This is not a blog about cosmology, nor the space-time continuum or our place in the universe. As much as I love these deep topics, today I’d like to discuss something, quite literally, more superficial: the aging of human skin.
As with other organs in our body, skin undergoes many changes as we get older. It looks different. It feels different due to loss of elasticity, and this has sparked great demand for “anti-aging” skin care products. But what is less commonly known is that there are also physiological differences in aged skin such as reduced Vitamin D production and poor wound healing. Thus, understanding the changes in skin physiology is more than just a cosmetic concern.
In the field of aging research, a molecular process that has been gaining attention over the last several years is protein glycation – the non-enzymatic modification of biological molecules with sugars. Following glycation, further rearrangements of chemical bonds form what are known as advanced glycation end products (AGEs; how apropos). The problem with AGEs is that they interact with other cellular molecules and receptors in a manner that alters gene expression, cell proliferation, and cellular production of extracellular matrix (ECM) proteins, in a deleterious fashion.
To be able to study the effect of AGEs on skin physiology, Dr. Stuchi Maria-Engler’s group, at the University of São Paulo in Brazil, has recently tissue engineered multilayered skin grafts that can be modified to study the effects of glycation. The dermal compartment is first formed by seeding a collagen I hydrogel with fibroblasts in a homogenous fashion (i.e. cells were well mixed into the gel vs. seeded on top). After the gel adopts a semi-solidified state, keratinocytes are seeded on top and are eventually exposed to air to simulate the air-liquid interface that helps promote their stratification and differentiation. To then simulate the more pathological aged skin phenotype, the synthesis process is repeated, but using collagen I – the most abundant type – that has been chemically pre-treated with a glycating agent. Targeting this one protein in vitro seems to be a reasonable choice, since extracellular matrix (ECM) proteins are major targets of glycation, and collagen I makes up a significant part of the dermal ECM.
Interestingly, when comparing these model grafts, the investigators found that when glycated collagen was used to form the dermal compartment, evidence of AGEs (e.g. one called carboxymethyllysine) could later be found in both the dermal and epidermal layers. Moreover, there were noticeable cellular and mechanical changes between the regular and modified skin grafts. For example, grafts using glycated collagen had thinner epidermal and dermal layers, as well as changes in epithelial cell stratification and patterns of cell-cell junctions. It is not hard to imagine how changes in the biomechanics and barrier properties of the skin could alter its ability to function properly.
While protein glycation of tissues in our bodies normally builds up over years, the chemical collagen modification process in Dr. Stuchi Maria-Engler’s construct can be performed over 24-72 hours. This has enabled her group to use the model as a screening tool for potential anti-AGE agents. In fact, to demonstrate the drug-screening potential of their constructs, they use the anti-glycating agent aminoguanidine (AG) as an example. For many of the readouts – e.g dermal thinning and detection of AGE deposits – co-treatment with AG significantly reduced the effects of the glycating agent.
Having a model to screen anti-AGE agents has implications beyond slowing the natural aging of the skin. In fact, diabetes, smoking, and UV exposure have also been shown to expedite AGE buildup. Of course, all models are imperfect at capturing the system they describe. The dermal compartment consists of more than just fibroblasts and is usually rich with blood vessels. Thus, the model does not capture the effect of AGEs on the immune system or the wound healing response. It is also important to remember that AGEs are likely not the sole contributor to the changes in skin with age. As a potentially contributing pathway though, the presented in vitro model may be a useful precursor to in vivo studies and could provide information that relates to AGE deposition in other tissues as well.
The AGE pathway presents many potential pharmaceutical targets that range from anti-glycating agents like AG to modifying the receptor for AGE (a.k.a. RAGE – isn’t that fantastic?). Using tissue-engineering strategies to form drug-screening platforms may reflect a not so distant contribution to the field of medicine, and time will tell how well they can predict useful clinically relevant therapeutics.
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