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Burke. Plast Aesthet Res 2020;7:59 I http://dx.doi.org/10.20517/2347-9264.2020.154 Page 9 of 16

nonsmokers; on albumin, adducts remain for 30 days, and on collagen, for up to 10 months. Oxygen
delivery is impeded and collagen structure is disrupted, leading to extrinsic aging of the skin.

The long-term exposure of mice to cigarette smoke and UV results in barrier disruption, with
transepidermal water loss, erythema, telangiectasis, decreased elasticity, visible crepe-like skin, and an
[43]
increased incidence of benign epitheliomas and squamous cell carcinomas . Increased mRNA for the
[44]
metalloproteinases MMP-1 and -3 with consequent breakdown of collagen I and III as well as of elastic
tissue is seen, accelerating extrinsic aging.

MECHANISM OF DETOXIFICATION: THE AHR
AHR evolved to detoxify food and airborne toxins. The AHR is found on cells of the gastrointestinal
tract, pulmonary epithelium, and is especially highly expressed on all cells of the skin - keratinocytes,
fibroblasts, and melanocytes as well as on regulatory T-cells and dendritic cells. The AHR recognizes
and binds xenobiotic pollutants, then signals gene transcription of enzymes and inflammatory cytokines
[45]
to metabolize these foreign substances . The AHR plays a key role in barrier function, pigmentation
[46]
regulation responding to environmental onslaughts, and skin inflammation . Specific ligands activate
specific genes. In the epidermis, UVB is absorbed by the amino acid tryptophan to form the photoproduct
6-formylindolo[3,2-b]carbazole (FICZ) and indoles which bind with high affinity to the AHR to induce the
protective signaling cascade. Other potent ligands are the PAHs of tobacco smoke and city pollution as well
as pesticide components such as tetrachlorodibenzo-p-dioxin (TCDD), the contaminant of Agent Orange,
and even normal skin flora such as bacteria (non-pathogenic as well as pathogenic staphylococci) and yeasts
(Malassezia furfur).

As seen in Figure 4, the inactive AHR is incorporated into a multi-protein complex in the cellular
cytoplasm. Binding of the pollutant ligand generates a conformational change that breaks this complex so
that ligand-AHR enters the nucleus where it dimerizes with AHR nuclear translocator (ARNT). This dimer
is a transcription factor which binds to genes to induce DNA transcription. AHR can selectively induce
transcription of NF-κB, leading to inflammatory cytokines such as NRF2 (which activates antioxidants) as
well as to cell cycle (proliferation) and immune modulators.

Alternatively, the ligand-AHR can induce the AHRR gene which inactivates the AHR by transcribing co-
[47]
repressors . Other inhibition of AHR is regulated by expulsion of the ligand-AHR from the nucleus for
degradation in the cytoplasm. Thus overstimulation by the pollutant-ligand-AHR complex is curtailed.
The co-chaperones that are released by the dissociation of the initial cytoplasm AHR complex after ligand
binding lead to important cellular reactions: The heat shock proteins which are co-chaperoned by p23
stabilize or refold proteins that act to mitigate cellular stress; p23 also binds to the progesterone receptor
that transports progesterone to the nucleus; the oncogene cSRC binds to the EGFR leading to activation of
cSRC kinase and carcinogenesis.

EPIDEMIOLOGICAL CORRELATION OF EXTRINSIC SKIN AGING AND POLLUTION
Outdoor pollution
Vierkötter et al. published an impressive epidemiological study showing the impact of urban pollution
[48]
on aging skin on four-hundred Caucasian women (70-80 years old) who had previously enlisted in a study
of the effect of industrial pollution on pulmonary aging. Half lived in urban Rohr and half in rural Bergen.
All were evaluated by the SCINEXA scale which distinguishes intrinsic from extrinsic aging. Childhood
sun exposure and smoking history were evaluated for each patient, and exposure to traffic and industrial
emission at each individual’s home were measured. The researchers concluded that traffic-generated PM
nanoparticles produced 16% more lentigines on the forehead and 17% more on the cheeks for each quartile