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. Author manuscript; available in PMC: 2022 Mar 10.
Published in final edited form as: Mech Ageing Dev. 2020 Jul 15;190:111315. doi: 10.1016/j.mad.2020.111315

Its written all over your face: the molecular and physiological consequences of aging skin

WE Lowry 1,2,3,4,5
PMCID: PMC8911920  NIHMSID: NIHMS1615998  PMID: 32681843

Abstract

Perhaps the most recognizable consequences of tissue aging are manifest in the skin. Hair graying and loss, telltale wrinkles, and age spots are indicative of physiological aging symptoms, many of which are analogous to processes in other tissues as well with less visible outcomes. While the study of skin aging has been conducted for decades, more recent work has illuminated many of the fundamental molecular and physiological causes of aging in the skin. Recent technological advances have allowed for the detection and quantification of a variety of physiological triggers that lead to aging in the skin and molecular methods have begun to determine the etiology of these phenotypic features. This review will attempt to summarize recent work in this area and provide some speculation about the next wave of studies.

Hallmark phenotypes of aging in skin

Superficially, signs of aging skin are obvious including hair thinning, hair graying, wrinkles and discoloration. Less obvious is what is occurring at the physiological level to produce these symptoms of aging. Work from a wide variety of labs has shown that aged skin shows epidermal and dermal thinning, miniaturization of follicles, impaired wound healing, and ineffective melanogenesis, and increased susceptibility to carcinogenesis.

Thinning of skin

As with most tissues, aging in the skin leads to profound morphological changes to the tissue. The most obvious changes are general thinning of each of the various layers. Careful quantification of epidermis and dermis have shown a substantial decrease in the number of cell layers of each(Lavker et al., 1986; Lavker et al., 1987; Longo et al., 2013; Matsumura et al., 2016). Thinning of the epidermis is associated with Asteatosis, or loss of barrier function(Lavker et al., 1986; Rinnerthaler et al., 2015). Barrier function is the primary responsibility of the epidermis as it creates a waterproof seal that prevents general dehydration(Ellis et al., 2019; Fuchs, 1998; Fuchs, 2008). The secondary function of the barrier is to prevent infection due to microorganisms. Barrier dysfunction due to aging is known to be associated with increased risk of infection and impaired wound healing, both of which are major clinical concerns(Hu et al., 2017; Suga et al., 2014; Wang et al., 2018). Thinning of the dermis is thought to be due to loss of collagen secretion by dermal fibroblasts. Due to the fact that the dermis represents a large portion of the total thickness of the skin, thinning of the dermis is responsible for major morphological changes in skin, including wrinkles.

Thinning hair

Another obvious phenotype associated with aging is hair loss, or Alopecia. Alopecia can be caused by chemotherapy, stress, androgen imbalance, autoimmunity, or aging. Aging associated Alopecia is known to be associated with follicle quiescence and miniaturization(Birch et al., 2001; El-Domyati et al., 2009; Matsumura et al., 2016; Sinclair et al., 2005). Hair follicles go through regular cycles of growth, degeneration and regeneration(Fuchs et al., 2001). The regenerative phase is mediated by hair follicle stem cells, whose activity appears to wane with aging(Lay et al., 2016; Van Neste and Tobin, 2004). Follicles that fail to activate due to aging retain stem cells, but do miniaturize relentlessly. As a result, hair shafts narrow and shorten with aging, leading to a “thinning” hair appearance. Eventually, it is thought that some follicles are lost completely thereby completely revoking the ability for regeneration.

Hair graying

Hair graying is probably the first major sign of aging for most people. Pigmentation of hair shafts is due to melanocytes injecting pigment into the keratinocytes that eventually differentiate to create the hair shaft. New melanocytes are born at the start of each hair cycle, and are differentiated from proliferative Melanocyte Stem Cells(Liu et al., 2019; Nishimura et al., 2005; Steingrimsson et al., 2005; Tobin and Paus, 2001). If the melanocyte stem cells fail to activate, melanocytes are not formed, and thus pigmentation of hair follicle keratinocytes is absent, and the hair shafts emerge as gray or white. It is interesting that both hair follicle stem cells and melanocyte stem cells are activated at the start of the hair cycle and are known to be intimately associated within the follicle(Chang et al., 2013; Tanimura et al., 2011). There is even evidence that the two stem cell populations can signal to each other(Chang et al., 2013; Rendl et al., 2005). The fact that hair graying generally precedes aging-induced alopecia could point to differential sensitivity to age related signaling and potentially provide novel targets for the study of aging.

Increased susceptibility to cancer

For all tissues, aging is considered to be the most prominent risk factor for cancer(Klein et al., 2007; Lauri et al., 2014; Singh et al., 2018; Stoll et al., 2013; Tyner et al., 2002; Van Neste and Tobin, 2004; Wei, 1998). It is certain that aged tissues show increased mutational burden due to accumulation of DNA damage and mistakes during DNA replication, particularly in proliferative tissues such as the epidermis(Klein et al., 2007; Lauri et al., 2014; Martincorena et al., 2015; Murai et al., 2018; Nassar et al., 2015; Singh et al., 2018; Tyner et al., 2002; Van Neste and Tobin, 2004; Wei, 1998). DNA sequencing of sun-exposed skin from healthy individuals uncovers mutations and copy number variations in established oncogenes and tumor suppressors with 100% penetrance(Martincorena et al., 2015). Less well understood is the contribution of chronic inflammation and failed wound healing to cancer initiation and progression in aged skin. Furthermore, there is some controversy as to whether there is a link between developmental potential and malignancy potential in the epidermis as data from murine models and humans are conflicting(Lapouge et al., 2012; Lapouge et al., 2011; White and Lowry, 2011; White et al., 2011; Youssef et al., 2010). Regardless, it is tempting to speculate that diminished stem cell activation because of aging acts to prevent tumorigenesis; or even the converse, that stem cell aging makes tissues more tumorigenic as they have had more opportunity to accumulate mutations over time.

The cell biology of skin aging

As physiological and molecular methods have advanced, critical discoveries have been made in the elucidation of the actual causes of skin aging. From the response to DNA damage, to various forms of stem cell exhaustion, to links between wound healing and the immune response, these efforts not only shed light on the process of aging, but also point to potential interventional strategies.

DNA damage

Slow cycling cells would be expected to be less subject to mutational burden over time. Hair follicle stem cells are more quiescent than all other cells of the epidermis (label-retaining cells)(Ma et al., 2004; Morris et al., 1986; Morris and Potten, 1994; Morris and Potten, 1999; Trempus et al., 2003), but do persist in the tissue for much longer compared to their more proliferative progeny. As a result, it has been argued that HFSCs take more care to protect their genome that their progeny. A study from the Blanpain group demonstrated this experimentally showing that HFSCs a primed to induce p53 activity to mediate repair following exposure to stressors such as UV light(Nassar et al., 2015; Sotiropoulou et al., 2013). As p53 is known to be a driver of cellular senescence and therefore aging, it is possible that stem cell aging in this context is related to the enhanced care HFSCs take to protect their genome. This is also interesting in the context that HFSCs have been shown to be cells of origin for Squamous Cell Carcinoma(Lapouge et al., 2011; White et al., 2011), so perhaps this primed p53 state is critical for the prevention of tumor formation at the potential extent of response to aging.

A series of studies from Phil Jones have identified more precisely the mutational burden in the interfollicular epidermis induced by UV light(Klein et al., 2010; Martincorena et al., 2015; Murai et al., 2018). They found that low dose p53 mutant clones can outcompete p53WT cells to occupy larger patches of cells in the interfollicular epidermis, but that over time, these dynamics can revert back to more balanced proportions unless higher levels of UV radiation are provided. Therefore, the interfollicular epidermis has probably evolved to adapt to DNA damage quite well, but eventually time and UV can catch up to these cells. Again, it is likely that the mechanisms that stem cells and their progeny in the epidermis employ to prevent tumorigenesis could also make them uniquely susceptible to aging related phenotypes.

Stem cell exhaustion

A significant cause of hair follicle aging is thought to be due to exhaustion of the stem cell population. This has been variously defined as either loss of cells over time, or loss of the ability to activate them. The Nishimura lab has published several studies proposing a novel model for the process by which epidermal stem cells lose their ability to activate with age. They modeled aging in the skin to identify key molecular changes that are associated with hair defects during aging. This led to the discovery that misregulation of a collagen protein (Col17a1) leads to disrupted association with the extracellular matrix(Liu et al., 2019; Matsumura et al., 2016). Their data suggest that DNA damage associated with aging leads to degradation of Col17a1, which then leads to premature HFSC differentiation. As the HFSCs differentiate, they fail to initiate new rounds of hair growth and eventually the follicle shrinks and sometimes disappears completely. Importantly, the authors showed that forced expression of Col17a1 can prevent age mediation follicle deficits. Previous studies found a very similar phenotype with either deletion of β-catenin or Wnt10A(Andl et al., 2002; Choi et al., 2013; Lowry et al., 2005; Millar et al., 1999), key mediators of Wnt signaling, in HFSCs leading to their premature differentiation towards an interfollicular lineage. Perhaps related to this, many groups are now attempting to use gain of function of Wnt signaling to counteract aging in skin and other tissues.

The Fuchs and Yi labs showed that either aging or repeated plucking of hairs eventually led HFSC exhaustion(Keyes et al., 2013; Lay et al., 2016; Wang et al., 2016). They also took similar approaches to look for gene expression changes associated with aging and uncovered aberrant BMP signaling and tied this to the transcription factor Nfatc1(Keyes et al., 2013; Wang et al., 2016). The Fuchs lab had previously showed that Nfatc1 is important in the regulation of BMP and the Calcineurin response in regulating HFSCs quiescence. Several groups had also shown that BMP and WNT regulate HFSCs through an antagonistic interaction, and together these data provide further evidence that aging alters the threshold by which HFSCs are activated in response to changes in their niche(Greco et al., 2009; Kobielak et al., 2003; Plikus, 2012; Plikus et al., 2008; Zhang et al., 2006). The fact that HFSCs still remain in the tissue suggests that interventions that counteract the imbalance between BMP and Wnt signaling could be exploited for reversal of aging.

Melanocyte stem cells are also exhausted with aging, and this is thought to be the primary cause of hair graying(Choi and Artandi, 2009; Inomata et al., 2009; Nishimura et al., 2005; Nishimura et al., 2010; Peters et al., 2011; Steingrimsson et al., 2005; Tobin, 2009). Again, because the HFSCs and MeSCs are located in the same niche, it is clear that they should be subject to the same signaling factors and environmental insults. Therefore, it is tempting to speculate that treatments that rejuvenate one of these stem cells could have the same effect on the other.

Wound Healing Defects

One of the great medical challenges facing older populations is defective wound healing. Aged skin does not heal well after injury or surgery, and chronic wounds become targets for inflammation and infection(Keyes et al., 2016; Levy et al., 2007). A study by the Fuchs lab shed light on this issue using mouse models of aging. They discovered changes in immune cell populations and signaling through Jak-Stat signaling. Specifically, aged skin shows deficiency of Dendritic Epithelial T-Cells (DETCs) at the edge of wounds(Keyes et al., 2016). They went on to find that loss of a class of expression of Skint genes underlies this defect and that this effect is mediated downstream of Interleukin signaling through the Jak-Stat pathway. Finally, re-expression of Skint in aged mice improves wound healing, and provides a potential clinical path to improve the situation for patients suffering from chronic wounds.

Circadian rhythm

Many important features of cell biology in the skin are known to vary with the light-dark cycle, such as proliferation, barrier formation, DNA damage repair(Comaish, 1969; Kahn et al., 1968; Tanioka et al., 2009; Wang et al., 2017; Wright et al., 1984). The Benitah-Aznar and Anderson groups were the first to show that disruption of Circadian Rhythm in the epidermis is sufficient to lead to premature aging which manifests as a disruption of the hair cycle, and epidermal thinning(Geyfman et al., 2012; Solanas et al., 2017; Wang et al., 2017; Watabe et al., 2013). Clinical evidence has linked circadian defects to psoriasis and alopecia in people(Boronat et al., 2004; Chen and Chuong, 2012; Comaish, 1969; Mirmirani, 2016). Using transgenic mice to delete members of the central oscillating clock specifically in epidermal cells, both groups found significant alterations consistent with premature aging in the epidermis. While circadian rhythm itself does not appear to dramatically change during aging in the skin, gene expression related to circadian rhythm is altered(Sato et al., 2017b; Solanas et al., 2017). Remarkably, there even appears to be evidence that peripheral tissues such as the skin have their own clocks that respond to the central oscillator, but can also act independently. If this proves to be the case in humans as well, it is likely that the aging of skin could not only be affected by circadian rhythm, but perhaps even the converse is true as well.

The Benitah-Aznar lab also showed similar effects of circadian disruption in human epidermal keratinocytes, suggesting relevance to human biology, and that these effects can be influenced by caloric restriction, a well-established regulator of aging(Janich et al., 2013; Sato et al., 2017a). In addition, the Andersen group nicely showed that altered circadian rhythm affects DNA repair in the epidermis(Wang et al., 2017), suggesting a potential mechanism by which disruption of light-dark signaling can influence physiological aging of cells.

Mitochondrial mutations

Aging in many tissues has been shown to correlate with mutations in mitochondrial DNA. Whether these mutations are causative, or a result of aging has been the subject of debate. The Larsson group showed that expression of defective mitochondrial polymerase with high mutation rate leads to premature aging in a variety of murine tissues including skin(Ross et al., 2013; Trifunovic et al., 2004). This study, along with many others led to the conclusion that accumulation of mitochondrial mutations is causative in aging(Feichtinger et al., 2014; Lauri et al., 2014; Ray et al., 2000; Singh et al., 2018; Trifunovic et al., 2004; Van Neste and Tobin, 2004). However, the situation could be more nuanced and depend on the genetic background in which mutations accumulate. A tour de force study suggested that genetic variation of strains of mitochondria can have a profound impact on aging in mice(Latorre-Pellicer et al., 2016). Comparing two inbred strains of mice, it was clear that they aged at very different rates, with obvious differences in skin (hair density and pigmentation). Using embryonic stem cells, they physically swapped mitochondria from one strain into another, putting the mitochondria for the poor-aging strain into ES cells of the good-aging strain (and vice versa). Remarkably, swapping the mitochondria reversed the phenotype variance between the two strains in both directions. These data strongly suggest that genetic differences in mitochondria can be a driver of aging, and therefore one should consider mutational burden of the mitochondria in a cell as a potential contributor to aging phenotypes. Metabolic deficiencies could actually present a potential useful clinical target as extensive knowledge of metabolic enzymes and pathways has led to development of numerous small molecule regulators with the capability to modulate metabolism.

Cell competition and Senescence

Recent studies from several groups have shown that as individual cells within a tissue become less capable at proliferating within the proliferative compartment of a tissue, a cell competition paradigm takes hold(Ellis et al., 2019; Lei and Chuong, 2018; Lynch et al., 2017; Murai et al., 2018). How tissues deal with these quiescent cells has been a very active area of investigation recently. A growing consensus suggests that a balance of “winner” and “loser” cells is maintained whereby winner cells either push out or even engulf “loser” cells to prevent the losers from dominating the tissue and thereby accelerating aging. Several studies in the epidermis have demonstrated various facets of this, as this is an ideal system to model cell competition from a logistical perspective(Ellis et al., 2019; Lei and Chuong, 2018; Liu et al., 2019; Lynch et al., 2017).

A perhaps related issue has been described in several tissues, where it has been shown that deleting senescent cells from the tissue can slow the aging process in a tissue. Using transgenic animals that kill off cells that express genes related to a senescence program such as p16, several groups have shown that elimination of these cells can promote regeneration in models of aging. Furthermore, drugs that kill senescent cells (senolytics) are now a hot new therapy potentially(Hou et al., 2018; Saraswat and Rizvi, 2017; Shetty et al., 2018). It is interesting to note that while pharmacological removal of senescent cells appears to be a viable clinical approach, the epidermis has found its own method for removing such cells through evolution. Whether the “loser” cells in cell competition studies correlate with senescent cells in an aging tissue remains an open question.

Conclusion

In summarizing the existing literature on skin aging, a few themes emerge. First, a great deal is known about the process and causes of aging, as much as in any other tissue. Second, the depth of our understanding of aging in the skin has allowed for the discovery of many new aging pathways and has provided new clinical targets for potentially reversing aspects of aging in this particularly accessible tissue. Third, a birds-eye view of this field raises the intriguing notion that aging and cancer are related. Essentially, most of the established modulators of aging have also been shown influence cancer initiation or progression (DNA damage, metabolic dysfunction, inflammation), thus it is tempting to speculate that aging could be an evolutionary defense against tumor formation. The fact that aging is perhaps the top risk factor for cancer could either serve to confirm this notion or refute it, depending on the context.

While aging in the skin is perhaps the most psychologically difficult aspect to aging, it is potentially also one of the most amenable to intervention. Its prominent location at the surface makes it highly prone to damage and insults from the environment that are known to promote aging, but this also makes it the most targetable for both prevention and rejuvenation. Measures to prevent damage are obvious including sunscreen, anti-inflammatory topical medicines, moisturizers, etc. Of course, those of us for whom prevention is no longer an option, rejuvenation measures are paramount. The obvious answer to rejuvenation would be re-activation of stem cells within the tissue i.e. reverse the stem cell exhaustion described above. Many pathways have been identified to stimulate stem cell activation including metabolic manipulation (glycolysis (Flores et al., 2017)), stimulation of growth factor signaling (Wnt, Fgf etc (DasGupta and Fuchs, 1999; Greco et al., 2009; Huch et al., 2013; Kimura-Ueki et al., 2012; Leishman et al., 2013; Lowry et al., 2005; Plikus, 2012), inducing wounds to stimulate activation (chemical peel, laser activation (Fischer et al., 2010; Peters, 1991; Samargandy and Raggio, 2020). However, these should be implemented with care to avoid potential tumorigenesis, as stem cells have been proposed to be cancer cells of origin in many settings(Barker et al., 2009; Goffart et al., 2013; Goldstein and Witte, 2013; Lapouge et al., 2011; Lawson et al., 2010; Li et al., 2013; Stoyanova et al., 2013; Wang et al., 2013; White et al., 2014; White and Lowry, 2015; White et al., 2011). On the other hand, the burgeoning field of senolytics suggesting that simply removing the ‘aged’ cells from the tissue can allow for the healthier cells to dominate and perhaps aging is simply a matter of imbalance of cell competition. So instead perhaps the answer to aging in the skin is to rebalance this competition.

Regardless, it is clear that the cosmetic, aesthetic, and pharmaceutical industries see reversing aging as a key market, and so resources to both study the causes, consequences, and potential treatments of aging should continue to increase. It is imperative that the scientific community remain engaged in these areas and hold the science accountable to avoid irrational exuberance that can lead to unnecessary risks for patients and consumers.

Highlights.

  • Review of the nature of aging physiology in the skin

  • Summary of recent findings to uncover the molecular origins of aging in the skin

  • A look forward to potential rejuvenative interventions based on previous studies

Acknowledgements

I would like to thank the members of my laboratory for their enthusiasm for this type of research, it is highly stimulating and inspirational for me. I would also like to thank our ongoing funding from NIAMS which supports our efforts in this area. Finally, I apologize to those whose work I neglected to cite due to space limitations.

Footnotes

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