Skin


AMP-activated kinase (AMPK) agonists mimic the effects of exercise, raising the possibility of a “workout pill” that could simulate the effects of vigorous activity. The applications to human health are, to mildly understate the case, significant; it sounds almost too good to be true, and it leaves one looking for the catch.

But it turns out that AMPK is activated by certain types of genotoxic stress, and contributes to UV-induced apoptosis in the skin. From Cao et al.:

AMP-activated protein kinase contributes to UV- and H2O2-induced apoptosis in human skin keratinocytes

AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H2O2-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H2O2 induce AMPK activation (Thr172 phosphorylation) in cultured human skin keratinocytes. UV and H2O2 also phosphorylate LKB1, an upstream signal of AMPK, in an EGFR dependent manner. … We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2 dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to AMPK’s pro-apoptotic effect on UV- or H2O2-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H2O2-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.

Note especially that last line (emphasis mine): activation of AMPK could exacerbate the pro-aging effects that UV light exerts on the skin. Judging from the peroxide results, this also applies to endogenously generated reactive oxygen species (ROS) — which one can’t avoid by simply staying out of the sun.

Before we panic and throw the exercise mimetic baby out with its gerontogenic bathwater, I’d want to see whether AMPK agonists like AICAR do in fact synergize with stresses like UV and peroxide to increase apoptotic cell death in the skin. If they do…well, I think we found that catch.

Advertisements

The transcription factor NF-κB has been well studied in its role as an inflammatory signaling factor, and more recently in the context of aging. In the context of inflammatory lung disease, NF-κB is downregulated by SIRT1, a pro-longevity protein. Furthermore, a focused analyses of its role in inflammaging have revealed that NF-κB expression is regulated by FOXO transcription factors, which are also involved in longevity assurance.

Fine; we know what sorts of factors can prevent NF-κB from wreaking its havoc in the first place — but what about havoc that has already been wrought? Knowing what might have inhibited NF-κB in the past is all well and good, but it’s cold comfort for individuals whose bodies are already undergoing its inflammatory ravages.

Happy news, then, from Adler et al., who report that genetic knockdown of NF-κB can actually reverse inflammatory damage in the skin of aged mice:

Reversal of aging by NFκB blockade

Genetic studies in model organisms such as yeast, worms, flies, and mice leading to lifespan extension suggest that longevity is subject to regulation. In addition, various system-wide interventions in old animals can reverse features of aging. To better understand these processes, much effort has been put into the study of aging on a molecular level. In particular, genome-wide microarray analysis of differently aged individual organisms or tissues has been used to track the global expression changes that occur during normal aging. Although these studies consistently implicate specific pathways in aging processes, there is little conservation between the individual genes that change. To circumvent this problem, we have recently developed a novel computational approach to discover transcription factors that may be responsible for driving global expression changes with age. We identified the transcription factor NFκB as a candidate activator of aging-related transcriptional changes in multiple human and mouse tissues. Genetic blockade of NFκB in the skin of chronologically aged mice reversed the global gene expression program and tissue characteristics to those of young mice, demonstrating for the first time that disruption of a single gene is sufficient to reverse features of aging, at least for the short-term.

Could NFκB inhibitors be used to turn back the clock in age-damaged skin, or in other organs? At the moment, the state of the art is decidedly not up to the task. Our own lab uses a wide range of pharmaceutical NFκB inhibitors for a variety of purposes, and the consensus is that these compounds make cells very unhappy (though we don’t know whether that is because of a direct effect on NFκB signaling or some off-target effect on other pathways). Beyond that, NFκB is actually useful in contexts where inflammation is useful, as when the immune system is fighting off infections (and some tumors).

What would be nice is if we could specifically turn off the transcription of NFκB in cells or tissues of interest, perhaps using therapeutic small RNAs or some other approach — but this is pie-in-the-sky assumption of a can opener; if we could turn off specific genes in specific cells we could basically do anything in biology. Then again, even decades before the technology becomes available, it doesn’t hurt to start compiling a prioritized list of the things we’d do with it.

The potential health benefits of green tea have been widely discussed in the press as well as the scholarly literature (e.g., see our earlier post on the ability of green tea-derived compounds to delay neurodegeneration). Add one more to the list: the green tea component epigallocatechin gallate prevents activation of collagen-degrading proteases in response to UV irradiation. This might in turn help prevent skin wrinkling, a consequence of protease action that is one of the most outwardly visible signs of aging.

Careful readers will remember a similarity between this report and another recent paper about a plant-derived compound: the plant alkaloid berberine has a similar effect on UV-irradiated skin cells. We know that senescent fibroblasts are a major source of matrix metalloproteases following DNA damage. Just as with the earlier paper, the important question is whether these plant-derived molecules are preventing activation of the tumor-suppressive senescence pathway (and therefore risking tumorigenesis later in life), or instead preventing senescent cells from engaging in a deleterious secretory program that damages the tissue microenvironment for no obvious good reason.

If you removed every living cell from a human body and looked at the result, you’d still see something recognizably human: bones, of course, and the keratins that make up our skin and hair…and, forming a fine lacework throughout the entire body, the extracellular matrix (ECM). The ECM, which is a particularly prominent feature of connective tissue, consists primarily of large protein complexes that provide structural support (e.g., collagen) as well as elasticity (e.g., the appropriately named elastin).

Elastin is involved in one of the most visible consequences of aging: Over time, elastin is broken down (possibly by proteases secreted by senescent cells), and the skin becomes less resistant to mechanical force. We fight the good fight but eventually gravity wins, and we get wrinkles, wattles, and various other sorts of unmentionable sags. This is specific to later life in part because elastin is only produced during early development and childhood: What you have when you’re an adult is basically all you’ll ever have.

Elastin also has important roles inside the body, most significantly in providing the vasculature and heart with resilience and load-bearing capacity. Indeed, as reported by Pezet et al., mice that are haploinsufficient for elastin display several vascular anomalies and signs of premature cardiac aging. These animals have high blood pressure, narrow and rigid arteries, and cardiac hypertrophy even as young adults. The mice have normal lifespans, but the strain used in these studies all die of a stereotyped set of tumors at an early-to-medium age (for a mouse), so total longevity may be uninformative here.

In light of such findings, it has been suggested (as in this review by Robert et al.) that the age-related breakdown of elastin may place an upper bound on the maximum natural lifespan of the human cardiovascular system (and therefore of any human dependent on such a system).

Solution. “More elastin” sounds obvious, though one would have to be very careful: even though elastin provides elasticity, too much of it might make the arteries and heart overly rigid and unable to perform functionally necessary deformations (think about trying to blow up two nested balloons). Furthermore, excessive deposition of ECM protein in general could result in fibrosis. I would propose a two-fold approach: attack the sources of elastin degradation — calcium deposition, sun damage, and proteases secreted by senescent cells — and in the meantime, figure out how to synthesize more elastin exactly (and only) when it’s needed, so that tissue homeostasis can be preserved without untoward consequences.

Nature‘s most recent “Insight” special section is devoted to the biology of the skin.

I was puzzled that the Insight didn’t include an article devoted to skin aging. After all, skin is the organ where the most rapid and visible advances in anti-aging therapeutics are likely to be manifested: It’s readily accessible (since it’s on the outside of the body); the regulatory hurdles for approving topical treatments are far less stringent than those for medications taken internally; and — from a financial standpoint — there’s already a huge market for the various snake oils (some more scientifically motivated than others) currently purveyed by the global pharmaceutical industry.

This glaring omission aside, I was semi-heartened to see Sheila MacNeil‘s piece on tissue engineering of the skin:

Tissue-engineered skin is now a reality. For patients with extensive full-thickness burns, laboratory expansion of skin cells to achieve barrier function can make the difference between life and death, and it was this acute need that drove the initiation of tissue engineering in the 1980s. A much larger group of patients have ulcers resistant to conventional healing, and treatments using cultured skin cells have been devised to restart the wound-healing process. In the laboratory, the use of tissue-engineered skin provides insight into the behaviour of skin cells in healthy skin and in diseases such as vitiligo, melanoma, psoriasis and blistering disorders.

The list of maladies at the end of the abstract — all of which are noble inspirations for serious clinical effort — omits “chronic loss of elasticity and regenerative capacity due to advancing age.” Still, presumably some of the tricks of the tissue-engineering trade will be useful in the effort to reverse the ravages of time in the body’s largest organ.

The Journal of Pathology‘s most recent issue is devoted entirely to the pathology of aging. From the introductory article by Martin and Sheaff:

The rising numbers and proportion of aged individuals in the population is a global demographic trend. The diseases associated with ageing are becoming more prevalent, and the associated healthcare costs are having a significant economic impact in all countries. With these changes have come great advances in our understanding of the mechanisms of ageing. The mechanisms of cellular ageing at a genetic, protein and organelle level are becoming clearer, as are some of the more complex associations between environment and ageing. System ageing is also becoming better understood, and the potential biological advantages of ageing are being explored. Many of the advances in these fields are opening up the prospect of targeted therapeutic intervention for ageing and age related disease.

The articles cut a broad swath through the field, from molecular changes in aging cells to tissue- and system-scale phenomena in immunology, reproductive endocrinology, and beyond. The authors are in many cases the same eminences grises who would have written comparable reviews in high-impact basic science journals.

J Path itself is the highest-impact journal devoted to pathology, and its readership consist primarily of MDs and academic pathology researchers. The devotion of an entire issue to this subject is just the latest example of the increasing mainstream attention being paid to the biology of aging.

For your delectation, the table of contents:

While J Path doesn’t have a newsstand price, I must say I’d be tempted to pay it for this issue.

Melatonin is a hormone involved in regulation of sleep and the circadian rhythm, as well as the immune system. The molecule has also been demonstrated to have a positive effect on lifespan in some rodent model systems, though it is unclear whether this is due to receptor-mediated functions or can instead be ascribed to its potent antioxidant activity.

A recent study by Eşrefoğlu et al. demonstrates that supplemental melatonin slows age-related deterioration, including severe mitochondrial dystrophy, in the skin of pinealectomized rats (the pineal gland is the site of melatonin production):

… The present study was aimed to determine the fine structure of the abdominal and thoracic skin in pinealectomized rats and the effect of melatonin on skin ultrastructure. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in prominent ultrastructural changes in the skin. Epidermal atrophy, disorganization and cytological atypia were obvious. Tonofilament distribution was not uniform, and intercellular space was narrow. Nuclear irregularity and heterochromatin condensation were detected. Many mitochondria were irregular and edematous with increased translucence of the matrix, either partial or total destruction of crests and frequently the presence of vacuoles, myelin figures and dense bodies. … The epidermis in melatonin administered pinealectomized rats was obviously thicker than that of pinealectomized rats. The cells of each layers had characteristic morphological and ultrastructural features. Nuclear irregularity and heterochromatin condensation were not seen. Mitochondria were generally normal in ultrastructural appearance but rarely vacuoles and myelin figures were observed. … This paper provides an additional ultrastructural evidence that the damage to mitochondria is the major contributory factor to skin aging and that melatonin has potent therapeutic effects in reducing age-related changes via protecting fine structure of the skin.

While the system may seem a little bit artificial (an major hormone-producing gland has been removed), I think the logic is sound: Pinealectomized rats undergo premature skin aging, implying that some product of the pineal is working to prevent skin aging in an unmolested rat. Adding back melatonin alone (of all the many hormones now absent) prevents this premature aging completely, implying that melatonin is the relevant pineal product.

One alternative interpretation is that the pineal produces some other product that prevents skin aging, but that the mechanism of skin aging is primarily oxidative, so that the truly gigantic doses of melatonin used here (4 mg/kg, or ~300 mg for a human adult; by comparison, the over-the-counter pills one can buy to help with jetlag or sleep disorders are 1 to 3 mg each) are acting via the compound’s antioxidant properties rather than its receptor-mediated functions.

An open question is whether supplemental melatonin will slow or prevent dermal aging in animals with intact pineal glands. The levels of melatonin produced at night do decrease with age, so it’s possible that at some point in the lifespan the hormone is present at insufficient levels to prevent the cellular damage described here. If that happens before other forces have wreaked havoc, and can therefore be considered a primary cause of early age-related decline in skin cells, then supplementation should be a good strategy for extending the healthy functionality of the body’s largest organ.

Something to think about. I’ll sleep on it.

Next Page »