Ageing research: rethinking primary prevention of skin cancer

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COMMENTARY
Ageing research: rethinking
primary prevention of skin
cancer
Nobody will argue the need for effective primary prevention of
skin cancers, the most common of cancers in humans with light
skin tone. Numerous campaigns, investigations and studies,
mainly focusing on UV-protection, have been conducted with
the noble goal of reducing morbidity, mortality and the socio-
economic burden of cutaneous malignancies. Yet, can we claim
a significant impact? While educational and behavioural inter-
ventions are believed to be the cornerstone of effective primary
prevention, efficacy and long-term outcomes are controver-
sial.
1,2
Efforts to improve, for example, the reach of and adher-
ence to UV-protective measures range from simply banning
artificial UV-sources like tanning beds for minors, and legally
binding regulations for outdoor workers with excessive UV-ex-
posure in some countries, to targeted social media adds and
gamified face-apps individually predicting and visualizing the
impact of UV-radiation over time.
3,4
However, there is no rea-
son to believe that any of the current measures, as astute as they
may be, will be sufficient to address the foreseen sweeping rise of
skin cancers, particularly in ageing societies.
5
As highlighted in
Fig. 1, preventing the negative effects of UV-radiation is both
important and actionable
6
; however, external noxa are only one
piece to the skin cancer puzzle. Epidemiological studies and data
from national registries call out that older age is the greatest risk
factor for skin cancers. While one can argue that old age is a sur-
rogate for cumulative exogenous skin damage, there is mounting
evidence that biological processes of skin ageing, which are inde-
pendent of external factors, also play a substantial role in skin
carcinogenesis. This commentary aims at being thought-provok-
ing. It touches on selected endogenously triggered biological
processes linked to ageing and cancer in view of potential future
interventions for primary skin cancer prevention.
Ageing research and cancer prevention
Ageing and age-associated diseases are often referred to as fate,
being inevitable, or even natural. Yet, technically suffering from
dysfunctional, ageing tissues and organs is about as natural as suf-
fering from appendicitis or skin cancer. Not too long ago, in the
1800s, appendicitis was a death sentence and cancers were treated
by bloodletting; nowhere close to what we happily appreciate from
modern medicine today. Still, viewing ageing as a disease and
treating it as a disease is still considered science-fiction. This is
deliberately provocative, for a good reason: Ageing is actually asso-
ciated with specific cellular processes that just begin to be unrav-
elled. The objective is nothing new with first explicit longevity
research being conducted more than 50 years ago. What is new
are today’s technological advancements to understand and inter-
fere with the biology of ageing, proving that we can indeed tweak
or even reverse some ageing processes in various animal species.
While it is unlikely that we can (or even should) aim at defeating
human ageing for various reasons, modifiers of ageing will still be
able to change both healthspan (the time we live without disease)
and lifespan. After all, who would not agree to an additional 20–40
healthy years? Such advancements will be realized by a significant
reduction of age-related diseases including the prevention of can-
cers. Why? Because there is substantial overlap between the hall-
marks of cancer and the hallmarks of ageing.
7,8
Thus, addressing
biological changes of ageing will also address prerequisites of
cancerogenesis. Effective primary skin cancer prevention needs to
focus on both exogenous noxa like UV-radiation and pollution, as
well as endogenous, ageing-related risk factors including senes-
cence, mitochondrial dysfunction and impaired autophagy among
others. This task is nothing short of a feat, as it is evident that the
biology of ageing is complex: Individuals age differently, and even
organs and organelles within one individual age differentially. It
appears obvious that there will be no silver bullet to solve it all.
Instead, personalized combinations of interventions will be
required to achieve a positive causatum. Breaking this big problem
down into many smaller problems is the way to start.
Senomorphics and senolytics
The posterchild of an ageing cell is a senescent cell, a cell in perma-
nent cell cycle arrest that is still metabolically active. Today, we
know several flavours of senescence including replicative senes-
cence, and senescence due to genotoxic stress, oxidative stress,
oncogenes or dysfunctional mitochondria. Today, it is well known
that such senescent cells contribute to skin cancer development
through a senescence-associated secretory phenotype (SASP) creat-
ing a smouldering, tumour-promoting inflammation, which in the
context of ageing is often referred to as ’inflammaging’.
9
Eliminat-
ing such pathological senescent cells has been shown to significantly
reduce the onset of skin cancers in animal models.
10
It is likely that
future compounds eliminating senescent cells, so-called senolytics,
or compounds neutralizing the SASP, so-called senomorphics, will
positively affect skin cancer incidence and, as a side effect, will
lower the risks for multiple other age-related diseases.
11
However,
senescence is involved in more than just pathological inflamma-
tion.Italsoplaysanimportantroleindevelopment,wound
©2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology
JEADV 2021, 35, 2216–2218
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
DOI: 10.1111/jdv.17660 JEADV

healing, tissue homeostasis, and in tumour suppression by virtue
of, for example, oncogene-induced senescence. This complicates
the search for compounds selectively targeting inflammatory senes-
cent cells with damaging properties. Intermittent elimination of
senescent cells in the elderly might be a path forward.
Protect, repair and reverse
The accumulation of DNA damage is a well-established risk fac-
tor for skin cancer. At younger age, we are typically well
equipped with repairing such damage, or if repair is impossible,
sending cells into apoptosis and clearing them through the
immune system. The DNA damage repair (DDR) machinery is
an orchestrated, lesion- and cell-specific, energy and substrate
consuming biological process. Dermatologists are well aware of
the x-fold increased skin cancer risk in patients with impaired
DDR as, for example, observed in young patients with xero-
derma pigmentosum. The best-known inducer of DNA damage
in the skin is UV-radiation. However, and especially with older
age, cell-intrinsic oxidative DNA damage, for example, due to
dysfunctional mitochondria significantly contributes to a con-
stant rise in single-strand breaks in (senescent) epithelial cells
setting the stage for keratinocyte cancers.
12
At the same time, the
ability to respond to DNA damage decreases with lower PARP1
and SIRT1 expression, as well as reduced levels of their substrate
NAD
+
in older tissues.
13
Interventions aiming at improving and
maintaining efficient DDR throughout life will protect from,
and repair most acute genetic damage. To date futuristic, but far
from impossible, seems the idea to also reverse established dam-
age in older individuals or correct germline variants in syn-
dromic disease using gene-editing technologies.
Conclusion
Ageing is a discrete and potent inducer of skin cancers that needs
to be addressed systematically for improving skin cancer preven-
tion in the future. Whether such measures will be individual
decisions in the form of drugs and supplements, or if we will see
the augmentation of foods and drinking water similar to the
addition of iodine to salt, or fluoride to tap water, will be up for
debate. Focusing efforts on both exogenous and endogenous risk
factors for skin cancer development has the potential to reduce
incidence at unprecedented rates, but the fact remains: people
will continue to get sick and develop skin cancers, no matter
how hard we try to prevent them. For this reason, it is important
to emphasize that measures to improve public health aim to
optimize tumour prevention at scale; this is different from ame-
liorating personalized treatment strategies for individuals with
active (skin-)cancers.
14
Both propositions are equally important.
It is only by developing treatments for ageing to advance pri-
mary skin cancer prevention, coupled with improving therapy
for established skin cancers, that we can further optimize care.
Acknowledgement
Open access funding enabled and organized by ProjektDEAL.
Conflict of interest
None declared.
Funding sources
None.
C. Posch
1,2,*
1
Department of Dermatology and Allergy, School of Medicine, German
Cancer Consortium (DKTK), Technical University of Munich, Munich,
Germany,
2
Faculty of Medicine, Sigmund Freud University Vienna, Vienna,
Austria
*Correspondence: C. Posch. E-mail: christian.posch@tum.de
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©2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology
JEADV 2021, 35, 2216–2218
Commentary 2217

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©2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
on behalf of European Academy of Dermatology and Venereology
JEADV 2021, 35, 2216–2218
2218 Commentary