Background: As the largest organ in the human body, the skin is continuously exposed to intrinsic and extrinsic stimuli that impact its functionality and morphology with aging. Skin aging entails dysregulation of skin cells and loss, fragmentation, or fragility of extracellular matrix fibers that are manifested macroscopically by wrinkling, laxity, and pigmentary abnormalities. Age-related skin changes are the focus of many surgical and nonsurgical treatments aimed at improving overall skin appearance and health. Summary: As a hallmark of aging, cellular senescence, an essentially irreversible cell cycle arrest with apoptosis resistance and a secretory phenotype, manifests across skin layers by affecting epidermal and dermal cells. Knowledge of skin-specific senescent cells, such as melanocytes (epidermal aging) and fibroblasts (dermal aging), will promote our understanding of age-related skin changes and how to optimize patient outcomes in esthetic procedures. Key Messages: This review provides an overview of skin aging in the context of cellular senescence and discusses senolytic intervention strategies to selectively target skin senescent cells that contribute to premature skin aging.

Aging, associated with a time-dependent functional decline in most living organisms, has piqued the quest to slow or reverse biological aging throughout the history of humankind [1, 2]. Skin aging, akin to organismal whole-body aging, is characterized by gradual loss of function and regenerative capacity [3]. The human epidermis has the innate capacity to renew approximately every 40–56 days but slows with aging [4]. Intrinsic and extrinsic insults drive the skin aging process [5]. Intrinsic aging primarily reflects genetic background, whereas extrinsic aging reflects environmental triggers, such as ultraviolet (UV) exposure, air pollution, smoking, alcohol intake, and poor nutrition, among others [6], resulting in reduced regenerative potential. Clinically, skin aging is linked to reduced barrier protection, poor wound healing [7], increased inflammation [8], deficient water and thermal homeostasis [9], and susceptibility to skin disorders, including skin cancers [10]. Indeed, the interlinked hallmarks of whole-body aging, characterized by a progressive loss of physiological integrity, include genomic instability [11], telomere attrition [12], epigenetic alterations [13], loss of proteostasis [14], deregulated nutrient-sensing [15], mitochondrial dysfunction [16], cellular senescence [17], stem cell exhaustion [18], and altered intercellular communication [19] (Fig. 1). In this review, we primarily focus on the role of cellular senescence in skin aging and regeneration.

Fig. 1.

Hallmarks of skin aging. An illustration of skin senescent cell accumulation and corresponding senescence-associated secretory phenotype (SASP) factor release in young versus old human skin models.

Fig. 1.

Hallmarks of skin aging. An illustration of skin senescent cell accumulation and corresponding senescence-associated secretory phenotype (SASP) factor release in young versus old human skin models.

Close modal

Cellular senescence is an essentially permanent state of cell cycle arrest with both beneficial and detrimental effects in development and aging. Leonard Hayflick and Paul Moorhead originally hypothesized the connection between aging and senescence in 1961 after noticing limited proliferative capacity in serially subcultured human primary fibroblasts [20]. While cellular senescence has an evolutionarily advantageous role in facilitating tissue remodeling during development and after injury, it can also play a damaging role in the aging process by impairing tissue regeneration, causing inflammation and fibrosis, and promoting tumor growth [21]. Senescent cells exhibit extensive alterations in chromatin architecture and gene expression in addition to growth arrest [22]. The senescence-associated secretory phenotype (SASP) is a prominent characteristic of senescent cells that can include the secretion of several pro-inflammatory cytokines, chemokines, growth factors, proteases, bioactive lipids (bradykinesia, ceramides, prostanoids), non-coding nucleotides (e.g., microRNAs and mitochondrial DNA), and other factors [23‒28]. The SASP portfolio, which includes factors that modulate immune cell proliferation and migration, allows senescent cells to activate, suppress, modulate, and/or evade the immune system [29] (shown in Fig. 1). Indeed, various types of cellular stressors can trigger cellular senescence in vitro [30]; yet, the identification of unique senescence markers, particularly in vivo, is still under investigation. Therefore, the field of translational geroscience continues to define the senescent phenotype in specific tissues and identify new pathways for therapeutic removal of senescent cells directly relevant to the skin.

Skin consists of three layers: the epidermis, dermis, and subcutaneous tissue. The epidermis, composed of multiple cell types including keratinocytes, melanocytes, Langerhans cells, and Merkel cells, is a stratified squamous epithelium that undergoes continuous renewal [31]. Histologically, skin aging results in epidermal thinning with flattening of the dermal-epidermal junction [32]. This manifests as increased skin fragility and reduced nutrient transfer between the dermis and epidermis, attributed to the loss of surface area of the dermal-epidermal interface. Furthermore, epidermal cell turnover decreases with age [33], which accounts for less effective desquamation and reduced wound healing.

Beyond the epidermis, the dermis experiences the most significant ultrastructural change with age [34]. The dermis, divided into the more superficial papillary dermis and the deeper reticular dermis, consists of extracellular matrix (ECM) fibers, which are crucial for maintaining the skin’s structural integrity [35]. Deterioration causes the dermis to separate from the epidermis, resulting in skin laxity and decreased epidermal stem cell renewal [36]. Fibroblasts, the most prevalent cells in the dermis, deposit the collagen and elastic fibers of the ECM [37]. Throughout the aging process, fibroblasts synchronously decrease in number and function [38]. Young dermal fibroblasts produce glycosaminoglycans and ECM fibers, including elastin and type I collagen, which make up approximately 90% of the ECM [39]. As the number and diameter of collagen fibers decrease with age, the ratio of type III collagen to type I collagen increases [40]. Furthermore, aged skin is associated with dermal collagen and elastin fragmentation, which presents as decreased skin elasticity and turgor [41]. Together, these age-dependent ultrastructural changes account for the physical manifestations of cutaneous aging [42, 43].

Markers of cellular senescence in skin, including nuclear and SASP markers, have been used to detect senescent cells in aging and disease. Upregulation or downregulation of various cellular senescence markers have been used to characterize cellular senescence burden in skin. Increase in SA-β-galactosidase has been extensively applied as a marker of cellular senescence [44, 45]. Similarly, the cell cycle markers p16INK4a and p21CIP1/WAF1 have been used to study senescent fibroblasts and melanocytes in skin [46‒48]. Alterations in the level of lamin B1 have been implicated as an early senescence marker in multiple tissues, including skin [49‒52]. Particularly, reductions in lamin B1 were found in dermal fibroblasts and keratinocytes from older donors [53], keratinocytes in photoaged skin [52], and melanocytes in melanocytic nevi [51]. Senescent fibroblasts have also been demonstrated to secrete HMGB1 before developing a SASP [54]. On the other hand, melanocytes and keratinocytes from older donors expressed reduced HMGB1 [48]. In addition to these, numerous biomarkers have been developed for skin aging, such as telomere-associated foci [48].

Keratinocytes are the most abundant cells in the epidermis and directly contribute to the skin barrier. As skin ages, there is a shift in keratinocyte morphology that contributes to epidermal thinning. Basal keratinocytes become shorter and larger, and corneocytes, which are terminally differentiated keratinocytes, also grow larger due to reduced epidermal turnover [55]. The notion of whether keratinocytes can acquire senescent phenotypes has been questioned given their highly proliferative state. p16INK4a, a marker of cellular senescence, was detected in human skin biopsies of sun-exposed areas [56‒58]. Skin tissues from photoprotected areas of young and old donors showed that p16INK4a-positive cells were predominantly melanocytes and not keratinocytes in the epidermal layer, highlighting the differences in senescence phenotypes given sun exposure [48, 59]. However, senescent cell markers were detected in keratinocytes from actinic keratoses, UV-associated lesions. Specifically, actinic keratosis was associated with increased p16INK4a and reduced lamin B1 and HMGB1, and p16INK4a expression was associated with development of squamous cell carcinoma [60, 61].

Melanocytes, or pigment-producing cells derived from the neural crest, are in spatial proximity to keratinocytes in the epidermal layer. It has been postulated that cellular senescence may provide an evolutionary protection against malignant transformation of melanocytes, as pigmentation is a strong defense against melanoma [62]. As such, melanin accumulation in the epidermis, through α-melanocyte stimulating hormone or cholera toxin, can induce melanocyte senescence through the p16/CDK4/pRB pathway [63]. Studies have also shown that p16INK4a-positive melanocytes accumulate in the aged human epidermis. A correlation between increased numbers of p16INK4a-positive melanocytes and facial aging phenotypes, such as wrinkles, morphological changes in elastic fibers, and dysfunctional telomeres, has been reported [48, 64‒66]. In addition, UV-irradiated melanocytes enter premature senescence with downregulation of DNA repair programs such as nucleotide excision repair pathway genes, especially genes involved in DNA damage recognition (RAD23B, XPC, ERCC3, ERCC8, and RPA1) [67]. Moreover, senescent melanocytes could result in tissue-level disruption. p16-positive melanocytes induce gamma-H2A-X foci in neighboring keratinocytes, indicating telomere dysfunction, and exposure to senescent-melanocyte-conditioned media induces telomere damage in fibroblasts [48]. Interestingly, clearance of senescent melanocytes with ABT-737, a BCL-2 inhibitor, or MitoQ, a mitochondrial-targeted antioxidant, attenuated telomere dysfunction [48]. Yet, caution must be utilized in its clearance as p16 has a function in suppressing or limiting growth of melanocytic nevi (moles) and germline mutations in p16 are often associated with dysplastic nevi and even melanomas [68].

Fibroblasts, as the most abundant cell type that resides in the dermis, largely contribute to hallmarks of skin aging [69]. Dermal fibroblasts subjected to in vitro aging protocols accumulate double-strand breaks [70], oxidative DNA damage, chromosomal and epigenetic abnormalities, telomere shortening or oxidation, and impaired DNA repair mechanisms [71]. Senescent fibroblasts garner defects in protein synthesis, folding, and degradation, in addition to defects in posttranslational modifications such as oxidation and cross-linking, which affect protein homeostasis (quantitative and qualitative of the cellular proteome). These changes cause senescent fibroblasts to display biomarkers such as increased senescence-associated beta-galactosidase (SA-β-gal), p16INK4a, and p21CIP1/WAF1 [72‒74].

Indeed, senescent fibroblasts in the skin can cause harmful effects through different mechanisms. UV-induced dermal senescence can alter the ECM as well as the function of adjacent cells, increasing the risk of carcinogenesis. For example, the cytokines IL-1α, IL-1β, ΙL-6, and TNF-α, are highly secreted by senescent cells and have been reported to induce skin carcinogenesis. Furthermore, the secretion of MMPs as a consequence of photodamage leads to collagen degradation, epithelial-mesenchymal conversion, angiogenesis, and inflammation [75, 76]. In cultured fibroblasts, UVA and/or a combination of UVA and UVB upregulate MMP-1 [77, 78], leading to skin aging phenotypes.

It has also been reported that an age-dependent increase in human fibroblast senescence occurs, as indicated by p16INK4a and SA-β-gal expression in skin biopsies from donors across the age groups of 0–20 years, 21–70 years, and 71–95 years [79]. Analysis of primary human dermal fibroblasts in multiple in vitro aging models, including UVB irradiation and accelerated proliferation of human dermal fibroblasts in young versus elderly donors, revealed reduced cell growth rate and premature senescence [80]. Further reports indicate that young skin is more resilient to wound healing, particularly in the context of chronic wounds that accumulate senescent cell phenotypes [81, 82]. However, a transient induction of senescent cells occurs in normal acute wound healing and could be beneficial [83]. These findings implicate senescent fibroblasts as a potential target for reducing the negative effects on the ECM due to SASP factors and for enhancing dermal skin rejuvenation.

Initial reports that conveyed an inverse association between senescent cell burden and health span led to the advent of senolytics – a class of drugs that selectively clears senescent cells [84‒86]. The impact of senescent cell accumulation was demonstrated when killing senescent cells via a suicide gene in a mouse model of premature aging reduced age-related diseases, such as sarcopenia, cataracts, and loss of subdermal adipose tissue in progeroid mice [87] and adipose and metabolic dysfunction in naturally aged mice [88]. Therapeutic interventions that target senescent cells are categorized as senotherapeutics. Specifically, modulation of cellular senescence can be achieved by selective induction of cell death (senolytics) or SASP inhibition (senomorphics). Skin presents as an ideal site for senotherapeutic testing due to its accessibility and established characterization. However, translation of senotherapeutics has been limited by the need for better in vitro models of skin aging for testing. Few models of skin aging have been described, and they are limited by cell type [89‒91].

A hypothesis-driven, mechanism-based drug discovery approach, stemming from the observation that senescent cells resist apoptosis, led to the development of the first senolytic drugs [84]. In particular, agents that transiently decrease anti-apoptotic regulators, such as Src kinases or Bcl-xL or other BCL-2 family members, were effective in disabling defenses of senescent cells against their own pro-apoptotic SASP, causing them to undergo apoptosis [86, 92]. Next, bioinformatics approaches were utilized to find compounds whose mechanisms of action targeted these senescent cell anti-apoptotic pathways. These agents included dasatinib (D), the Src tyrosine kinase inhibitor, and quercetin (Q), a naturally occurring flavonoid found in apple peels that targets other senescent cell anti-apoptotic pathways. First-generation senolytics also include fisetin, luteolin, curcumin, navitoclax (ABT263), and procyanidin C1 among others [84, 86, 93‒96] (PMID: 34873338). Second-generation senolytic agents are being identified through other drug discovery methods, including random high-throughput drug library screens, vaccines, toxin-loaded nanoparticles preferentially lysed by senescent cells, and immunomodulators [45, 97‒99]. In particular, the first-generation senolytic dasatinib and quercetin (D + Q) showed trends of reducing p16 and p21 expression in the human epidermis, suggesting their potential efficacy [100].

Senomodifiers or senomorphics are drugs that suppress the adverse effects of senescent cells without directly clearing them, such as JAK inhibitors [101] or rapamycin [102]. Rapamycin, which targets the mTOR pathway regulating cell growth, metabolism, protein synthesis, and autophagy, has been found to reduce senescent cells in human skin, specifically dermal fibroblasts [56, 103], possibly because the SASP spreads senescence [92] and, hence, inhibiting the SASP could reduce senescent cell burden. Rapamycin inhibits the upregulation of IL-1α in senescent fibroblasts, which subsequently blocks IL-1α-induced secretion of other pro-SASP factors [104‒106]. In accordance, rapamycin reduced signs of cellular skin aging in murine skin fibroblasts following UVB irradiation [105]. Indeed, 5 μm rapamycin significantly decreased SA-β-gal-positive cells, preserved elongated fibroblast morphology, and attenuated irradiation-induced reactive oxygen species release [105]. This was also described with the senomorphic and mTOR inhibitor, AZD8055, in foreskin fibroblasts [107]. Taken together, these observations suggest that targeting cellular senescence, in part, may contribute to skin rejuvenation and overall skin health. In addition, senotherapeutics could potentially block cancer pathways associated with cellular senescence, making them candidates to treat or prevent precancerous lesions, such as actinic keratoses.

This review highlights the importance of understanding cellular mechanisms of skin aging, especially cellular senescence. Age-dependent physiological consequences of epidermal (keratinocytes and melanocytes) aging and dermal (fibroblasts) aging considerably affect skin health in the elderly population. Targeting cellular senescence as a driver of biological aging may allow modulation of age-related dysfunction to alleviate multimorbidity. However, there is need for future studies to evaluate senescent cell types and interactions in skin using large-scale datasets and bioinformatics. With deeper understanding of cellular senescence in skin aging, applications of senotherapeutics for skin aging raise many possibilities. Can senotherapeutics reverse skin aging phenotypes resulting from premature senescence and/or photoaging? How can we selectively target senescent cells that compromise skin tissue functionality while retaining the evolutionary benefit of senescence as a barrier to tumorigenesis? These questions warrant further research into testing senotherapeutics in the context of human skin aging.

We thank Ms. Traci Paulson for her contribution to formatting the manuscript.

Patents on senolytic drugs to J.L.K. and T.T. are held by the Mayo Clinic. S.P.W. has a nonrelevant financial interest in Rion LLC. The authors have no financial interest to declare in relation to the content of this article. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies.

This work was supported by Robert and Arlene Kogod Center on Aging (S.P.W.); National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K.), AG082919 (S.P.W), and AR076347 (A.G.); the Translational Geroscience Network (AG061456: J.L.K.); the Connor Group (J.L.K.); Robert J. and Theresa W. Ryan (J.L.K.); the Noaber Foundation (J.L.K.); and the Mayo Clinic Medical Scientist Training Program institutional training grant (T32 GM065841, G.T.Y.).

S.P.W., J.D.C., P.D., G.Y., J.Q.Y., A.G., T.T., and J.L.K. contributed to the writing and review of the manuscript. J.L.K. approved the final version of the review article.

1.
Dodig
S
,
Cepelak
I
,
Pavic
I
.
Hallmarks of senescence and aging
.
Biochem Med
.
2019
;
29
(
3
):
030501
.
2.
López-Otín
C
,
Blasco
MA
,
Partridge
L
,
Serrano
M
,
Kroemer
G
.
The hallmarks of aging
.
Cell
.
2013
;
153
(
6
):
1194
217
.
3.
Gruber
F
,
Kremslehner
C
,
Eckhart
L
,
Tschachler
E
.
Cell aging and cellular senescence in skin aging: recent advances in fibroblast and keratinocyte biology
.
Exp Gerontol
.
2020
;
130
:
110780
.
4.
Halprin
KM
.
Epidermal “turnover time”: a re-examination
.
Br J Dermatol
.
1972
;
86
(
1
):
14
9
.
5.
Ho
CY
,
Dreesen
O
.
Faces of cellular senescence in skin aging
.
Mech Ageing Dev
.
2021
;
198
:
111525
.
6.
Puizina-Ivic
N
.
Skin aging
.
Acta Dermatovenerol Alp Pannonica Adriat
.
2008
;
17
(
2
):
47
54
.
7.
Keyes
BE
,
Liu
S
,
Asare
A
,
Naik
S
,
Levorse
J
,
Polak
L
.
Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin
.
Cell
.
2016
;
167
(
5
):
1323
38.e14
.
8.
Pilkington
SM
,
Bulfone-Paus
S
,
Griffiths
CEM
,
Watson
REB
.
Inflammaging and the skin
.
J Invest Dermatol
.
2021
141
4S
1087
95
.
9.
Sreedhar
A
,
Aguilera-Aguirre
L
,
Singh
KK
.
Mitochondria in skin health, aging, and disease
.
Cell Death Dis
.
2020
;
11
(
6
):
444
.
10.
Ke
Y
,
Wang
XJ
.
TGFβ signaling in photoaging and UV-induced skin cancer
.
J Invest Dermatol
.
2021
141
4S
1104
10
.
11.
Niedernhofer
LJ
,
Gurkar
AU
,
Wang
Y
,
Vijg
J
,
Hoeijmakers
JHJ
,
Robbins
PD
.
Nuclear genomic instability and aging
.
Annu Rev Biochem
.
2018
;
87
:
295
322
.
12.
Chakravarti
D
,
LaBella
KA
,
DePinho
RA
.
Telomeres: history, health, and hallmarks of aging
.
Cell
.
2021
;
184
(
2
):
306
22
.
13.
Sen
P
,
Shah
PP
,
Nativio
R
,
Berger
SL
.
Epigenetic mechanisms of longevity and aging
.
Cell
.
2016
;
166
(
4
):
822
39
.
14.
Labbadia
J
,
Morimoto
RI
.
The biology of proteostasis in aging and disease
.
Annu Rev Biochem
.
2015
;
84
:
435
64
.
15.
Aunan
JR
,
Watson
MM
,
Hagland
HR
,
Søreide
K
.
Molecular and biological hallmarks of ageing
.
Br J Surg
.
2016
;
103
(
2
):
e29
46
.
16.
Picca
A
,
Guerra
F
,
Calvani
R
,
Bucci
C
,
Lo Monaco
MR
,
Bentivoglio
AR
.
Mitochondrial dysfunction and aging: insights from the analysis of extracellular vesicles
.
Int J Mol Sci
.
2019
;
20
(
4
):
805
.
17.
Regulski
MJ
.
Cellular senescence: what, why, and how
.
Wounds
.
2017
;
29
(
6
):
168
74
.
18.
Ren
R
,
Ocampo
A
,
Liu
GH
,
Izpisua Belmonte
JC
.
Regulation of stem cell aging by metabolism and epigenetics
.
Cell Metab
.
2017
;
26
(
3
):
460
74
.
19.
Schaum
N
,
Lehallier
B
,
Hahn
O
,
Pálovics
R
,
Hosseinzadeh
S
,
Lee
SE
.
Ageing hallmarks exhibit organ-specific temporal signatures
.
Nature
.
2020
;
583
(
7817
):
596
602
.
20.
Hayflick
L
,
Moorhead
PS
.
The serial cultivation of human diploid cell strains
.
Exp Cell Res
.
1961
;
25
:
585
621
.
21.
Hernandez-Segura
A
,
Nehme
J
,
Demaria
M
.
Hallmarks of cellular senescence
.
Trends Cell Biol
.
2018
;
28
(
6
):
436
53
.
22.
Pathak
RU
,
Soujanya
M
,
Mishra
RK
.
Deterioration of nuclear morphology and architecture: a hallmark of senescence and aging
.
Ageing Res Rev
.
2021
;
67
:
101264
.
23.
Di Micco
R
,
Krizhanovsky
V
,
Baker
D
,
d’Adda di Fagagna
F
.
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
.
Nat Rev Mol Cell Biol
.
2021
;
22
(
2
):
75
95
.
24.
Chaib
S
,
Tchkonia
T
,
Kirkland
JL
.
Cellular senescence and senolytics: the path to the clinic
.
Nat Med
.
2022
;
28
(
8
):
1556
68
.
25.
Iske
J
,
Seyda
M
,
Heinbokel
T
,
Maenosono
R
,
Minami
K
,
Nian
Y
.
Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation
.
Nat Commun
.
2020
;
11
(
1
):
4289
.
26.
Wiley
CD
,
Campisi
J
.
The metabolic roots of senescence: mechanisms and opportunities for intervention
.
Nat Metab
.
2021
;
3
(
10
):
1290
301
.
27.
Hamsanathan
S
,
Gurkar
AU
.
Lipids as regulators of cellular senescence
.
Front Physiol
.
2022
;
13
:
796850
.
28.
Abdelmohsen
K
,
Panda
A
,
Kang
M-J
,
Xu
J
,
Selimyan
R
,
Yoon
J-H
.
Senescence-associated lncRNAs: senescence-associated long noncoding RNAs
.
Aging Cell
.
2013
;
12
(
5
):
890
900
.
29.
Prata
L
,
Ovsyannikova
IG
,
Tchkonia
T
,
Kirkland
JL
.
Senescent cell clearance by the immune system: emerging therapeutic opportunities
.
Semin Immunol
.
2018
;
40
:
101275
.
30.
Höhn
A
,
Weber
D
,
Jung
T
,
Ott
C
,
Hugo
M
,
Kochlik
B
.
Happily (n)ever after: aging in the context of oxidative stress, proteostasis loss and cellular senescence
.
Redox Biol
.
2017
;
11
:
482
501
.
31.
Khavkin
J
,
Ellis
DA
.
Aging skin: histology, physiology, and pathology
.
Facial Plast Surg Clin North Am
.
2011
;
19
(
2
):
229
34
.
32.
Montagna
W
,
Carlisle
K
.
Structural changes in aging human skin
.
J Invest Dermatol
.
1979
;
73
(
1
):
47
53
.
33.
Baumann
L
.
Skin ageing and its treatment
.
J Pathol
.
2007
;
211
(
2
):
241
51
.
34.
Shin
JW
,
Kwon
SH
,
Choi
JY
,
Na
JI
,
Huh
CH
,
Choi
HR
.
Molecular mechanisms of dermal aging and antiaging approaches
.
Int J Mol Sci
.
2019
;
20
(
9
):
2126
.
35.
Watt
FM
,
Fujiwara
H
.
Cell-extracellular matrix interactions in normal and diseased skin
.
Cold Spring Harb Perspect Biol
.
2011
3
4
a005124
.
36.
Baumann
L
,
Bernstein
EF
,
Weiss
AS
,
Bates
D
,
Humphrey
S
,
Silberberg
M
.
Clinical relevance of elastin in the structure and function of skin
.
Aesthet Surg J Open Forum
.
2021
3
3
ojab019
.
37.
Driskell
RR
,
Lichtenberger
BM
,
Hoste
E
,
Kretzschmar
K
,
Simons
BD
,
Charalambous
M
.
Distinct fibroblast lineages determine dermal architecture in skin development and repair
.
Nature
.
2013
;
504
(
7479
):
277
81
.
38.
Lee
H
,
Hong
Y
,
Kim
M
.
Structural and functional changes and possible molecular mechanisms in aged skin
.
Int J Mol Sci
.
2021
;
22
(
22
):
12489
.
39.
Ge
B
,
Wang
H
,
Li
J
,
Liu
H
,
Yin
Y
,
Zhang
N
.
Comprehensive assessment of Nile Tilapia skin (Oreochromis niloticus) collagen hydrogels for wound dressings
.
Mar Drugs
.
2020
;
18
(
4
):
178
.
40.
Lovell
CR
,
Smolenski
KA
,
Duance
VC
,
Light
ND
,
Young
S
,
Dyson
M
.
Type I and III collagen content and fibre distribution in normal human skin during ageing
.
Br J Dermatol
.
1987
;
117
(
4
):
419
28
.
41.
Asserin
J
,
Lati
E
,
Shioya
T
,
Prawitt
J
.
The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials
.
J Cosmet Dermatol
.
2015
;
14
(
4
):
291
301
.
42.
Balansin Rigon
R
,
Kaessmeyer
S
,
Wolff
C
,
Hausmann
C
,
Zhang
N
,
Sochorová
M
.
Ultrastructural and molecular analysis of ribose-induced glycated reconstructed human skin
.
Int J Mol Sci
.
2018
;
19
(
11
):
3521
.
43.
Breitenbach
JS
,
Rinnerthaler
M
,
Trost
A
,
Weber
M
,
Klausegger
A
,
Gruber
C
.
Transcriptome and ultrastructural changes in dystrophic Epidermolysis bullosa resemble skin aging
.
Aging
.
2015
;
7
(
6
):
389
411
.
44.
Itahana
K
,
Campisi
J
,
Dimri
GP
.
Methods to detect biomarkers of cellular senescence
. In:
Tollefsbol
TO
, editor.
Biological aging: methods and protocols
Totowa (NJ)
Humana Press
2007
. p.
21
31
.
45.
Fuhrmann-Stroissnigg
H
,
Santiago
FE
,
Grassi
D
,
Ling
Y
,
Niedernhofer
LJ
,
Robbins
PD
.
SA-β-Galactosidase-based screening assay for the identification of senotherapeutic drugs
.
J Vis Exp
.
2019
;
148
:
e58133
.
46.
Itahana
K
,
Zou
Y
,
Itahana
Y
,
Martinez
JL
,
Beausejour
C
,
Jacobs
JJ
.
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1
.
Mol Cell Biol
.
2003
;
23
(
1
):
389
401
.
47.
Stein
GH
,
Drullinger
LF
,
Soulard
A
,
Dulić
V
.
Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts
.
Mol Cell Biol
.
1999
;
19
(
3
):
2109
17
.
48.
Victorelli
S
,
Lagnado
A
,
Halim
J
,
Moore
W
,
Talbot
D
,
Barrett
K
.
Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction
.
The EMBO J
.
2019
;
38
(
23
):
e101982
.
49.
Freund
A
,
Laberge
RM
,
Demaria
M
,
Campisi
J
.
Lamin B1 loss is a senescence-associated biomarker
.
Mol Biol Cell
.
2012
;
23
(
11
):
2066
75
.
50.
Freund
A
,
Orjalo
AV
,
Desprez
P-Y
,
Campisi
J
.
Inflammatory networks during cellular senescence: causes and consequences
.
Trends Mol Med
.
2010
;
16
(
5
):
238
46
.
51.
Ivanov
A
,
Pawlikowski
J
,
Manoharan
I
,
van Tuyn
J
,
Nelson
DM
,
Rai
TS
.
Lysosome-mediated processing of chromatin in senescence
.
J Cell Biol
.
2013
;
202
(
1
):
129
43
.
52.
Wang
AS
,
Ong
PF
,
Chojnowski
A
,
Clavel
C
,
Dreesen
O
.
Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin
.
Sci Rep
.
2017
;
7
(
1
):
15678
.
53.
Dreesen
O
,
Chojnowski
A
,
Ong
PF
,
Zhao
TY
,
Common
JE
,
Lunny
D
.
Lamin B1 fluctuations have differential effects on cellular proliferation and senescence
.
J Cell Biol
.
2013
;
200
(
5
):
605
17
.
54.
Davalos
AR
,
Kawahara
M
,
Malhotra
GK
,
Schaum
N
,
Huang
J
,
Ved
U
.
p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
.
J Cell Biol
.
2013
;
201
(
4
):
613
29
.
55.
Farage
MA
,
Miller
KW
,
Elsner
P
,
Maibach
HI
.
Characteristics of the aging skin
.
Adv Wound Care
.
2013
;
2
(
1
):
5
10
.
56.
Chung
CL
,
Lawrence
I
,
Hoffman
M
,
Elgindi
D
,
Nadhan
K
,
Potnis
M
.
Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial
.
Geroscience
.
2019
;
41
(
6
):
861
9
.
57.
Yoon
JE
,
Kim
Y
,
Kwon
S
,
Kim
M
,
Kim
YH
,
Kim
JH
.
Senescent fibroblasts drive ageing pigmentation: a potential therapeutic target for senile lentigo
.
Theranostics
.
2018
;
8
(
17
):
4620
32
.
58.
Fitsiou
E
,
Pulido
T
,
Campisi
J
,
Alimirah
F
,
Demaria
M
.
Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging
.
J Invest Dermatol
.
2021
141
4s
1119
26
.
59.
Waaijer
MEC
,
Gunn
DA
,
van Heemst
D
,
Slagboom
PE
,
Sedivy
JM
,
Dirks
RW
.
Do senescence markers correlate in vitro and in situ within individual human donors
.
Aging
.
2018
;
10
(
2
):
278
89
.
60.
Hodges
A
,
Smoller
BR
.
Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin
.
Mod Pathol
.
2002
;
15
(
11
):
1121
5
.
61.
Wang
AS
,
Nakamizo
S
,
Ishida
Y
,
Klassen
G
,
Chong
P
,
Wada
A
.
Identification and quantification of senescent cell types by lamin B1 and HMGB1 in Actinic keratosis lesions
.
J Dermatol Sci
.
2022
;
105
(
1
):
61
4
.
62.
Bennett
DC
,
Medrano
EE
.
Molecular regulation of melanocyte senescence
.
Pigment Cell Res
.
2002
;
15
(
4
):
242
50
.
63.
Bandyopadhyay
D
,
Medrano
EE
.
Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1
.
Ann N Y Acad Sci
.
2000
;
908
:
71
84
.
64.
Pawlikowski
JS
,
McBryan
T
,
van Tuyn
J
,
Drotar
ME
,
Hewitt
RN
,
Maier
AB
.
Wnt signaling potentiates nevogenesis
.
Proc Natl Acad Sci U S A
.
2013
;
110
(
40
):
16009
14
.
65.
Waaijer
ME
,
Gunn
DA
,
Adams
PD
,
Pawlikowski
JS
,
Griffiths
CE
,
van Heemst
D
.
P16INK4a positive cells in human skin are indicative of local elastic fiber morphology, facial wrinkling, and perceived age
.
J Gerontol A Biol Sci Med Sci
.
2016
;
71
(
8
):
1022
8
.
66.
Waaijer
ME
,
Parish
WE
,
Strongitharm
BH
,
van Heemst
D
,
Slagboom
PE
,
de Craen
AJ
.
The number of p16INK4a positive cells in human skin reflects biological age
.
Aging Cell
.
2012
;
11
(
4
):
722
5
.
67.
Sha
J
,
Arbesman
J
,
Harter
ML
.
Premature senescence in human melanocytes after exposure to solar UVR: an exosome and UV-miRNA connection
.
Pigment Cell Melanoma Res
.
2020
;
33
(
5
):
671
84
.
68.
Hayward
N
.
New developments in melanoma genetics
.
Curr Oncol Rep
.
2000
;
2
(
4
):
300
6
.
69.
Wlaschek
M
,
Maity
P
,
Makrantonaki
E
,
Scharffetter-Kochanek
K
.
Connective tissue and fibroblast senescence in skin aging
.
J Invest Dermatol
.
2021
141
4S
985
92
.
70.
Nowotny
K
,
Jung
T
,
Grune
T
,
Höhn
A
.
Accumulation of modified proteins and aggregate formation in aging
.
Exp Gerontol
.
2014
;
57
:
122
31
.
71.
Rodier
F
,
Coppé
JP
,
Patil
CK
,
Hoeijmakers
WA
,
Muñoz
DP
,
Raza
SR
.
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
.
Nat Cell Biol
.
2009
;
11
(
8
):
973
9
.
72.
He
S
,
Sharpless
NE
.
Senescence in health and disease
.
Cell
.
2017
;
169
(
6
):
1000
11
.
73.
Huang
W
,
Hickson
LJ
,
Eirin
A
,
Kirkland
JL
,
Lerman
LO
.
Cellular senescence: the good, the bad and the unknown
.
Nat Rev Nephrol
.
2022
;
18
(
10
):
611
27
.
74.
Mohamad Kamal
NS
,
Safuan
S
,
Shamsuddin
S
,
Foroozandeh
P
.
Aging of the cells: insight into cellular senescence and detection Methods
.
Eur J Cell Biol
.
2020
;
99
(
6
):
151108
.
75.
Nagase
H
,
Visse
R
,
Murphy
G
.
Structure and function of matrix metalloproteinases and TIMPs
.
Cardiovasc Res
.
2006
;
69
(
3
):
562
73
.
76.
Pittayapruek
P
,
Meephansan
J
,
Prapapan
O
,
Komine
M
,
Ohtsuki
M
.
Role of matrix metalloproteinases in photoaging and photocarcinogenesis
.
Int J Mol Sci
.
2016
;
17
(
6
):
868
.
77.
Fagot
D
,
Asselineau
D
,
Bernerd
F
.
Direct role of human dermal fibroblasts and indirect participation of epidermal keratinocytes in MMP-1 production after UV-B irradiation
.
Arch Dermatol Res
.
2002
;
293
(
11
):
576
83
.
78.
Fagot
D
,
Asselineau
D
,
Bernerd
F
.
Matrix metalloproteinase-1 production observed after solar-simulated radiation exposure is assumed by dermal fibroblasts but involves a paracrine activation through epidermal keratinocytes
.
Photochem Photobiol
.
2004
;
79
(
6
):
499
505
.
79.
Ressler
S
,
Bartkova
J
,
Niederegger
H
,
Bartek
J
,
Scharffetter-Kochanek
K
,
Jansen-Dürr
P
.
p16INK4A is a robust in vivo biomarker of cellular aging in human skin
.
Aging Cell
.
2006
;
5
(
5
):
379
89
.
80.
Lago
JC
,
Puzzi
MB
.
The effect of aging in primary human dermal fibroblasts
.
PLoS One
.
2019
;
14
(
7
):
e0219165
.
81.
Telgenhoff
D
,
Shroot
B
.
Cellular senescence mechanisms in chronic wound healing
.
Cell Death Differ
.
2005
;
12
(
7
):
695
8
.
82.
Wilkinson
HN
,
Hardman
MJ
.
Senescence in wound repair: emerging strategies to target chronic healing wounds
.
Front Cell Dev Biol
.
2020
;
8
:
773
.
83.
Demaria
M
,
Ohtani
N
,
Youssef
SA
,
Rodier
F
,
Toussaint
W
,
Mitchell
JR
.
An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA
.
Dev Cell
.
2014
;
31
(
6
):
722
33
.
84.
Kirkland
JL
,
Tchkonia
T
.
Senolytic drugs: from discovery to translation
.
J Intern Med
.
2020
;
288
(
5
):
518
36
.
85.
Wissler Gerdes
EO
,
Zhu
Y
,
Tchkonia
T
,
Kirkland
JL
.
Discovery, development, and future application of senolytics: theories and predictions
.
FEBS J
.
2020
;
287
(
12
):
2418
27
.
86.
Zhu
Y
,
Tchkonia
T
,
Pirtskhalava
T
,
Gower
AC
,
Ding
H
,
Giorgadze
N
.
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs
.
Aging Cell
.
2015
;
14
(
4
):
644
58
.
87.
Baker
DJ
,
Wijshake
T
,
Tchkonia
T
,
LeBrasseur
NK
,
Childs
BG
,
van de Sluis
B
.
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
.
Nature
.
2011
;
479
(
7372
):
232
6
.
88.
Xu
M
,
Palmer
AK
,
Ding
H
,
Weivoda
MM
,
Pirtskhalava
T
,
White
TA
.
Targeting senescent cells enhances adipogenesis and metabolic function in old age
.
Elife
.
2015
;
4
:
e12997
.
89.
Adamus
J
,
Aho
S
,
Meldrum
H
,
Bosko
C
,
Lee
JM
.
p16INK4A influences the aging phenotype in the living skin equivalent
.
J Invest Dermatol
.
2014
;
134
(
4
):
1131
3
.
90.
Diekmann
J
,
Alili
L
,
Scholz
O
,
Giesen
M
,
Holtkötter
O
,
Brenneisen
P
.
A three-dimensional skin equivalent reflecting some aspects of in vivo aged skin
.
Exp Dermatol
.
2016
;
25
(
1
):
56
61
.
91.
Weinmüllner
R
,
Zbiral
B
,
Becirovic
A
,
Stelzer
EM
,
Nagelreiter
F
,
Schosserer
M
.
Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging
.
NPJ Aging Mech Dis
.
2020
;
6
:
4
.
92.
Xu
M
,
Pirtskhalava
T
,
Farr
JN
,
Weigand
BM
,
Palmer
AK
,
Weivoda
MM
.
Senolytics improve physical function and increase lifespan in old age
.
Nat Med
.
2018
;
24
(
8
):
1246
56
.
93.
Xu
Q
,
Fu
Q
,
Li
Z
,
Liu
H
,
Wang
Y
,
Lin
X
.
The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
.
Nat Metab
.
2021
;
3
(
12
):
1706
26
.
94.
Yousefzadeh
MJ
,
Zhu
Y
,
McGowan
SJ
,
Angelini
L
,
Fuhrmann-Stroissnigg
H
,
Xu
M
.
Fisetin is a senotherapeutic that extends health and lifespan
.
EBioMedicine
.
2018
;
36
:
18
28
.
95.
Zhu
Y
,
Doornebal
EJ
,
Pirtskhalava
T
,
Giorgadze
N
,
Wentworth
M
,
Fuhrmann-Stroissnigg
H
.
New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463
.
Aging
.
2017
;
9
(
3
):
955
63
.
96.
Zhu
Y
,
Tchkonia
T
,
Fuhrmann-Stroissnigg
H
,
Dai
HM
,
Ling
YY
,
Stout
MB
.
Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors
.
Aging Cell
.
2016
;
15
(
3
):
428
35
.
97.
Chen
Z
,
Hu
K
,
Feng
L
,
Su
R
,
Lai
N
,
Yang
Z
.
Senescent cells re-engineered to express soluble programmed death receptor-1 for inhibiting programmed death receptor-1/programmed death ligand-1 as a vaccination approach against breast cancer
.
Cancer Sci
.
2018
;
109
(
6
):
1753
63
.
98.
Muñoz-Espín
D
,
Rovira
M
,
Galiana
I
,
Giménez
C
,
Lozano-Torres
B
,
Paez-Ribes
M
.
A versatile drug delivery system targeting senescent cells
.
EMBO Mol Med
.
2018
;
10
(
9
):
e9355
.
99.
Nakagami
H
.
Cellular senescence and senescence-associated T cells as a potential therapeutic target
.
Geriatr Gerontol Int
.
2020
;
20
(
2
):
97
100
.
100.
Hickson
LJ
,
Langhi Prata
LGP
,
Bobart
SA
,
Evans
TK
,
Giorgadze
N
,
Hashmi
SK
.
Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease
.
EBioMedicine
.
2019
;
47
:
446
56
.
101.
Xu
M
,
Tchkonia
T
,
Ding
H
,
Ogrodnik
M
,
Lubbers
ER
,
Pirtskhalava
T
.
JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age
.
Proc Natl Acad Sci U S A
.
2015
112
46
E6301
10
.
102.
Herranz
N
,
Gallage
S
,
Mellone
M
,
Wuestefeld
T
,
Klotz
S
,
Hanley
CJ
.
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
.
Nat Cell Biol
.
2015
;
17
(
9
):
1205
17
.
103.
Thapa
RK
,
Nguyen
HT
,
Jeong
JH
,
Kim
JR
,
Choi
HG
,
Yong
CS
.
Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles
.
Sci Rep
.
2017
;
7
:
43299
.
104.
Laberge
RM
,
Sun
Y
,
Orjalo
AV
,
Patil
CK
,
Freund
A
,
Zhou
L
.
MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
.
Nat Cell Biol
.
2015
;
17
(
8
):
1049
61
.
105.
Qin
D
,
Ren
R
,
Jia
C
,
Lu
Y
,
Yang
Q
,
Chen
L
.
Rapamycin protects skin fibroblasts from ultraviolet B-Induced photoaging by suppressing the production of reactive oxygen species
.
Cell Physiol Biochem
.
2018
;
46
(
5
):
1849
60
.
106.
Tomimatsu
K
,
Narita
M
.
Translating the effects of mTOR on secretory senescence
.
Nat Cell Biol
.
2015
;
17
(
10
):
1230
2
.
107.
Walters
HE
,
Deneka-Hannemann
S
,
Cox
LS
.
Reversal of phenotypes of cellular senescence by pan-mTOR inhibition
.
Aging
.
2016
;
8
(
2
):
231
44
.