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as those formed by fibrillary components of the connective tissue. Additionally, these compounds may, in a
similar fashion to specific pharmacological agents, sensitize skin to UV radiation [5,42] .

ENDOGENOUS MOLECULAR MECHANISMS DETERMINING THE IMPACT OF THE SKIN
EXPOSOME
A majority of environmental stressors provoke skin damage and aging through either direct disruption
of cell and tissue structures, such as DNA damage by light radiation, or by fostering the accumulation of
toxic molecules, such as ROS, upon perturbation of cell metabolism - most importantly, mitochondrial
function [18,43] . While these events can trigger proapoptotic signaling networks, such as the p53/BclX/Bcl-2
axis and the caspase activation cascade, adaptive mechanisms have evolved to counteract these aggressions
to cell integrity and promote repair, as well as for efficiently and safely disposing of xenotoxins [Figure 1].
Reflecting the intimate relationship those molecular mechanisms have with the natural process of aging,
these adaptive networks are integrated with general cell stress responses and repair mechanisms, including
autophagy, proteostatic Unfolded Protein Responses (UPR), inflammation, and the DNA damage response
(DDR) [44-48] . All of these mechanisms have been found essential to counteract skin damage and aging and
leveraging on them is considered a priority strategy for therapeutic intervention [43,49,50] .

Antioxidant and proteostatic responses
A major aspect of cell response to exposome aggression is the deployment of adaptive responses aiming
at reducing the impact of oxidative damage to cell components. Reflecting the multiple sources of oxidant
molecular species, both endogenous (e.g., physiological metabolism, inflammatory states) and exogenous,
several stress responses also converge on the activation of these programs, as is the case for proteostatic
responses such as UPR, DDR (polyADP rybosylation, H2AX phosphorylation, and downstream networks),
the ERK/p38/JNK stress signaling network, and both bulk autophagy and mitophagy [47,48,51-55] . Importantly,
inflammation signaling (such as the NF-kB transcriptional node) is integrated with these stress responses,
feeding from and into ROS levels, and can drive tissue repair and protection as well as damage, depending
on its amplitude [49,50,54-57] . Evidence supports all these responses exerting protective and antiaging roles in
different organisms, and in human skin in particular [44-46] . In fact, natural aging is intimately associated with
the decline of these mechanisms. Identifying compounds to specifically intervene in these mechanisms is
therefore a priority for the prevention of skin aging exposome influence [58-60] .

AhR axis
AhR is a conserved helix-loop-helix nuclear receptor that, upon binding with certain low molecular
weight ligands, is released from quenching chaperones in the cytoplasm and orchestrates the expression
of different gene subsets, primarily detoxifying and antioxidant enzymes. Both exogenous, “synthetic
contaminants” and cyclic compounds generated endogenously upon exposure to UV radiation can activate
AhR [61-64] . Importantly, the sustained activation of this pathway itself underlies the physiopathology of the
impact of different xenotoxins, and its controlled modulation is currently studied intensively for therapeutic
purposes.

Stromal remodeling and repair enzymes
As stated above, a prime target of environmental damage and aging progression in the skin is the connective
tissue servicing other structures. Indeed, a key hallmark of skin insult (which can be readily detected upon
rather moderate cues such as visible light exposure) is the upregulation of certain extracellular matrix (ECM)
remodeling enzymes such as matrix metalloproteases [e.g., MMP1, matrix metalloprotease 3 (MMP3)]
and subsequent alterations in the architecture of ECM fibers [5,14,15,27,65-67] . Other skin structural components
ensuring skin barrier integrity and protection, such as loricrin, cell-cell adhesion complex components,
and E-cadherin, are accordingly highly sensitive to these responses and their changes are likely to play