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Link to original content: https://www.ncbi.nlm.nih.gov/pubmed/37997995
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Review
. 2023 Nov 2;12(11):1396.
doi: 10.3390/biology12111396.

The Skin and Inflamm-Aging

Rashi Agrawal  1 , Anne Hu  1 , Wendy B Bollag  1   2   3
Affiliations
Review

The Skin and Inflamm-Aging

Rashi Agrawal et al. Biology (Basel). .

Abstract

With its unique anatomical location facing both the external and internal environment, the skin has crucial functions, including shielding the body from damage caused by ultraviolet radiation and chemicals, preventing water loss, acting as a primary barrier against pathogens, participating in metabolic processes like vitamin D production and temperature control and relaying information to the body through sensory and proprioceptor nerves. Like all organ systems, skin is known to undergo multiple changes with aging. A better understanding of the mechanisms that mediate aging-related skin dysfunction may allow the creation of targeted therapeutics that have beneficial effects not only on aged skin but also on other organs and tissues that experience a loss of or decline in function with aging. The skin is the largest organ of the body and can contribute to serum inflammatory mediator levels. One alteration known to occur with age is an impairment of skin barrier function; since disruption of the barrier is known to induce inflammation, skin may be a major contributor to the sustained, sub-clinical systemic inflammation associated with aging. Such "inflamm-aging" may underlie many of the deleterious changes observed in aged individuals. This review explores the role of age-related skin changes, skin inflammation and inflamm-aging.

Keywords: aging; atopic dermatitis; epidermal barrier; epidermis; inflammation; keratinocytes; psoriasis; skin; xerosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Mechanisms of aging. The mechanisms thought to underlie the aging process include proteostatic dysfunction, inhibition of autophagy, mitochondrial dysfunction (which results in increased oxidative stress), stem cell exhaustion, telomere erosion, senescence (and the associated senescence-associated secretory program, or SASP), epigenetic alterations, DNA damage and genomic instability, and nutrient signaling dysfunction. These various mechanisms often increase inflammation, which leads to inflamm-aging. Modified from [15,21] and created with Biorender.com.
Figure 6
Figure 6
Possible molecular mechanisms of keratinocyte and epidermal aging. In the aged epidermis, a number of molecular changes have been observed. For example, aging keratinocytes in the epidermis have been found to express lower levels of the calcium-sensing receptor (CaSR), leading to impaired calcium signaling and reduced E-cadherin levels and cell adhesion [95]. The levels of the transcriptional co-activator peroxisome proliferator activator-γ co-activator-1 (PGC1) are also altered with age, and the genetic knockdown of PGC1 expression reproduces characteristics of aged keratinocytes/epidermis [77,81]. On the other hand, the transcriptional activity of the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), is increased with age [13]. The ability of NF-κB to induce the expression of inflammatory mediators might underlie chronic low-level inflammation associated with aging. Finally, the mRNA and protein expression of the aquaglyceroporin, aquaporin-3 (AQP3), is reduced in aged skin [88,89,90]. Because evidence supports an important role for AQP3 in keratinocyte proliferation, differentiation and migration, as well as skin hydration, wound healing and permeability barrier function [28], decreased levels of this protein might mediate, at least in part, age-related skin changes. Created with Biorender.com.
Figure 1
Figure 1
The skin. The skin comprises three layers: the epidermis, the dermis and the hypodermis. In addition to vasculature and nerve fibers, the skin also contains skin appendages, such as sweat glands, sebaceous glands and hair follicles. There are also corpuscles (Merkel cells) that allow sensation. The epidermis is also composed of multiple layers and contains several cell types. Approximately 90% of epidermal cells are keratinocytes, with interspersed melanocytes, Langerhans cells and T cells. The dermis comprises connective tissue containing fibroblasts. Created with Biorender.com.
Figure 3
Figure 3
Immune functions of the skin. The skin has several important immune functions: in addition to forming a barrier to protect against microbial invasion, keratinocytes play a role in sensing and responding to environmental insults, as do Langerhans cells, resident dendritic cells. Resident T cells, macrophages and natural killer (NK) cells also monitor the tissue for potential harmful actors. Many of these cells can be activated by microbial products (pathogen-associated molecular patterns, or PAMPs) or endogenous molecules released by endangered or damaged cells (danger- or damage-associated molecular patterns, or DAMPs). In addition, these cells can recruit other immune cells into the skin to mount an immune response. Thus, infiltrating neutrophils, monocytes/macrophages and T and B cells may also participate in the response of the immune system.
Figure 4
Figure 4
Cytokine signaling in atopic dermatitis. Atopic dermatitis lesions are characterized by elevated levels of IL-4 and IL-13, which can signal through their receptors, IL-4Rα and IL-13Rα1, respectively, to activate Janus kinase-2 (JAK2) and tyrosine kinase-2 (TYK2). These kinases phosphorylate and activate members of the signal transducer and activator of transcription (STAT) family of transcription factors, STAT1, STAT3 and STAT6. The decoy receptor, IL-13Rα2, can bind IL-13 and prevent it from binding to IL-13Rα1, thus inhibiting signaling through the JAK–STAT pathway.
Figure 5
Figure 5
Skin aging. Over time, aging skin undergoes a number of alterations that contribute to dysfunction. In addition to chronological aging, certain external stimuli can accelerate aging; these include ultraviolet (UV) and γ-irradiation and exposure to pollution and other environmental insults, such as cigarette smoke [11,50]. Skin function declines with age. Reduced extracellular matrix proteins in the dermis result in wrinkling, elastosis and thinner skin (since the dermis represents 90% of the skin thickness [52]), and abnormalities in pigmentation lead to lentigines (liver spots) and ephelides (freckles) [10]. Epidermal dysfunction results in a thinner epidermis (due to decreased proliferation of aged epidermal keratinocytes) and xerosis (from reduced production of proteins involved in skin hydration and deficiencies in the epidermal permeability barrier) [53]. Telangectasias and thinning of the subcutaneous fat (in some but not all regions of the body) [11,54] also characterize aged skin. Created with Biorender.com.
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