natural hair
composed mostly of lobules of adipocytes which are surrounded color is lost due to a reduced transfer of pigment from follicular
by a lattice of collagen septae and blood vessels. It provides melanocytes to hair keratinocytes and air inclusions into the hair
the link of the skin with the underlying muscles and fasciae. shaft (Fernandez-Flores et al., 2019). Sebum production decreases
The dermis consists mostly of extracellular matrix (ECM) with age in particular in women after menopause. Similarly,
with collagen, elastin, and glycosaminoglycans as the principal sweat secretion decreases with aging (Dufour and Candas, 2007).
components, all of which are produced by fibroblasts, the most Furthermore, chronic pruritus or itch is common problem in
abundant cell type within the dermis. The dermal ECM provides the elderly, indicating an age-related conversion of touch to itch
the skin with both strong mechanical resistance and elasticity sensation due to loss or defects of Merkel cells (Feng et al., 2018).
(Bruckner-Tuderman, 2012). Embedded into the dermis are In contrast to intrinsic or chronological aging, photoaging
networks of blood and lymphatic vessels, which supply oxygen concerns only body regions which are chronically exposed to

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Eckhart et al. Autophagic Control of Skin Aging

FIGURE 1 | Cells of the skin and their changes during aging. The structure of the skin is schematically depicted with oval symbols representing cells. Molecular and
cellular features of aging are indicated in the right panel and in the box. For simplification, the diversity of immune cells and dermal cell populations are not
depicted here.

sunlight or to artificial sources of ultraviolet (UV) radiation system components such as DNA, cells, and tissues. Here, we
(Kligman and Balin, 1989; Yaar and Gilchrest, 1998; Gilchrest, put forward the hypothesis that drivers of aging mediate their
2013). The difference between intrinsic aging and photoaging effects differentially on the various types of cells in the skin
can most easily be observed in a given individual when and perhaps also in other tissues. We propose to distinguish
comparing UV-exposed skin sites such as the outer forearm three categories of cells that change during aging in different
to non-exposed sites such as the inner upper arm. Whereas ways (Figure 2).
intrinsic aging is characterized by a loss of ECM, photoaged First, stem cells have a long lifetime and relatively low
skin contains abundant elastin and collagen fibers, however, metabolic activity. Within the epidermis the stem cells themselves
they are not arranged like in non-exposed skin but are do not directly contribute to the epidermal barrier, but they give
fragmented and disorganized due to the action of UV-induced rise to differentiating daughter cells that achieve this function.
proteases (Gilchrest, 2013). In fact the appearance of photoaged A decline in the number and activity of stem cells is both
skin has been likened to scar tissue (Fisher et al., 1997). driver and marker of skin aging. Of note, epithelial structures
In addition, photoaged skin displays very distinct pigment with a high cell turnover, such as epidermal keratinocytes
irregularities referred to as age spots and, on the histological strongly depend on stem cells during homeostasis whereas other
level, immune cell infiltrates including mast cells, resulting in a skin compartments require stem cells predominantly or only
subclinical chronic inflammation. At the molecular level, UV- during wound repair.
signature mutations can be detected mainly in keratinocytes Second, there are cell types that differentiate and undergo
and melanocytes long before they become clinically relevant by fast turnover when they fulfill their function. The metabolic
causing actinic keratoses, basal cell carcinomas or melanomas activity of these cells is very high. Examples for this category are
(Jonason et al., 1996). epithelial cells of the interfollicular epidermis, sebaceous glands,
hair follicles, and the duct of the sweat gland. The maintenance
of function of these differentiating cells requires their continuous
derivation from stem cells.
SKIN AGING AT THE CELLULAR LEVEL: Third, differentiated skin cells of diverse developmental
STEM CELLS, SHORT-LIVED EPITHELIAL histories fulfill specific functions over prolonged periods
CELLS AND LONG-LIVED of time or even during the entire life of an organism.
DIFFERENTIATED CELLS Typically, these cells have significant metabolic activity over
long times. Examples of this cell category are neurons,
Aging is a complex phenomenon which includes many effects at melanocytes, Merkel cells, secretory cells of sweat glands,
the systemic level but also critical changes at the level of isolated and fibroblasts.

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Eckhart et al. Autophagic Control of Skin Aging

FIGURE 2 | Three categories of cells play different autophagy-dependent roles in skin aging. We propose that the aging of the skin is driven by changes in the
distinct types of skin cells that we categorize according to lifetime (inversely correlated to turnover) and differentiation (execution of specific function within the tissue
context). The main roles of autophagy and aging-associated changes are summarized for each cell category.

SKIN AGING AT THE CELLULAR LEVEL: Autophagy was reported to play various roles in the
DIFFERENTIAL ROLES OF AUTOPHAGY homeostasis and stress response of skin cells that were reviewed
previously (Sukseree et al., 2013a; Sil et al., 2018). Most recently,
IN THREE CATEGORIES OF CELLS the roles of autophagy in immune cells of the skin were
characterized (Das et al., 2019). For the main types of skin
The skin provides several examples to illustrate the two main
cells, the roles of autophagy and their relevance for aging will
interactions between autophagy and aging: (1) Autophagy
be discussed below. According to the above categorization of
decreases the rate of aging and (2) the activity of autophagy
skin cells, autophagy has different sensitivities to aging-associated
declines during aging. Autophagy suppresses aging in a cell-
processes and different roles in driving processes that enhance
autonomous manner by maintaining intracellular homeostasis
skin aging (Figure 2).
and in a non-autonomous manner by contributing to various
cell features that protect other cells. For instance, autophagy
supports the differentiation of epithelial cells which allows them (1) Long-lived and mostly quiescent stem cells require
to protect other cells against external noxae (Velarde, 2017). Since autophagy for intracellular homeostasis and for continuous
autophagy achieves the removal and recycling of intracellular ability to supply functional progeny cells (García-Prat et al.,
material only to a certain extent, potential toxic cell components 2016; Boya et al., 2018). Inherent decline or exogenous
and dysfunctional lysosomes tend to accumulate during the life- suppression of autophagy leads to stem cell loss by
time of cells. Some of the compromised cells succumb to cell competition, differentiation, or cell death (Figure 3).
death whereas others remain alive but lose their capacity to (2) In short-lived differentiating cells, autophagy also
execute intracellular processes, including autophagy, with full contributes to intracellular homeostasis, however,
efficiency. Loss and dysfunction of cells manifest in aging. autophagic activity needs to be maintained only over

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Eckhart et al. Autophagic Control of Skin Aging

FIGURE 3 | Roles of autophagy in skin cells. The contributions of autophagy to cornification, holocrine secretion, and homeostasis of stem cells and long-lived
differentiated cells (exemplified by a sweat gland secretory cell) are schematically shown. Time-dependent changes, such as a decline of autophagy, affect mainly
stem cells and long-lived differentiated cells. Short-lived keratinocytes and sebocytes are continuously generated from stem cells and then differentiate rapidly.
Autophagy contributes to the formation of corneocytes and sebum, which protect the living cells of the skin against stress factors from the environment. The
conversion of stem cells into (short-lived) differentiating keratinocytes and sebocytes occurs throughout life while the conversion of stem cells into long-lived
differentiated secretory cells occurs rarely in adult life. Note that specialized stem cells exist in the interfollicular epidermis and in skin appendages whereas only one
stem cell is shown in this simplified schematic drawing.

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Eckhart et al. Autophagic Control of Skin Aging

a short time for these cells to be functional. External and AUTOPHAGY IN EPITHELIAL CELLS OF
internal factors have little time to impair autophagy during THE SKIN
differentiation and consequently an aging-associated
decline of autophagy is less likely to occur in these
Autophagy in Epidermal Keratinocytes
cells. Nevertheless, autophagy defects can be inherited
Keratinocytes are the main cell type of the epidermis where
from the long-lived precursor cells (stem cells) and
they represent more than 95% of the total cell population
potentially compromise processes such as the defense
and autonomously establish a stratified epithelium. Keratinocyte
against microbes, the release of cytokines, and most
stem cells reside in the basal layer of the epidermis and in
importantly, the protection against stress factors from the
special locations of epidermal appendages, such as the bulge
environment (Figure 3).
of hair follicles and the duct of sweat glands (Figure 1).
(3) In long-lived differentiated cells, autophagy contributes to
Proliferating keratinocytes, so-called transit amplifying cells,
the maintenance of cell survival and function. A decrease
require attachment to the basement membrane and therefore
of autophagy leads to the accumulation of damaged or even
are also restricted to the basal layer. Upon detachment from
toxic components and/or energy crisis. These disturbances
the basement membrane, keratinocytes activate a genetically
of intracellular homeostasis impair the processes essential
controlled terminal differentiation program that leads to
for cell functions and eventually lead to a loss of these
the enhancement of the cytoskeleton as the cells move
cells (Figure 3).
toward the epidermal surface and ultimately to cornification
Importantly, the process of aging is not fully understood (Eckhart et al., 2013; Figures 1, 3).
at present and several new concepts of aging drivers have Due to the fast turnover of keratinocytes, keratinocyte
not yet been investigated for their potential interaction aging manifests mainly in changes of stem cell numbers and
with autophagy. For instance, stem cell competition for functions. In addition, changes in epidermal structure and
adherence to the basement membrane depending on proteolytic stress responsiveness decrease the function of the epidermis as
decrease of COL17A (Settembre et al., 2018; Liu et al., protection against pro-aging stress factors (Velarde, 2017).
2019) has emerged as an important process that contributes There are multiple extrinsic drivers of aging including
to aging of skin epithelia. Another emerging mechanism UV irradatiation, exposure to environmental toxins, and
with an impact on aging is the immune surveillance of disruptions of the barrier by low humidity, detergents, and
senescent cells (Ovadya et al., 2018). The potential roles microbes. Intrinsic drivers of aging are stem cell competition,
of autophagy in proteolysis and antigen processing during oxidative stress due to mitochondrial dysfunctions, and others
the above-mentioned process will be interesting topics of (Gilchrest and Krutmann, 2006). Keratinocyte autophagy
future investigations. is suppressed in carriers of a mutation in AP1S3, leading
to accumulation of p62/sequestosome-1 (Sqstm1) and
inflammation (Mahil et al., 2016).
Autophagy is active both in proliferating and differentiating
AUTOPHAGY IN THE DIFFERENT CELL
keratinocytes of human and mouse epidermis (Haruna et al.,
TYPES OF THE SKIN 2008; Rossiter et al., 2013; Sukseree et al., 2013b; Yoshihara
et al., 2015). The programmed degradation of the nucleus and
The literature on roles of autophagy in the skin is largely
mitochondria during cornification is reminiscent of autophagy
organized into reports that focus on cell types of specific
and, indeed, there is correlative evidence for a role of the
developmental origins. Here, we review these reports in separate
autophagy machinery in organelle degradation within the
sections, divided in epithelial and non-epithelial cell types. Non-
granular layer of the epidermis (Akinduro et al., 2016).
epithelial skin cells are largely long-lived and differentiated,
Keratinocyte-specific deletion of Atg5 and Atg7 in mice led to
i.e., category 3 cells as defined in the previous sections
thickening of the stratum corneum but did not block the removal
of this article, with regard to autophagy and skin aging.
of the nucleus in cornifying keratinocytes (Rossiter et al., 2013;
Among the non-epithelial skin cells, there are also stem cells
Sukseree et al., 2013b).
(category 1), but the changes in long-lived differentiated cells
are considered the main contributors to aging. Epithelial cells
of the skin include only a quantitatively minor portion of Roles of Autophagy in Keratinocyte Stem
long-lived differentiated cells (category 3), such as Merkel Cells
cells and secretory cells of the sweat glands, whereas the Autophagy supports the maintenance of stem cells (Cho et al.,
main portion of epithelial cells are short-lived, differentiating 2019). Both self-renewal and quiescence of stem cells were
cells (category 2), such as keratinocytes of the interfollicular reported to require autophagy (García-Prat et al., 2016; Wang
epidermis, hair follicle keratinocytes, sebocytes, and sweat et al., 2018). In keratinocyte stem cells, the expression of
duct cells. The replenishment of the differentiating epithelial autophagy-regulatory genes changes during the circadian rhythm
cells strongly depends on epithelial stem cells (category 1) and during aging (Solanas et al., 2017). Suppression of autophagy
(Figure 2). The contributions of autophagy to the maintenance by epithelium-specific deletion of Atg5 or Atg7 can maintain a
and functions of stem cells and differentiated cells are discussed functional skin barrier during aging, suggesting that autophagy
in detail below. is not critically required for epidermal stem cell maintenance

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Eckhart et al. Autophagic Control of Skin Aging

under non-stressed housing conditions of mice (Rossiter et al., role of autophagy in cornification (Jaeger et al., 2019).
2013; Sukseree et al., 2013b). Interestingly, mice with epithelium- Proteomic comparison of nails formed by autophagy-competent
specific Atg7 knockout developed a thicker epidermis and larger and by autophagy-deficient keratinocytes showed numerous
sebaceous glands than wild-type mice and thereby resembled differences that suggest an active participation of autophagy in
other mouse lines with keratinocyte hyperproliferation (Rossiter cornification and a broad substrate specificity of cornification-
et al., 2013, Rossiter et al., 2018). Quantitative studies of stem associated autophagy. Deletion of Atg7 in keratinocytes of
cell numbers and functions at different age of mice are needed the nail unit and other epidermal compartments led to a
to explore the role of autophagy in epidermal stem cells. decrease in the content of keratins and keratin-associated
proteins and to a concomitant increase of non-cytoskeletal
Roles of Autophagy in Stress Resistance proteins, including enzymes and proteins with regulatory
functions. Most prominently, components of multi-protein
of Epidermal Keratinocytes molecular machines, such as ribosomes, chaperonins and
Autophagy has been implicated in the response of keratinocytes proteasomes, accumulated upon suppression of autophagy
to various types of stress, most of which accelerate skin aging. (Jaeger et al., 2019). It appears very likely, but remains to
The best characterized environmental stress on skin is UV be experimentally confirmed that autophagy plays equivalent
radiation which induces oxidation of skin molecules and damages roles in the cornification of keratinocytes in hair follicles and
the genetic material. UVB irradiation of the skin induces interfollicular epidermis (Figure 3).
DNA damage and inflammation (Gilchrest, 2013). Autophagy
improves DNA damage recognition by nucleotide excision repair Autophagy in Hair Follicle Keratinocytes
(Qiang et al., 2016) and reduces inflammation and consequently Hair is formed by a special type of cornification of keratinocytes
also inflammation-enhanced tumorigenesis of the epithelium in which essentially the entire cell is filled with cross-
(Qiang et al., 2017). However, it has also been reported that linked keratin filaments, and hair keratinocytes are stably
autophagy facilitates tumor development under genotoxic stress interconnected to form a long fiber. The growth of hair
via suppressing p62-mediated p38 activation and promotion of requires a cylindrical architecture of follicles ensheathing the
cell survival (Qiang et al., 2013). hair fiber. Growth of hair depends on proliferation and
UVA causes oxidation of phospholipids in keratinocytes, differentiation of keratinocytes which occur at the bottom
but it also induces autophagy which promotes the removal of the follicle. At this site melanocytes deliver pigment into
of these oxidation products in epidermal keratinocytes (Zhao hair and dermal fibroblasts play important regulatory roles
et al., 2013). Suppression of Atg7-dependent autophagy increased (Figure 1). The growth of hair is terminated when the
DNA damage in response to UVA (Song et al., 2017). UVA hair fiber reaches a certain, hair type-dependent length, the
irradiation also activates transcription factor EB (TFEB) and fiber is shed and a new cycle of hair growth is initiated.
upregulates expression of p62 as well as cyclooxygenase- A recent report showed that autophagy is active during hair
2 (COX-2), a prostaglandin synthase implicated in skin growth in an organ culture of human scalp hair follicles
cancer development (Sample et al., 2017). In vitro studies and inhibition of autophagy promotes hair follicle regression
suggest that the levels of oxidative damage and autophagic (Parodi et al., 2018).
activity determine whether senescent keratinocytes undergo A decline in hair growth and progressive loss of active
programmed cell death or evade senescence with potential terminal hair follicles are characteristic for aging. Recently,
neoplastic activity (Deruy et al., 2014). These findings emphasize it was shown that hair follicle stem cell aging causes the
that cellular senescence, i.e., a state of arrested proliferation stepwise miniaturization of hair follicles and eventual hair loss
and altered metabolism (Muñoz-Espín and Serrano, 2014), in a process that that depended on the proteolysis of type
is not only a driver of aging but also a cancer-preventive XVII collagen (Matsumura et al., 2016). The cyclic growth and
mechanism and therefore should not be regarded as entirely shedding of hair requires a complex communication between
detrimental. In summary, the roles of autophagy in the stress epithelial and mesenchymal cells. While autophagy is active in
responses of keratinocytes are complex and pharmaceutical hair keratinocytes (Parodi et al., 2018) and mesenchymal cells
modulation of autophagic activity in the epidermis should surrounding hair follicles (Nicu et al., 2019), it remains to
be evaluated in both homeostatic and stress conditions be determined whether and how autophagy contributes to the
(Tschachler and Eckhart, 2017). signaling between different cells of hair follicles.
Recently, small molecule activators of autophagy, such as
Autophagy in Nail Keratinocytes alpha-ketoglutarate and alpha-ketobutyrate, were reported to
Keratinocytes of the nail unit differentiate and cornify to induce a switch from telogen (the quiescent phase of the hair
become components of the nail. Genetic suppression of cycle) to anagen (the phase of active hair growth) in mice (Chai
autophagy does not abolish growth of nails during aging et al., 2019). Similarly, rapamycin and metformin stimulated
(Sukseree et al., 2013b; Jaeger et al., 2019), suggesting that growth of hair and their effects could be blocked by autophinib,
autophagy is dispensable for the maintenance of nail epithelial an inhibitor of autophagosome formation (Chai et al., 2019).
stem cells. However, the conversion of nail keratinocytes Studies in mouse models of alopecia and in humans are needed to
into regular cornified nail requires autophagy. Murine nails determine whether the pharmacological activation of autophagy
have been successfully used as a model to decipher the is able to counteract hair loss.

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Eckhart et al. Autophagic Control of Skin Aging

Autophagy in Sebaceous Glands organized in touch domes or in circular arrangement in the

Hair follicles are invariably associated with sebaceous glands that upper part of the hair fiber (Sukseree et al., 2018b). Upon
release sebum into the upper hair canal. The sebaceous gland physical stimulation, they release serotonergic vesicles at synapses
is composed of acini with proliferating cells attached to the with nerve fibers that transmit the signal further (Figure 1).
basement membrane and differentiating and lipid-accumulating It was hypothesized that autophagy is active in Merkel cells to
cells being passively moved to the interior where they disintegrate degrade a fraction of serotonergic vesicles and thereby to control
to release a mix of lipid and other cell content into the sebaceous the strength of signaling at serotonergic synapses (Sukseree
duct (Figure 1). This process of holocrine secretion involves et al., 2018b). The sensation of soft touch is important for
degradation of the nucleus and cytoplasmic changes that are spatial awareness and communication. Aging and some diseases
poorly characterized except for the massive accumulation of are associated with the pathologic sensation of innocuous
large lipid droplets (Figure 3). Suppression of autophagy by mechanical stimuli as itch, a phenomenon known as alloknesis
either deletion of Atg7 or Atg5 leads to premature breakdown of (Feng et al., 2018).
the nucleus in differentiating sebocytes (Sukseree et al., 2013b; In Atg7f /f K14-Cre mice (Sukseree et al., 2012), the deletion
Fischer et al., 2017). The current hypothesis is that autophagy of Atg7 led to marked accumulation of p62 in Merkel cells,
contributes to the stabilization of lysosomes or to the removal suggesting a particular requirement for autophagy in these cells
of defective lysosomes in normally differentiating sebocytes, (Sukseree et al., 2018b). Merkel cells have a longer life time than
whereas lack of these maintenance and repair mechanisms keratinocytes, which allows stronger accumulation of p62. Based
allows defective lysosomes to trigger cell death that involves on the studies in mouse models (Feng et al., 2018; Sukseree et al.,
degradation of nuclear DNA by the lysosomal endonuclease 2018b), the potential link between the role of autophagy in Merkel
DNase2 (Fischer et al., 2017). cell homeostasis and aging-associated defects of touch sensation
represents a promising topic of future research.
Autophagy in Sweat Glands
Sweat has an essential function in thermoregulation of human Autophagy in Non-epithelial Cells of the
skin. It is produced by secretory cells and reaches the skin Skin
surface via the duct of sweat glands. These glands are Besides the quantiatively predominant epithelial cells, a
developmentally derived from K14-positive epithelial cells but developmentally and functionally diverse set of other cells
most cells of the mature sweat gland reduce expression of K14 including melanocytes, fibroblasts, Langerhans cells, Schwann
and upregulate other keratins such as K18 in the secretory cells, and neurons reside in the skin. These cells have in
portion of the glands. The cells of the secretory portion of common low turnover and long lifetime which predisposes
the sweat gland do not proliferate whereas cells of the duct them to the negative effects of declining autophagy during
proliferate to maintain a connection to the surface of the aging (Figure 2). Melanocytes are the most studied non-
constantly renewing epidermis (Lu and Fuchs, 2014). Aging epithelial skin cells with regard to roles of autophagy. Autophagy
of human sweat glands is characterized by the accumulation in fibroblasts, nerves, endothelial cells, and immune cells
of lipofuscin, an autofluorescent mixture of oxidized proteins has been studied mainly in other organs than the skin
and lipids, in secretory sweat gland cells (Cawley et al., 1973; as well as in vitro.
Sukseree et al., 2018a; Figure 1).
Deletion of Atg7 in skin epithelial cells of the mouse, in Autophagy in Melanocytes
which sweat glands are restricted to toe and foot pads, led to Melanocytes of the skin produce melanin and deliver it to
accumulation of p62 in secretory cells of sweat glands but not in neighboring keratinocytes that reside either in hair follicles, thus
eccrine duct epithelial cells (Sukseree et al., 2018a). The size and determining hair color, or in the interfollicular epidermis to
numbers of p62 aggregates increased with age. Moreover, Atg7- determine complexion. Aging is associated with the changes
deficient glands showed a decrease in cellularity and an aberrant of hair color, pallor and appearance of age spots (lentigo
widening of the lumen. The density of functional sweat glands senilis), indicating that the function of melanocytes changes
was significantly decreased at around 1 year of age (Sukseree et al., with age (Yaar and Gilchrest, 2001). The most important
2018a). Thus, autophagy is essential to suppress the accumulation effect of melanocyte dysfunction in aging is graying of the
of p62 during normal aging of long-lived sweat-secreting cells hair. The follicular melanocytes which supply pigment to
and to maintain the function of sweat glands (Sukseree et al., the hair respond to signals of the hair growth cycle, and
2018a). These data should be followed up by studies of autophagic their age-related depletion and change in shape (Itou, 2018)
activity and its possible negative correlation with the abundance together with an increase in redox stress are implicated in
of lipofuscin deposits in human sweat glands. age-related dysfunction of the hair follicle pigmentary unit
(Tobin, 2015).
Autophagy in Merkel Cells The incidence of melanocyte-derived cancers is generally
Merkel cells are sensors of soft touch in the epidermis and correlated with increasing age, however, malignant melanoma
hair follicles. They differentiate from epithelial cells that express is also relatively frequent in young adults. Nevus cell
keratin K5/K14 and switch to a K8/K18-dependent cytoskeleton. nevi, commonly known as moles, show age-related
Merkel cells reside in the basal layer where they are either variations in shape and appearance (Zalaudek et al., 2006;

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Eckhart et al. Autophagic Control of Skin Aging

Schäfer et al., 2006). Non-proliferating melanocytes in nevi uncontrolled proliferation of melanocytes (Liu et al., 2013).
show signs of cellular senescence (Tran and Rizos, 2013), Sample and colleagues reported that the autophagy adapter p62,
nevertheless one third of melanomas derive from nevi. which we had found to accumulate in melanocytes upon UVA
Current models hypothesize that mTOR signaling, which exposure (Zhang et al., 2015), was elevated in abundance in both
is linked to the control of autophagy, plays a role in the nevi and malignant melanoma, and proposed p62 as an oncogene
mechanism by which the senescent growth arrest is overcome in melanoma development (Sample et al., 2018). In a different
(Damsky and Bosenberg, 2017). As the following recent study, pharmacological blockade of autophagy sensitized
studies of melanocytes indicate, autophagy may affect age- melanoma cells to chemotherapy induced cell death (Qiao
related changes in melanogenesis, melanosome transfer, et al., 2013). In contrast, starvation elevated both autophagy
melanocyte cell death, melanocyte redox stress control, and cisplatin chemotoxicity in a murine model (Antunes
melanocyte proliferation rate, melanocyte senescence and et al., 2018). One of the possible connectors of autophagy,
inflammatory signaling. cell cycle control and aging in melanocytes and melanoma
is the p53 activating protein ARF, which acts as emergency
Roles of Autophagy in Melanogenesis, control of superoxide levels in mitochondrial dysfunction. This
protein is rendered non-functional in suppressing superoxide
Melanosome Transfer, and Pigmentation
and melanoma cell proliferation when CDKN2A is mutated
Proteins of the autophagic machinery facilitate the movement
(Christensen et al., 2014). ARF is however also an autophagy
of developing melanosomes within the melanocytes on
agonist (Balaburski et al., 2010), and this activity does not
microtubules and actin filaments (Ramkumar et al., 2017).
depend on the CDKN2A mutation. Whether modulation of
The melanosomes are transferred to keratinocytes in which
autophagy would be an advisable strategy to promote the
autophagy limits the accumulation of transferred melanin
success of chemotherapy, or biologics will need further in-depth
(Murase et al., 2013, 2016). Interestingly, mutations in the
investigation (Li et al., 2019).
autophagy gene EPG5 cause a recessive neurodevelopmental
multisystem disorder, Vici syndrome, which is associated with
hypopigmentation (Cullup et al., 2013). Autophagy in Dermal Fibroblasts
Our group has observed mild but age-correlated effects on The fibroblasts of the human dermis are long-lived cells
pigmentation in mice devoid of Atg7-dependent autophagy and thus prone to accumulate intrinsic and extrinsic
in melanocytes. The deletion of Atg7 under the control of damage. Dermal fibroblasts do not represent a uniform
the Tyrosinase promoter resulted in age-dependent changes population because they can take on at least two phenotypes,
of skin pigmentation (Zhang et al., 2015), accumulation of i.e., papillary and reticular (Driskell et al., 2013). The
p62 in pigment cells of the eye (Sukseree et al., 2016), and phenotypic plasticity of fibroblasts likely depends on the
aging-related p62 aggregation in neurons and neuroepithelial microenvironment (Korosec et al., 2019), in which the ECM
cells (Sukseree et al., 2018c). Atg7-deficient skin melanocytes is undergoes aging-related changes (Larroque-Cardoso et al.,
developed premature senescence and showed a dysregulated 2015). During skin aging the balance between these two
antioxidant response and lipid homeostasis in culture (Zhang fibroblast types shifts toward the reticular lineage phenotype
et al., 2015). We observed hyperinduction of the redox responsive (Mine et al., 2008).
Nrf2 system, probably due to accumulation of the autophagy Changes in autophagic flux in fibroblasts have been implicated
adaptor and Nrf2 agonist p62, which did not prevent elevated in aging (Dumit et al., 2014; Demirovic et al., 2015; Kim et al.,
melanocyte redox stress. The autophagy deficient melanocytes 2018). Recent findings discussed below suggest that autophagy
displayed a senescence associated secretory phenotype (SASP) and its age-related dysfunction may affect the microenvironment
(Ni et al., 2016). This low-grade inflammation is typical for in chronologic and UV-induced aging as well as in premature
senescent cells, and melanocyte SASP is implicated in the aging phenotypes.
pathogenesis of vitiligo (Bellei et al., 2013; Qiao et al., 2016)
and hypopigmented macules in tuberous sclerosis complex Roles of Fibroblast Autophagy in
(Yang et al., 2018). Premature Aging and Age-Related
Diseases
Roles of Autophagy in Melanocyte Cockayne syndrome is a premature aging disease affecting
Senescence, Proliferation, and Death the skin and causing UV hypersensitivity and subcutaneous
Several recent studies have established links between autophagy fat wasting. Fibroblasts from patients deficient in Cockayne
and the control of proliferation, senescence and death of syndrome B (CSB) protein display impaired autophagy due to
melanocytes as well as melanoma cells. The autophagy gene interaction of CSB with HDAC6 and cytoskeletal components.
ATG5 is expressed at reduced levels in melanoma but not in Importantly, the restoration of autophagic function could
benign melanocytes in nevi (Liu et al., 2013). In melanoma revert the premature aging and photosensitivity phenotype in
cells cultured in vitro, activation of ATG5 reduced proliferation a CSB mouse model (Majora et al., 2018). The movement
and induced senescence. The authors concluded that in early of the autophagic-lysosomal components along cytoskeletal
stages of melanoma development, inhibition of autophagy might components through motor proteins was demonstrated in a
delay the onset of oncogene-induced senescence and promote study in mouse fibroblasts. A genetic reduction of the motor

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Eckhart et al. Autophagic Control of Skin Aging

protein KIF3C led to diminished autophagic flux and impaired UVB induced senescence by limiting ROS production (Qin
proteostasis, similar in effect to a reduction of KIFC3 levels et al., 2018). Autophagy was proposed to be required for
in naturally aged cells (Bejarano et al., 2018). Autophagy UV mediated senescence induction (Cavinato and Jansen-
degraded nuclear anomalies resulting from mutation of lamin Dürr, 2017; Sample and He, 2017) but this hypothesis remains
A (Park et al., 2009), and stimulation of autophagy and the to be tested in different cells under different regimens of
connected Nrf2-mediated antioxidant response promote the UV exposure. Current evidence suggests that autophagy
clearance of the truncated pre-lamin A protein (progerin) counteracts the accumulation of damage that promotes
which accumulates in fibroblasts of patients with Hutchinson cellular senescence.
Gilford progeria (Gabriel et al., 2017). Dermal fibroblasts from
Parkinson’s disease patients displayed dysfunctional autophagy,
mitochondrial damage, and impaired redox stress tolerance CONCLUSION
(Teves et al., 2018). The skin is a potential source of prognostic
Skin aging is a complex process which, according to the
biomarkers for age-related neurodegenerative diseases (Can
concept described above, depends on changes in three categories
Akerman et al., 2019), and markers related to skin fibroblasts may
of cells with differential roles of autophagy. Epithelial stem
also be relevant for disease-free skin aging.
cells require autophagy for homeostasis during their long
lifetime whereas short-lived differentiating epithelial cells utilize
Roles of Autophagy in Proteostasis of autophagy mainly for intracellular remodeling. Long-lived
Aging Fibroblasts differentiated cells of both epithelial and non-epithelial origin
Loss of homeostasis in protein quality control – termed need autophagy to suppress the accumulation of noxious
proteostasis – and thereby the accumulation of oxidized compounds. We propose that inefficiencies of cellular processes
proteins is observed in the chronologic and photo-aging (intrinsic drivers of aging) and damaging effects from the
processes of the skin (Tigges et al., 2014). Proteostasis was environment (extrinsic drivers of aging) compromise the
identified as the ontology category predominantly affected machinery of autophagy, leading to a self-accelerating decline
by aging of human fibroblasts (Waldera-Lupa et al., 2014). in cellular waste disposal and recycling in long-lived skin cells
Loss of proteostasis is attributed to dysregulation of the and decreasing protective functions of skin epithelia. Together,
proteasome and autophagy in aging (Korovila et al., 2017). autophagy-dependent and independent processes lead to tissues
A comparison of proteostasis in phylogenetically related short- changes that manifest in skin aging. Further characterization
and long-lived mammalian species indicated higher autophagic of autophagy in distinct skin cells may help to identify new
activity in the longer lived species (Pride et al., 2015). approaches for maintaining the normal function of the skin in
In humans, loss of proteostasis has been observed in skin aged individuals.
fibroblasts upon chronologic aging and UV exposure (Bulteau
et al., 2007). The loss of capacity to remove oxidized and
misfolded protein can lead to activation of DNA damage AUTHOR CONTRIBUTIONS
repair (DDR) pathways and thereby to the induction of
LE, ET, and FG wrote the manuscript.
cellular senescence (Chondrogianni and Gonos, 2008) and SASP
(Catalgol and Grune, 2009).
Fibroblast autophagy is required for clearance of lipofuscin, FUNDING
an accumulation of misfolded and modified proteins and
lipids (Höhn et al., 2012). Impairment of autophagy in This work was supported by funding from the Federal Ministry
senescent human fibroblasts (Ott et al., 2016) may thus be for Digital and Economic Affairs of Austria and the National
related to the aberrant deposition of lipofuscin that underlies Foundation for Research, Technology and Development of
age-related pigmentation irregularities. Declining autophagy Austria to the Christian Doppler Laboratory for Biotechnology
in aging dermal fibroblasts was also implicated in another of Skin Aging, grants from the Herzfelder’sche Familienstiftung
hallmark of skin aging, i.e., modifications of the ECM to FG and LE, and a research grant from Chanel R&T,
(Tashiro et al., 2014). Pantin, France to the Department of Dermatology, Medical
University of Vienna.
Roles of Autophagy in the Control of
DNA Damage in Fibroblasts ACKNOWLEDGMENTS
The function of autophagy in the protection against stress
and damage was investigated in several studies on effects of The authors thank Supawadee Sukseree and Marie
ultraviolet irradiation of fibroblasts. UVB exposure, which Sophie Narzt for helpful discussions. LE and FG
promotes photoaging and senescence of dermal fibroblasts, participated in the COST Action CA15138, European
induced proteasome inhibition and autophagy (Cavinato and Network of Multidisciplinary Research and Translation
Jansen-Dürr, 2017), whereas chronic UVA exposure led to of Autophagy knowledge (TRANSAUTOPHAGY) that
blockage of autophagic flux (Lamore and Wondrak, 2013). is supported by the European Union Framework
In vitro, activation of autophagy by rapamycin prevented Programme Horizon 2020.

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Eckhart et al. Autophagic Control of Skin Aging

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(2013b). Targeted deletion of Atg5 reveals differential roles of autophagy in conducted in the absence of any commercial or financial relationships that could
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Sukseree, S., Mildner, M., Rossiter, H., Pammer, J., Zhang, C.-F., Watanapokasin, Copyright © 2019 Eckhart, Tschachler and Gruber. This is an open-access article
R., et al. (2012). Autophagy in the thymic epithelium is dispensable for the distributed under the terms of the Creative Commons Attribution License (CC BY).
development of self-tolerance in a novel mouse model. PLoS One 7:e38933. The use, distribution or reproduction in other forums is permitted, provided the
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