Skin laxity may be caused by the combination of loose skin and heavy skin. Loose skin may be the result of redundant skin after rapid weight loss, by damaged collagen, by reduced collagen production as people age, and/or by reduced muscle tone due to immobility. Skin may be heavy due to subcutaneous fat accumulation and/or due to water retention in the dermis.
Collagen is the most abundant protein in the extracellular matrix of the skin and due to its slow turnover rates it is a frequent target of modifications by reactive compounds. Collagen is damaged by sunlight exposure, endogenous- and dietary AGEs/ALEs and free radicals in general. Elevated exposure will accelerate age-related exhaustion of collagen production. Solar UV irradiation causes photoaging, characterized by fragmentation and reduced production of type I collagen fibrils that provide strength to skin. Long-term exposure to sunlight, including ultraviolet A and B, produces signs associated with photoaging and photodamage, including laxity. Exposure to UV-B irradiation suppresses collagen synthesis. Daily life low-dose UV-A1 exposures promote photoaging by affecting collagen breakdown. Responsive darkening of the skin does not prevent UV-A1-induced collagenolytic changes. Resveratrol has antioxidant properties and promotes autophagy, stimulating mitochondrial biogenesis. Topically applied Resveratrol (1%) in combination with vitamin E (1%) and baicalin (0.5%) may reduce skin laxity in 12 weeks. Topically applied Pogostemon cablin may inhibit UV-induced photaging, due to its antioxidative property. Radiofrequency produces thermal effects at various depths, promoting collagen remodeling while sparing the overlying tissue. Precise and controlled subdermal heating may promote subdermal skin tightening. Radiofrequency may be more effective than cutaneous and subcutaneous administration of CO2
AGEs/ALEs accumulate in aged skin. AGE accumulation is associated with age, smoking and obesity. AGEs (advanced glycation end products) and ALEs (advanced lipoxidation end products) are ingested with diet and formed endogenously. In diabetes, endogenous formation of AGEs is elevated, and may lead to 5-fold higher collagen glycation. Creatinine is a potent precursor of specific AGEs (HCAs), and creatinine clearance is negatively associated with accumulation of AGEs in the skin. Skin AGEs are robust long-term markers of microvascular disease progression. AGEs and ALEs are associated with age-related NADH oxidase, which may generate free radicals (superoxide), creating oxidative damage leading to cross-linking of skin proteins , such as collagen and elastin. Collagenase naturally degrades damaged collagen, but it may be unable to degrade collagen damaged by cross-linking too heavily. Crosslinking may cause the increased age-related stiffness of the skin  and stiffening of blood vessels.
The distribution of fluids in our body is regulated by the renin-angiotensin system. Estrogen and progesterone exposure have important effects on body fluid regulation by impacting blood pressure responses to sodium loads. When renal blood flow is reduced, renin is secreted, which creates Angiotensin I. Angiotensin I is converted to Angiotensin II. Angiotensin II causes the blood vessels to constrict, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of aldosterone and vasopressin  and may inhibit the effects of luteinizing hormone. These thirst- and fluid-regulating hormones respond to both osmotic and volume stimuli. Estrogen increases osmotic sensitivity.  Fluctuations in drinking behavior during the estrous cycle may be due to interaction between estrogen and angiotensin II.
Aldosterone causes the kidneys to increase the reabsorption of sodium and water into the blood (in exchange for potassium), this may also result in the absorption of fluids from the skin. Progesteron may compete with aldosterone for receptors and attenuate aldosterone-mediated sodium retention. Though progesterone and estrogen levels are elevated or suppressed simultaneously during the menstrual cycle, progesterone may increase plasma volume, independent of estrogen. Progesterone-based oral contraceptives, on the other hand, tend to decrease plasma volume. Atrial natriuretic peptide (ANP) opposes the actions of Aldosterone; it generates sodium loss. Its release is induced by exercise  and caloric restriction , and indirectly by elevated sodium levels. ANP also stimulates the breakdown of bodyfat into glycerol and free fatty acids. and the adrenoceptors (adrenaline etc, through NPR-C).
Vasopressin (anti-diuretic hormone) is subject to a circadian rhythm.. Vasopressin stimulates reabsorption of water in the kidneys, the appetite for salt, and thirst. Estrogen may indirectly modulate the activity of vasopressin. Estradiol may stimulate and inhibit vasopressin expression through different receptors. In young women, high estradiol results in lower plasma sodium (and electrolytes in general), reflecting the downward resetting of the osmoreceptors. Estradiol increases plasma volume. Estrogen (through serotonin) inhibits the vasopressin-induced appetite for salt  and may also modulate vasopressin release. Vasopressin concentrations may be highest at the beginning of painful menstruations and at ovulation. In young women taking oral contraceptives, sodium excretion may be slightly reduced in the luteal phase of the menstrual cycle  and the high estrogen may lead to greater fluid retention. The small but consistently present water retention associated with estradiol administration may be a function of greater sodium retention rather than vasopressin-induced increases in free water retention.
Water may be retained in the dermis due to elevated levels of hydrophylic compounds, such as salt, sugars and proteins. Levels of electrolytes are maintained within relatively narrow margins, as too high as well as too low levels of sodium, chloride, potassium and calcium will inhibit muscle functioning and cell functioning in general. The renin-angiotensin system regulates the amount of fluids and sodium in the body. Sodium is the most prominent cation in extracellular fluid , available for local swelling of the skin. Sodium levels are normally maintained between approximately 135-145 mmol/L. Lower levels may reseult in spasms, cramps, seizures and eventually coma. Mildly elevated levels may result in lethargy and edema, levels over 157 mmol/L are considered severe. Values above 180 mmol/L are associated with a high mortality rate. Thus, normal serum sodium fluctuations are 25% maximally.
Glucose levels in the blood are also maintained within a relatively narrow margin. Glucose is the primary source of energy for the brain. When glucose levels are too low, you will faint. A range 70 to 99 mg/dl before a meal is normal. Levels of 101–125 mg/dl may be an indication of possible prediabetes. Levels over 126 mg/dl constitute a risk of diabetes. After a 12‑hour fast, a range of 70.2 to 100 mg/dl is normal; a level of 100 to 126 mg/dl is considered a sign of prediabetes. A level of less than 140 mg/dl, 90 minutes after a meal is considered normal. 24 hours serum glucose fluctuations may be about 100% maximally. Fasting serum glucose levels may fluctuate 39%. Taking also in consideration that the total amount of sugar in the blood is only 5 grams (2 sugar packets for coffee or tea) , the role of sugar in water retention in the skin is negligible.
Protein levels may vary much more widely, as it is the main structural component of cells, and cells desintegrate and are (re)constructed continuously. Differences between upper and lower serum reference values for some individual amino acids are 271% (taurine), 289% (glycine), 625% (hydroxyproline), 769% (glutamic acid), 1000% (methionine) and 3067% (cystine). These value are for fasting individuals (24 hours fluctuations will be larger)  During the day, protein degradation remainders may accumulate in the dermis, prior to deportation by the lymphe system  during the night. One of the main functions of the lymph system is to provide an accessory return route (the lymphatics) to the blood for the surplus ~3 litres of fluid that did not get reabsorbed into the blood ; the removal of interstitial fluid from tissues. The absorption of protein by the lymphatics is accompanied by salt and water in the same concentrations that exist in the tissue fluid. The disappearance of sodium from subcutaneous tissue is much more rapid than that of protein. Ions are principally cleared from the extrastitial fluid by direct diffusion into the blood stream. Sodium reabsorption is pressure controlled. Edema fluid is high in protein.
Even from the healthy adult human gastrointestinal tract, immunologically significant amounts of dietary proteins are absorbed , such as from milk or eggs. In healthy adults, about 2% of undigested dietary protein is absorbed from the intestinal tract. Exposure to dietary antigens may, or may not potentiate immune responses.  In (90% of ) healthy adults undegraded dietary antigens are absorbed after a meal (containing ovalbumin from egg whites; made up of 385 amino acids), and circulate regularly in minute amounts apparently as native protein and/or as immune complexes, mostly containing IgG antibodies , and occasionally IgA antibodies. In the small intestine, the antibody secreting cells are primarily IgA (~80%), IgM (15–20%), and IgG (3–4%) -secreting cells. These immunoglobulins are actively transported accross the epithelium via immunoglobulin receptors. The uptake route strongly influences immune responsiveness. IgA-deficiency is associated with higher levels of systemic antibody responses to foods antigens  and with allergies. The level of IgA corresponds with the level of protection against sensitization. Systemic sensitization to foods may reflect a lack of appropriate compartmentalization of food antigens. In non-sensitized individuals there is systemic immunological tolerance (“oral tolerance”), as opposed to sensitized individuals, such as with celiac disease or food allergies.
Heating reduces epithelial transport and triggering of reactions (immune responses; the sensitizing effect). Heating of food with various ingredients (eg eggs and wheat) may result in the formation of insoluble aggregates. Protein-rich food matrices delay gastrointestinal degradation and reduce epithelial transport of food allergens and the subsequent sensitizing effect (immune responses). Food-specific antibodies in circulation are commonly found despite a state of clinical tolerance to that particular food. Antibodies for wheat- and milk-proteins are found in varying levels in healthy (symptom-free) individuals. Uptake of proteins from eggs, peanuts and milk is increased by the presence of long-chain troglycerides (in those foods). Peptide fragments from digested peanut proteins may still evoke allergic reactions. Many other allergens are resistant to digestion, as from mustard , Brazil nuts , sesame seeds , grapes  and cherries.
Several milk proteins are relatively resistant against proteolysis in the gastrointestinal tract, such as κ-casein, lysozyme, haptocorrin, α-lactalbumin (binds to Ca2+ and Zn2+), lactoperoxidase, and quantitatively most significant: lactoferrin and secretory immunoglobulin A. (Also protected against proteolysis ) Milk also contains physiologic significant amounts  of protease inhibitors α1-antitrypsin and antichymotrypsin that escape digestion  and may limit the activity of pancreatic enzymes , particularly preventing the degradation of lactoferrin. Lactoferrin may bind to iron  facilitating its uptake, but not by lactoferrin from cow's milk in humans (due to different receptor affinity). β-casein may bind to calcium , keeping it soluble, thus facilitating its absorption. Haptocorrin binds to vitamin B12 in milk , facilitating its uptake. Folate-binding protein in milk  is also relatively protected against enzymatic degradation. Similarly, IGF-binding proteins bind to insulin-like growth factors , protecting them from being digested.
Some peptides from rapeseed  and part of the orally ingested opioid peptides from spinach (from d-ribulose-1,5-bisphosphate carboxylase/oxygenase) and soy also survive digestion (after being released from the β-Conglycinin β-Subunit by intestinal proteases). Wheat gluten (particularly gliadin) contains various opoid peptides. Opioid peptides in general chronically induce the release of stress hormones; CRF (corticotropin-releasing factor) en ACTH (Adrenocorticotropic hormone). The resulting increase in cortisol (and other corticosteroids) evokes the breakdown of tissue proteins into smaller chuncks.
Soy contains high levels of various isoflavones / phytoestrogens. Free isoflavones are hydrophobic. About 3.2% to 5.8% of total isoflavones are 'free' (unconjugated) genistein and daidzein. Conjugating isoflavones (with glucose groups) increases water solubility of isoflavones. Most isoflavones (<65%) are conjugated to sugar molecules to form glycosides. High water soluble isoflavone glycosides are not readily absorbed across the gastrointestinal tract in adults. Metabolism of isoflavone glycosides begins with hydrolysis of the compounds to their respective aglycones, a step that must occur before the compounds can enter the systemic circulation. Genistein and daidzein (-aglycones) are conjugated with glucuronic acid by uridine diphosphate-glucuronosyltransferase or (to a much lesser extent) with sulfate by sulfotransferases. Glucuronidation occurs mainly in the intestine (genistein), kidney and particularly the liver (daidzein).
After consumption of soy, isoflavones are usually absorbed as aglycones, and occur predominantly as water-soluble glucuronide conjugates in the human milk of lactating women , and as water-soluble glucuronide conjugates in adults in general. Isoflavones primarily circulate in conjugated form. Glucuronides may represent 69–98% of circulating genistein and 40–62% of circulating daidzein. The levels of isoflavones in the blood may peak at about 6 hours after ingestion. The half lives of soy-isoflavones in the human blood are about 6 to 8 hours. Elimination half-lives were reported at ~ 4–6 hr for genistein glucuronide, 3–4 hr for daidzein glucuronide, and 5–10 hr for equol after intake of ≤100 mg of each isoflavone through soy milk. Consuming mainly unconjugated isoflavones, half-lives for genistein and daidzein may be 6–13 and 4–16 hours. The levels of isoflavones may return to baseline levels after 2–4 days.
Glucosinolates may be precursors for isothiocyanates. Glucosinolates are generally water-soluble, whereas isothiocyanates are generally hydrophobic, volatile and highly reactive. The sprouts of Brassica plants (particularly broccoli and cauliflower, but also arugula, bok choy, Brussels sprouts, cabbage, Chinese cabbage, collards, cress, daikon, kale, kohlrabi, mustard, turnip, and watercress) may contain high levels of glucosinolates. Broccoli sprouts contain primarily alkylthioglucosinolates. Glucosinolates (β-thioglucoside N-hydroxysulfates) are hydrolyzed to isothiocyanates by myrosinase (β-thioglucoside glucohydrolase). Myrosinase is normally segregated from glucosinolates and is released when plant cells are injured (chewed on). Dietary glucosinolates are also converted to isothiocyanates by the myrosinase activity of enteric microflora. Isothiocyanates are absorbed and metabolized by sequential enzymatic reactions, the first of which is conjugation with glutathione.
The major glucosinolates in mature broccoli are typically indoles: glucobrassicin, neoglucobrassicin.  Indole glucosinolates may account for 67% of the total glucosinolates in adult broccoli. (and the other Brassica ) Indole glucosinolates are hydrolyzed to indole-3-carbinol, indole-3-nitrile, indole-3-carbazole and 3,3′-diindolylmethane by myrosinase.
- Indole-3-carbinol increases catechol (C-2) estrogen production , by increasing 2-hydroxylation of estrogens , lowering levels of estradiol, estrone, estriol, and 16α-hydroxyestrone, per saldo lowering overall estrogenic stimulation. Estradiol increases plasma volume. High estrogen may lead to greater fluid retention.
- Indole-3-carbazole (a minor indole-3-carbinol derivate) may bind to the aromatic hydrocarbon receptor (which is is able to modulate melanogenesis ), similar to astaxanthin, canthaxanthin (with a feedback from P450 ), tryptophan metabolites (eg tryptamine ), heterocyclic amines , and polycyclic aromatic hydrocarbons.
- 3,3′-diindolylmethane is the primary digestive derivative of indole-3-carbinol and an androgen antagonist , downregulating androgen receptors. Androgens (dehydroepiandrosterone and androstenedione) are the precursors of all estrogens.
Edema is the extreme manifestation of dermal fluid retention. It may be measured by skin-fold thickness, which is compared to WHO reference charts. Edema of the skin may occur when the colloid osmotic pressure in the skin is significantly lower (due to higher protein) than the serum colloid osmotic pressure (due to lower protein). The relationship between serum oncotic pressure and interstitial edema is non-linear, i.e. edema becomes progressively greater per mm decrease of the oncotic pressure. The serum protein level (the serum colloid osmotic pressure) determines the excretion/retention ratio of a given water and sodium load. Of the total fluid retention, fat and muscle each may accommodate 25%, whereas the skin, which contributes only 7% to the total body weight, may accounted for 37%, and may increased its volume by roughly one third. The skin is particularly susceptible to the development of edema because its extracellular space is three times larger than the average whole-body value.
Increased intestinal permeability is a common clinical observation in patients with alcoholic liver disease , celiac disease (related to wheat gluten), diabetes mellitus , and inflammatory bowel disease . In parralel, edema is a common clinical observation in patients with alcoholic liver disease (and in alcohol intoxicated rats), celiac disease , diabetes mellitus (induced diabetes in rats), and inflammatory bowel disease (subcutaneous swelling)(mesenteric swelling).
Kwashiorkor is a type of protein-energy malnutrition where diet protein deficit is found, in spite of appropriate caloric intake. Cutaneous manifestations include abnormally dry (eczema-like) skin and edema. In severe acute malnutition, the children with edema utilize cystein more efficiently than the children without edema. In children with edema, the ratio of dermal- to serum-protein may be elevated (contributing to edema), conserving (and gradually delivering) more cysteine for construction purposes (in glutathione, mucin etc) rather than catabolism. In the edematous children, fluxes of cysteine and methionine are slower , due to a slower whole-body protein breakdown rate,  and not associated with slower actual utilization (transsulfuration and transmethylation). Also, methionine supplementation increased cysteine flux from body protein (methionine to cysteine conversion) but had no significant effect on glutathione synthesis rates (which requires cysteine). Thus edema may be the correct (slowing, sparing) response to nutrient deprivation. As elevated dermal-protein exacerbates epidermal dehydration, healing of the flaky-paint dermatitis lesions takes relatively long in the edematous children.
Moderate  to substantial amounts of alcohol temporarily destabilise the intercellular junctions of the epithelium and thus promote the absorption of materials which are normally excluded , increasing intestinal permeability , which may persist for up to 2 weeks after cessation of drinking. In alcoholics, the mucosal surface is decreased. Daily alcohol consumption disrupts intestinal barrier function throughout the gut. The deleterious effect of chronic alcohol exposure on small bowel barrier function comes first. Longer exposure to daily alcohol is required for disruption of colonic barrier, promoting intestinal hyperpermeability , which is developed in about 30% of alcoholics. Drinking alcoholics have an increased sensitivity to osmotic loads. Coma of the liver in alcoholics is related to the absorption of nitrogenous metabolites from the intestine. Even viable bacteria  and also microbial products (lipopolysaccharide, lipoteichoic acid, bacterial DNA, peptidoglycans, and verious fragments, e.g., muramyldipeptide)  may pass the epithelial mucosa, and eventually into the mesenteric lymph nodes. If the epithelium is not physically damaged, the lymphatic route might be the principal pathway of bacterial translocation. Some studies have shown an association between increased intestinal permeability and severity of cirrhosis. Oedema is commonly found in cirrhotic patients.
Author of this article is Thijs Klompmaker, born in 1966
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