Life Extension Magazine®

Issue: Mar 2017

Skin ceramides, Cortisol, Tobacco, and Oral health

Skin ceramides, Cortisol, Tobacco, and Oral health

Skin ceramides

The moisturizing effect of a wheat extract food supplement on women’s skin: a randomized, double-blind placebo-controlled trial.

Ceramides, specific lipid components of the skin, represent 35-40% of the intercellular cement binding cells together and contributing to skin hydration. A wheat extract rich in ceramides and digalactosyl-diglycerides was developed by Hitex in two forms: wheat extract oil (WEO) and wheat extract powder (WEP). In vitro tests and two clinical studies demonstrated promising efficacy results with WEP on skin hydration. To confirm these early results, a double-blind, randomized, placebo-controlled study was carried out on 51 women aged 20-63 years with dry to very dry skin who received either 350 mg of WEO or placebo for 3 months. Evaluation of skin hydration on legs, arms and face, assessed at baseline (D0) and at study end (D84) was performed by the dermatologist using dermatological scores (dryness, roughness, erythema), skin hydration measurement (corneometry) and self-assessment scores (Visual Analogue Scale: VAS). Perceived efficacy was noted by participants throughout the study; tolerability and overall acceptability of the study products were evaluated by the dermatologist and the participants at the end of study. Skin hydration was significantly increased between D0 and D84 on the arms (P < 0.001) and legs (P = 0.012) in the WEO group compared with placebo. Even if no significant statistical differences between groups were observed for the dermatological evaluation, skin dryness and redness tended to be reduced in the WEO group. Moreover, from D0 to D84, the VAS index had a tendency to increase in favour of WEO for the overall skin hydration (P = 0.084) indicating that participants perceived an improvement. The WEO capsules were perceived by participants as being more effective than placebo on all skin dryness signs. In conclusion, WEO capsules were well tolerated and appreciated. After 3 months’ treatment, a significant increase in skin hydration and an improvement in associated clinical signs were observed in women with dry skin.

Int J Cosmet Sci. 2011 Apr;33(2):138-43

Evaluation of skin-moisturizing effects of oral or percutaneous use of plant ceramides.

This study was undertaken to evaluate the assay performance of two methods for measuring the water-holding capacity of the skin: Skicon-200 and Tewameter which determine the water content in the stratum corneum and transepidermal water loss, respectively. Based on these findings, we studied the effects of newly developed skin moisturizers made of plant ceramides. The within-run as well as day-to-day reproducibility of the methods were both satisfactory. When rice-derived NIPPN ceramide RC was used topically for 3 weeks by 23 healthy volunteers, the water content in the stratum corneum of the leg was significantly increased to 141% of the baseline value in comparison with that after placebo use (111%) (p < 0.05), and the transepidermal water-loss was significantly suppressed to 23% of the baseline in comparison with that after placebo use (39%) (p < 0.01). When 20 mg or 40 mg/day of corn-derived NIPPN ceramide CP was given orally for 3 weeks, the water content in the stratum corneum of the leg was significantly increased to 290% and 394% of the baseline value, respectively, in comparison with that after placebo administration (141%) (p <0.05), and the transepidermal water loss was suppressed to 33 and 14% (p < 0.05) of the baseline values, respectively, in comparison with that after placebo administration (69%). These data by Skicon-200 and Tewameter suggest that the two plant ceramides are promising as skin-moisturizing agents not only for topical use but also for oral use.

Rinsho Byori. 2007 Mar;55(3):209-15

Effect of lipid-containing, positively charged nanoemulsions on skin hydration, elasticity and erythema--an in vivo study.

Dry skin and other skin disorders such as atopic dermatitis are characterized by impaired stratum corneum (SC) barrier function and by an increase in transepidermal water loss (TEWL) leading to a decrease in skin hydration. The possibility that dermatological and cosmetic products containing SC lipids could play a part in the restoration of disturbed skin barrier function is of great interest in the field of dermatology and cosmetics. The aim of the present study was to evaluate the effect of positively charged oil/water nanoemulsions (PN) containing ceramide 3B and naturally found SC lipids (PNSC) such as ceramide 3, cholesterol, and palmitic acid on skin hydration, elasticity, and erythema. Creams of PNSC were compared to PN creams, to creams with negatively charged o/w nanoemulsion and SC lipids (NNSC) and to Physiogel cream, a SC lipid containing formulation, which is already on the market. The formulations (PN, PNSC, and NNSC) were prepared by high-pressure homogenization. After adding Carbopol 940 as thickener, particle size and stability of the creams were not significantly changed compared to the nanoemulsions. The studies were carried out on three groups, each with 14 healthy female test subjects between 25 and 50 years of age, using Corneometer 825, Cutometer SEM 575 and Mexameter 18 for measurements of skin hydration, elasticity, and erythema of the skin, respectively. The creams were applied regularly and well tolerated throughout the study. All formulations increased skin hydration and elasticity. There was no significant difference between PNSC and Physiogel. However, PNSC was significantly more effective in increasing skin hydration and elasticity than PN and NNSC indicating that phytosphingosine inducing the positive charge, SC lipids and ceramide 3B are crucial for the enhanced effect on skin hydration and viscoelasticity.

Int J Pharm. 2006 Jan 13;307(2):232-8

Stratum corneum lipids: the effect of ageing and the seasons.

Stratum corneum lipids play a predominant role in maintaining the water barrier of the skin. In order to understand the biological variation in the levels and composition of ceramides, ceramide 1 subtypes, cholesterol and fatty acids, stratum corneum lipids collected from tape strippings from three body sites (face, hand, leg) of female Caucasians of different age groups were analysed. In addition, we studied the influence of seasonal variation on the lipid composition of stratum corneum from the same body sites. The main lipid species were quantified using high-performance thin-layer chromatography and individual fatty acids using gas chromatography. Our findings demonstrated significantly decreased levels of all major lipid species, in particular ceramides, with increasing age. Similarly, the stratum corneum lipid levels of all the body sites examined were dramatically depleted in winter compared with spring and summer. The relative levels of ceramide 1 linoleate were also depleted in winter and in aged skin whereas ceramide 1 oleate levels increased. The other fatty acid levels remained fairly constant with both season and age, apart from lignoceric and heptadecanoic acid which showed a decrease in winter compared with summer. The decrease in the mass levels of intercellular lipids and the altered ratios of fatty acids esterified to ceramide 1, are likely to contribute to the increased susceptibility of aged skin to perturbation of barrier function and xerosis, particularly during the winter months.

Arch Dermatol Res. 1996 Nov;288(12):765-70

Ceramides and skin function.

Ceramides are the major lipid constituent of lamellar sheets present in the intercellular spaces of the stratum corneum. These lamellar sheets are thought to provide the barrier property of the epidermis. It is generally accepted that the intercellular lipid domain is composed of approximately equimolar concentrations of free fatty acids, cholesterol, and ceramides. Ceramides are a structurally heterogeneous and complex group of sphingolipids containing derivatives of sphingosine bases in amide linkage with a variety of fatty acids. Differences in chain length, type and extent of hydroxylation, saturation etc. are responsible for the heterogeneity of the epidermal sphingolipids. It is well known that ceramides play an essential role in structuring and maintaining the water permeability barrier function of the skin. In conjunction with the other stratum corneum lipids, they form ordered structures. An essential factor is the physical state of the lipid chains in the nonpolar regions of the bilayers. The stratum corneum intercellular lipid lamellae, the aliphatic chains in the ceramides and the fatty acids are mostly straight long-chain saturated compounds with a high melting point and a small polar head group. This means that at physiological temperatures, the lipid chains are mostly in a solid crystalline or gel state, which exhibits low lateral diffusional properties and is less permeable than the state of liquid crystalline membranes, which are present at higher temperatures. The link between skin disorders and changes in barrier lipid composition, especially in ceramides, is difficult to prove because of the many variables involved. However, most skin disorders that have a diminished barrier function present a decrease in total ceramide content with some differences in the ceramide pattern. Formulations containing lipids identical to those in skin and, in particular, some ceramide supplementation could improve disturbed skin conditions. Incomplete lipid mixtures yield abnormal lamellar body contents, and disorder intercellular lamellae, whereas complete lipid mixtures result in normal lamellar bodies and intercellular bilayers. The utilization of physiological lipids according to these parameters have potential as new forms of topical therapy for dermatoses. An alternative strategy to improving barrier function by topical application of the various mature lipid species is to enhance the natural lipid-synthetic capability of the epidermis through the topical delivery of lipid precursors.

Am J Clin Dermatol. 2003;4(2):107-29

Ceramide synthesis in the epidermis.

The epidermis and in particular its outermost layer the stratum corneum provides terrestrial vertebrates with a pivotal defensive barrier against water loss, xenobiotics and harmful pathogens. A vital demand for this epidermal permeability barrier is the lipid-enriched lamellar matrix that embeds the enucleated corneocytes. Ceramides are the major components of these highly ordered intercellular lamellar structures, in which linoleic acid- and protein-esterified ceramides are crucial for structuring and maintaining skin barrier integrity. In this review, we describe the fascinating diversity of epidermal ceramides including 1-O-acylceramides. We focus on epidermal ceramide biosynthesis emphasizing its metabolic and topological requirements and discuss enzymes that may be involved in a- and w-hydroxylation. Finally, we turn to epidermal ceramide regulation, highlighting transcription factors and liposensors recently described to play crucial roles in modulating skin lipid metabolism and epidermal barrier homeostasis. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.

Biochim Biophys Acta. 2014 Mar;1841(3):422-34

Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin?

Stratum corneum lipids are an important determinant for both water-retention function and permeability-barrier function in the stratum corneum. However, their major constituent, ceramides, have not been analyzed in detail in skin diseases such as atopic dermatitis that show defective water-retention and permeability-barrier function. In an attempt to assess the quantity of ceramides per unit mass of the stratum corneum in atopic dermatitis, stratum corneum sheet was removed from the forearm skin by stripping with cyanoacrylate resin and placed in hexane/ethanol extraction to yield stratum corneum lipids. The stratum corneum was dispersed by solubilization of cyanoacrylate resin with dimethylformamide, and after membrane filtration, the weight of the stratum corneum mass was measured. The ceramides were quantified by thin-layer chromatography and evaluated as microgram/mg stratum corneum. In the forearm skin of healthy individuals (n = 65), the total ceramide content significantly declined with increasing age. In atopic dermatitis (n = 32-35), there was a marked reduction in the amount of ceramides in the lesional forearm skin compared with those of healthy individuals of the same age. Interestingly, the non-lesional skin also exhibited a similar and significant decrease of ceramides. Among six ceramide fractions, ceramide 1 was most significantly reduced in both lesional and non-lesional skin. These findings suggest that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry skin.

J Invest Dermatol. 1991 Apr;96(4):523-6


Effect of a proprietary Magnolia and Phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial.

To determine the efficacy of a dietary supplement ingredient containing proprietary extracts of Magnolia officinalis and Phellodendron amurense in helping overweight, otherwise healthy, premenopausal female adults, who typically eat more in stressful situations manage their body weight. DESIGN: Randomized, double-blind, placebo-controlled clinical study. Setting Miami Research Associates, a clinical research organization consisting of 32 board-certified physicians, Miami, Fla. SUBJECTS: Healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scored above the national mean for women on self-reported anxiety. INTERVENTIONS: Two-hundred-fifty-mg capsules or identical placebo capsules 3 times a day for 6 weeks. MAIN OUTCOME MEASURES: Salivary cortisol levels, weight change, psychological measures of stress and anxiety. RESULTS: Twenty-eight subjects completed the study. Extracts of M officinalis and P amurense were well tolerated. There was a significant weight gain during the study for the placebo group (P < ,01), but no significant weight gain for the group receiving extracts of M officinalis and P amurense (P < .89). Paired t-tests comparing baseline to post-treatment weight showed an average gain of 1.5 kg in the placebo group and no change in the treatment group (P = .89). When groups were divided into gainers (ie, participants who gained at least 1 kg or more) and maintainers or losers, 75% of the control group were gainers versus 37% of the treatment group (P < .04). There was a nonsignificant trend for lowered average cortisol in the treatment group at the end of the study (group X time interaction, F = 1.1, P < .15). This difference was due to a treatment effect on evening cortisol. There was a marginally significant group X time interaction (P = .06), showing the treatment group tended to have lower levels of cortisol in the evening, whereas the control group tended to have higher levels of cortisol in the evening. Bedtime cortisol levels decreased in the treatment group and increased in the placebo group. Participants in both the treatment and placebo groups had improved scores on a number of psychological measures during the study. There was a correlation between perceived stress and weight change. CONCLUSION: The results of this pilot clinical study indicate that obese subjects who eat in response to stress may benefit from taking a dietary supplement ingredient containing proprietary extracts of M officinalis and P amurense. The mechanism of action appears to be through reduction of cortisol levels and possibly perceived stress, thereby helping participants maintain body weight. The sample size was small, however, and there was higher attrition in the control group than in the treatment group.

Altern Ther Health Med. 2006 Jan-Feb;12(1):50-4

Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial.

BACKGROUND: Recent research has established correlations between stress, anxiety, insomnia and excess body weight and these correlations have significant implications for health. This study measured the effects of a proprietary blend of extracts of Magnolia officinalis and Phellodendron amurense (Relora) on anxiety, stress and sleep in healthy premenopausal women. METHODS: This randomized, parallel, placebo controlled clinical study was conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scores above the national mean for women on self-reporting anxiety. The intervention was Relora (250 mg capsules) or identical placebo 3 times daily for 6 weeks. Anxiety as measured by the Spielberger STATE-TRAIT questionnaires, salivary amylase and cortisol levels, Likert Scales/Visual Analog Scores for sleep quality and latency, appetite, and clinical markers of safety. The study was conducted by Miami Research Associates, a clinical research organization in Miami, FL. RESULTS: The intent-to-treat population consisted of 40 subjects with 26 participants completing the study. There were no significant adverse events. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not effective in reducing long-standing feelings of anxiety or depression as measured using the Spielberger TRAIT questionnaire. Other assessments conducted in this study including salivary cortisol and amylase levels, appetite, body morphology and sleep quality/latency were not significantly changed by Relora in comparison to placebo. CONCLUSION: This pilot study indicates that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety. There were no safety concerns or significant adverse events observed in this study.

Nutr J. 2008 Apr 21;7:11.

Oligonol supplementation modulates plasma volume and osmolality and sweating after heat load in humans.

Oligonol is a low-molecular-weight polyphenol that possesses antioxidant and anti-inflammatory properties. This study investigated the effects of Oligonol supplementation on sweating response, plasma volume (PV), and osmolality (Osm) after heat load in human volunteers. We conducted a placebo-controlled crossover trial. Participants took a daily dose of 200 mg Oligonol or placebo for 1 week. After a 2-week washout period, the subjects were switched to the other study arm. As a heat load, half-body immersion into hot water (42°C±0.5°C for 30 min) was performed in an automated climate chamber. Tympanic and mean body temperature (Tty, mTb) and whole-body sweat loss volume (WBSLV) were measured. Changes in PV, Osm, and serum levels of aldosterone and sodium were analyzed. Oligonol intake attenuated increases in Tty, mTb, and WBSLV after heat load compared with the placebo (P<.01, P<.05, and P<.01, respectively). In addition, serum aldosterone was maintained at a relatively low degree and serum sodium was maintained at a relatively high degree with Oligonol compared to the placebo (P<.01 and P<.05, respectively). However, PV decreased and Osm increased significantly with Oligonol compared to the placebo (P<.05 and P<.05, respectively). This study demonstrates that Oligonol supplementation for 1 week can attenuate elevation of body temperature and excessive sweating under heat load in healthy humans, but interpretation of the results requires caution due to the potent diuretic effect of Oligonol.

J Med Food. 2015 May;18(5):578-83

Oligonol supplementation affects leukocyte and immune cell counts after heat loading in humans.

Oligonol is a low-molecular-weight form of polyphenol and has antioxidant and anti-inflammatory activity, making it a potential promoter of immunity. This study investigates the effects of oligonol supplementation on leukocyte and immune cell counts after heat loading in 19 healthy male volunteers. The participants took a daily dose of 200 mg oligonol or a placebo for 1 week. After a 2-week washout period, the subjects were switched to the other study arm. After each supplement, half-body immersion into hot water was made, and blood was collected. Then, complete and differential blood counts were performed. Flow cytometry was used to enumerate and phenotype lymphocyte subsets. Serum concentrations of interleukin (IL)-1β and IL-6 in blood samples were analyzed. Lymphocyte subpopulation variables included counts of total T cells, B cells, and natural killer (NK) cells. Oligonol intake attenuated elevations in IL-1b (an 11.1-fold change vs. a 13.9-fold change immediately after heating; a 12.0-fold change vs. a 12.6-fold change 1h after heating) and IL-6 (an 8.6-fold change vs. a 9.9-fold change immediately after heating; a 9.1-fold change vs. a 10.5-fold change 1h after heating) immediately and 1 h after heating in comparison to those in the placebo group. Oligonol supplementation led to significantly higher numbers of leukocytes (a 30.0% change vs. a 21.5% change immediately after heating; a 13.5% change vs. a 3.5% change 1h after heating) and lymphocytes (a 47.3% change vs. a 39.3% change immediately after heating; a 19.08% change vs. a 2.1% change 1h after heating) relative to those in the placebo group. Oligonol intake led to larger increases in T cells, B cells, and NK cells at rest (p < 0.05, p < 0.05, and p < 0.001, respectively) and immediately after heating (p < 0.001) in comparison to those in the placebo group. In addition, levels of T cells (p < 0.001) and B cells (p < 0.001) were significantly higher 1 h after heating in comparison to those in the placebo group. These results demonstrate that supplementation with oligonol for 1 week may enhance the immune function under heat and suggest a potential useful adjunct to chemotherapy in malignant diseases.

Nutrients. 2014 Jun 24;6(6):2466-77

Beneficial effect of Oligonol supplementation on sweating response under heat stress in humans.

Oligonol is a low-molecular weight polyphenol that possesses antioxidant and anti-inflammatory properties. However, nothing is known regarding the impact of Oligonol on sudomotor activity. This study investigated the effects of Oligonol supplementation on sudomotor activity during heat load in humans. Initially, we conducted a placebo-controlled, cross-over trial where participants took a daily dose of Oligonol 200 mg or placebo for one week. After a 2 week washout period, the subjects were switched to the other study arm. As a heat load, half-body immersion into hot water (42 ± 0.5 °C for 30 min) was performed in an automated climate chamber. Tympanic and skin temperatures were measured. Sudomotor activity, including onset time, sweat rate (SR) and volume (SV), active sweat gland density (ASGD), and sweat gland output (SGO), was tested in four or eight areas of skin. When compared with placebo, Oligonol attenuated increases in tympanic and skin temperatures after the heat load. There was an increasing trend in local sweat onset time, but there was a decrease in local SR, SV, ASGD, and SGO for Oligonol compared to placebo. The mean ASGD was significantly higher in the Oligonol group than in the placebo group for 10, 20, and 30 min. This study demonstrates that Oligonol appears to be worthy of consideration as a natural supplement to support more economical use of body fluids against heat stress.

Food Funct. 2014 Oct;5(10):2516-20

Oligonol supplementation attenuates body temperature and the circulating levels of prostaglandin E2 and cyclooxygenase-2 after heat stress in humans.

Oligonol, a phenolic production from lychee, has been reported to exhibit anti-oxidative and anti-inflammatory effects. This study investigated the effect of Oligonol supplementation on circulating levels of prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2, as well as body temperature, after heat stress in 17 healthy human male volunteers (age, 21.6±2.1 years). All experiments were performed in an automated climate chamber (26.0°C±0.5°C, relative humidity 60%±3.0%, air velocity less than 1 m/sec) between 2 and 5 p.m. Subjects ingested an Oligonol (100 mg)-containing beverage or placebo beverage before half-body immersion into hot water (42°C±0.5°C for 30 min). Tympanic and skin temperatures were measured and mean body temperatures were calculated. Serum concentrations of PGE2 and COX-2 were analyzed before, immediately after, and 60 min after immersion. Oligonol intake significantly prevented elevation of tympanic (temperature difference: 0.17°C at Post, P<.05; 0.17°C at Re-60, P<.05) and mean body temperatures (temperature difference: 0.18°C at Post, P<.05; 0.15°C at Re-60, P<.05), and lowered concentrations of serum PGE2 (increased by 13.3% vs. 29.6% at Post, P<.05) and COX-2 (increased by 15.6% vs. 21.8% at Post, P<.05), compared to placebo beverage. Our result suggests that Oligonol has the potential to suppress increases in body temperature under heat stress, and this is associated with decreases in serum levels of PGE2 and COX-2.

J Med Food. 2013 Apr;16(4):318-23

Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer’s disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Annu Rev Med. 2000;51:245-70

The effect of Oligonol intake on cortisol and related cytokines in healthy young men.

This study investigated the effects of Oligonol intake on cortisol, interleukin (IL)-1beta, and IL-6 concentrations in the serum at rest and after physical exercise loading. Nineteen healthy sedentary male volunteers participated in this study. The physical characteristics of the subjects were: a mean height of 174.2 +/- 2.7 cm, a mean weight of 74.8 +/- 3.6 kg and a mean age of 22.8 +/- 1.3 years. Each subject received 0.5 L water with Oligonol (100 mg/day) (n = 10) or a placebo (n = 9) daily for four weeks. The body composition, the white blood cell (WBC) and differential counts as well as the serum cortisol, IL-1beta, and IL-6 concentrations were measured before and after Oligonol intake. The cortisol concentration and serum levels of IL-1beta and IL-6 after Oligonol intake were significantly decreased compared to before treatment (P < 0.01, respectively). In addition, the rate of increase of these factors after exercise was decreased compared to the placebo group. There was no change in the WBC and differential cell counts. These results suggest that oral Oligonol intake for four weeks had a significant effect on inhibition of inflammatory markers in healthy young men.

Nutr Res Pract. 2010 Jun;4(3):203-7


Relationship between biomarkers of cigarette smoke exposure and biomarkers of inflammation, oxidative stress, and platelet activation in adult cigarette smokers.

BACKGROUND: Cigarette smoking is a risk factor for several diseases, including cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, but the role of specific smoke constituents in these diseases has not been clearly established. METHODS: The relationships between biomarkers of potential harm (BOPH), associated with inflammation [white blood cell (WBC), high sensitivity C-reactive protein (hs-CRP), fibrinogen, and von Willebrand factor (vWF)], oxidative stress [8-epi-prostaglandin F(2α) (8-epiPGF(2α))] and platelet activation [11-dehydro-thromboxin B(2) (11-dehTxB(2))], and machine-measured tar yields (grouped into four categories), biomarkers of exposure (BOE) to cigarette smoke: nicotine and its five metabolites (nicotine equivalents), 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (total NNAL), carboxyhemoglobin, 1-hydroxypyrene, 3-hydroxypropylmercapturic acid, and monohydroxybutenyl-mercapturic acid, were investigated in 3,585 adult smokers and 1,077 nonsmokers. RESULTS: Overall, adult smokers had higher levels of BOPHs than nonsmokers. Body mass index (BMI), smoking duration, tar category, and some of the BOEs were significant factors in the multiple regression models. Based on the F value, BMI was the highest ranking factor in the models for WBC, hs-CRP, fibrinogen, and 8-epiPGF(2a), respectively, and gender and smoking duration for 11-dehTxB(2) and vWF, respectively. CONCLUSIONS: Although several demographic factors and some BOEs were statistically significant in the model, the R(2) values indicate that only up to 22% of the variability can be explained by these factors, reflecting the complexity and multifactorial nature of the disease mechanisms.

Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1760-9

Smoking and mortality--beyond established causes.

BACKGROUND: Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. METHODS: We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. RESULTS: During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. CONCLUSIONS: A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society

N Engl J Med. 2015 Feb 12;372(7):631-40

Smoking as a risk factor for end-stage renal failure in men with primary renal disease.

BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.

Kidney Int. 1998 Sep;54(3):926-31

How cigarette smoke skews immune responses to promote infection, lung disease and cancer.

A complex and multilayered immune defence system protects the host against harmful agents and maintains tissue homeostasis. Cigarette smoke exposure markedly impacts the immune system, compromising the host’s ability to mount appropriate immune and inflammatory responses and contributing to smoking-related pathologies. These adverse effects on the immune system not only occur in active smokers, but also in those exposed to smoke passively in contaminated environments, and may persist for decades after exposure has ended.

Nat Rev Immunol. 2009 May;9(5):377-84

Cigarette smoking and variations in systemic immune and inflammation markers.

BACKGROUND: A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease. METHODS: Levels of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1,819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models. RESULTS: Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin [IL]-15, IL-1RA, IL-1b, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval [CI] = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1b, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking. CONCLUSIONS: Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.

J Natl Cancer Inst. 2014 Oct 1;106(11).

Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study.

CONTEXT: Cigarette smoking is a powerful risk factor for incident heart disease and stroke, but the relationship of active and passive smoking with the progression of atherosclerosis has not been described. OBJECTIVE: To examine the impact of active smoking and exposure to environmental tobacco smoke (ETS) on the progression of atherosclerosis. DESIGN: A longitudinal assessment of the relationship between smoking exposure evaluated at the initial visit and the 3-year change in atherosclerosis. SETTING: A population-based cohort of middle-aged adults from 4 communities in the United States. PARTICIPANTS: A total of 10,914 participants from the Atherosclerosis Risk in Communities (ARIC) study enrolled between 1987 and 1989. MAIN OUTCOME MEASURE: Change in atherosclerosis from baseline to the 3-year follow-up as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound and adjusted for demographic characteristics, cardiovascular risk factors, and lifestyle variables. RESULTS: Exposure to cigarette smoke was associated with progression of atherosclerosis. Relative to never smokers and after adjustment for demographic characteristics, cardiovascular risk factors, and lifestyle variables, current cigarette smoking was associated with a 50% increase in the progression of atherosclerosis (mean progression rate over 3 years, 43.0 microm for current and 28.7 microm for never smokers, regardless of ETS exposure), and past smoking was associated with a 25% increase (mean progression rate over 3 years, 35.8 microm for past smokers and 28.7 microm for never smokers). Relative to those not exposed to ETS, exposure to ETS was associated with a 20% increase (35.2 microm for those exposed to ETS vs 29.3 microm for those not exposed). The impact of smoking on atherosclerosis progression was greater for subjects with diabetes and hypertension. Although more pack-years of exposure was independently associated with faster progression (P<.001), after controlling for the number of pack-years, the progression rates of current and past smokers did not differ (P=.11). CONCLUSIONS: Both active smoking and ETS exposure are associated with the progression of an index of atherosclerosis. Smoking is of particular concern for patients with diabetes and hypertension. The fact that pack-years of smoking but not current vs past smoking was associated with progression of atherosclerosis suggests that some adverse effects of smoking may be cumulative and irreversible.

JAMA. 1998 Jan 14;279(2):119-24

Smoking and prostate cancer survival and recurrence.

CONTEXT: Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer-specific outcomes. OBJECTIVE: To assess the relation of cigarette smoking and smoking cessation with overall, prostate cancer-specific, and cardiovascular disease (CVD) mortality and biochemical recurrence among men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 5,366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study. MAIN OUTCOME MEASURES: Hazard ratios (HRs) for overall, prostate cancer-specific, and CVD mortality, and biochemical recurrence, defined by an increase in prostate-specific antigen (PSA) levels. RESULTS: There were 1,630 deaths, 524 (32%) due to prostate cancer and 416 (26%) to CVD, and 878 biochemical recurrences. Absolute crude rates for prostate cancer-specific death for never vs current smokers were 9.6 vs 15.3 per 1,000 person-years; for all-cause mortality, the corresponding rates were 27.3 and 53.0 per 1000 person-years. In multivariable analysis, current vs never smokers had an increased risk of prostate cancer mortality (HR, 1.61; 95% confidence interval [CI], 1.11-2.32), as did current smokers with clinical stage T1 through T3 (HR, 1.80; 95% CI, 1.04-3.12). Current smokers also had increased risk of biochemical recurrence (HR, 1.61; 95% CI, 1.16-2.22), total mortality (HR, 2.28; 95% CI, 1.87-2.80), and CVD mortality (HR, 2.13; 95% CI, 1.39-3.26). After adjusting for clinical stage and grade (likely intermediates of the relation of smoking with prostate cancer recurrence and survival), current smokers had increased risk of prostate cancer mortality (HR, 1.38; 95% CI, 0.94-2.03), as did current smokers with clinical stage T1 through T3 (HR, 1.41; 95% CI, 0.80-2.49); they also had an increased risk of biochemical recurrence (HR, 1.47; 95% CI, 1.06-2.04). Greater number of pack-years was associated with significantly increased risk of prostate cancer mortality but not biochemical recurrence. Current smokers of 40 or more pack-years vs never smokers had increased prostate cancer mortality (HR, 1.82; 95% CI, 1.03-3.20) and biochemical recurrence (HR, 1.48; 95% CI, 0.88-2.48). Compared with current smokers, those who had quit smoking for 10 or more years (HR, 0.60; 95% CI, 0.42-0.87) or who have quit for less than 10 years but smoked less than 20 pack-years (HR, 0.64; 95% CI, 0.28-1.45) had prostate cancer mortality risks similar to never smokers (HR, 0.61; 95% CI, 0.42-0.88). CONCLUSIONS: Smoking at the time of prostate cancer diagnosis is associated with increased overall and CVD mortality and prostate cancer-specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer-specific mortality risks similar to those who have never smoked.

JAMA. 2011 Jun 22;305(24):2548-55

Oral health

A review of the relationship between tooth loss, periodontal disease, and cancer.

Recent studies have investigated the association between periodontal disease, tooth loss, and several systemic diseases including cancer, cardiovascular disease, and preterm birth. Periodontal disease, a chronic inflammatory condition, is highly prevalent in adult populations around the world, and may be preventable. Estimates of prevalence vary between races and geographic regions, with a marked increase in the occurrence of periodontal disease with advancing age. Worldwide estimates for the prevalence of severe periodontal disease generally range from 10 to 15%. The relationship between oral health and cancer has been examined for a number of specific cancer sites. Several studies have reported associations between periodontal disease or tooth loss and risk of oral, upper gastrointestinal, lung, and pancreatic cancer in different populations. In a number of studies, these associations persisted after adjustment for major risk factors, including cigarette smoking and socioeconomic status. This review provides a summary of these findings, discusses possible biological mechanisms involved, and raises methodological issues related to studying these relationships.

Cancer Causes Control. 2008 Nov;19(9):895-907.

Periodontal infections and cardiovascular disease: the heart of the matter.

BACKGROUND: Oral infection models have emerged as useful tools to study the hypothesis that infection is a cardiovascular disease (CVD) risk factor. Periodontal infections are a leading culprit, with studies reporting associations between periodontal disease and CVD. The results, however, have varied, and it often is unclear what conclusions can be drawn from these data. SUMMARY: An association exists between periodontal disease and CVD. It is unknown, however, whether this relationship is causal or coincidental. Early studies predominantly used nonspecific clinical and radiographic definitions of periodontal disease as surrogates for infectious exposure. While most studies demonstrated positive associations between periodontal disease and CVD, not all studies were positive, and substantial variations in results were evident. More recent studies have enhanced the specificity of infectious exposure definitions by measuring systemic antibodies to selected periodontal pathogens or by directly measuring and quantifying oral microbiota from subgingival dental plaque. Results from these studies have shown positive associations between periodontal disease and CVD. CONCLUSIONS: Evidence continues to support an association among periodontal infections, atherosclerosis and vascular disease. Ongoing observational and focused pilot intervention studies may inform the design of large-scale clinical intervention studies. Recommending periodontal treatment for the prevention of atherosclerotic CVD is not warranted based on scientific evidence. Periodontal treatment must be recommended on the basis of the value of its benefits for the oral health of patients, recognizing that patients are not healthy without good oral health. However, the emergence of periodontal infections as a potential risk factor for CVD is leading to a convergence in oral and medical care that can only benefit the patients and public health.

J Am Dent Assoc. 2006 Oct;137 Suppl:14S-20S; quiz 38S

Folate mouthwash: effects on established gingivitis in periodontal patients.

A double blind study was designed to determine the effects of folate mouthwash (MW) on established gingivitis in non-pregnant adults. 60 subjects who had greater than 20 teeth, visible gingival inflammation around greater than 6 teeth, no complicated medical history, currently not receiving periodontal treatment or medication, and not wearing dentures, were randomly assigned to control or experimental groups. Full mouth assessment included plaque scores, gingival colour changes, bleeding tendency around every tooth and experience of disease and local factors. Subjects used 5 ml of MW twice daily for 4 weeks, rinsing for 1 min before expectorating. Experimental MW contained 5 mg folate per 5 ml. The control group used a placebo MW. A detailed 3-day diet record was kept by each subject. The oral examination was repeated after 4 weeks. Initially, groups were similar except that the experimental group exhibited more bleeding sites at the outset, but after 4 weeks, the experimental group showed a significant decrease in mean number of colour change sites (from 70.17 +/- 12.89 to 56.62 +/- 17.42) and in bleeding sites (from 48.59 +/- 24.28 to 29.28 +/- 19.64) compared with control group (colour: from 66.93 +/- 15.27 to 66.20 +/- 18.83; bleeding: from 36.93 +/- 16.96 to 39.47 +/- 16.67) p less than 0.001. Dietary analysis showed that few subjects ate greater than 200 micrograms folate daily. However, the level of dietary folate did not correlate with changes in inflammation in experimental subjects, r = 0.097. Folate MW appears to have an influence on gingival health through local rather than systemic influence.

J Clin Periodontol. 1984 Oct;11(9):619-28

Periodontal disease and systemic conditions: a bidirectional relationship.

For decades, physicians and dentists have paid close attention to their own respective fields, specializing in medicine pertaining to the body and the oral cavity, respectively. However, recent findings have strongly suggested that oral health may be indicative of systemic health. Currently, this gap between allopathic medicine and dental medicine is quickly closing, due to significant findings supporting the association between periodontal disease and systemic conditions such as cardiovascular disease, type 2 diabetes mellitus, adverse pregnancy outcomes, and osteoporosis. Significant effort has brought numerous advances in revealing the etiological and pathological links between this chronic inflammatory dental disease and these other conditions. Therefore, there is reason to hope that the strong evidence from these studies may guide researchers towards greatly improved treatment of periodontal infection that would also ameliorate these systemic illnesses. Hence, researchers must continue not only to uncover more information about the correlations between periodontal and systemic diseases but also to focus on positive associations that may result from treating periodontal disease as a means of ameliorating systemic diseases.

Odontology. 2006 Sep;94(1):10-21

Diabetes mellitus and inflammatory periodontal diseases.

PURPOSE OF REVIEW: Perio-dontal diseases are inflammatory conditions that were once thought to have manifestations localized to the oral cavity alone, and were therefore considered the concern of only dentists and other oral health professionals. Emerging evidence has changed this view and now suggests that periodontal diseases may play a role in numerous conditions that impact systemic well being, including diabetes mellitus. This review examines the relationships that exist between periodontal diseases and diabetes mellitus, with a focus on potential common pathophysiologic pathways including those associated with inflammation, altered host responses, and insulin resistance. RECENT FINDINGS: Periodontal inflammation is associated with an elevated systemic inflammatory state and an increased risk of major cardiovascular events such as myocardial infarction and stroke, adverse pregnancy outcomes such as preeclampsia, low birth weight and preterm birth, and altered glycemic control in people with diabetes. Intervention trials suggest that periodontal therapy, which decreases the intraoral bacterial bioburden and reduces periodontal inflammation, can have a significant impact on systemic inflammatory status. Evidence suggests that periodontal therapy is associated with improved glycemic control in many patients with both diabetes and periodontal diseases. SUMMARY: Recognition of the bilateral relationships between oral and systemic health will challenge physicians and dentists to work together closely in the future when managing patients with diabetes and periodontal disease.

Curr Opin Endocrinol Diabetes Obes. 2008 Apr;15(2):135-41

Markers of systemic bacterial exposure in periodontal disease and cardiovascular disease risk: a systematic review and meta-analysis.

BACKGROUND: Recent meta-analyses reported a weak association between periodontal disease (PD) on clinical examination and cardiovascular disease (CVD). Systemic bacterial exposure from periodontitis, which correlates poorly with the clinical examination, has been proposed as the more biologically pertinent risk factor. The purpose of this study was to review and analyze the association between PD with elevated systemic bacterial exposure and CVD. METHODS: We searched in the PubMed, Cochrane Controlled Trials Register, EMBASE, and SCOPUS databases for all literature examining PD and CVD. From 10 selected publications, we extracted 12 cohort (N = 5) and cross-sectional (N = 7) studies and included 11 of these in a meta-analysis. With stratified analyses, this resulted in 14 analyses of coronary heart disease (CHD; N = 7), stroke (N = 4), and carotid intima-medial thickening (CIMT; N = 3) as a measure of early atherosclerosis. Systemic bacterial exposure was measured by periodontal bacterial burden (N = 1), periodontitis-specific serology (N = 12), or C-reactive protein (N = 1). RESULTS: Periodontal disease with elevated markers of systemic bacterial exposure was associated strongly with CHD compared to subjects without PD, with a summary odds ratio of 1.75 (95% confidence interval (CI): 1.32 to 2.34; P <0.001). This group was not associated with CVD events or with stroke but was associated with a significant increase in mean CIMT (0.03 mm; 95% CI: 0.02 to 0.04). CONCLUSION: Periodontal disease with elevated bacterial exposure is associated with CHD events and early atherogenesis (CIMT), suggesting that the level of systemic bacterial exposure from periodontitis is the biologically pertinent exposure with regard to atherosclerotic risk.

J Periodontol. 2007 Dec;78(12):2289-302

Comparison of body composition and periodontal disease using nutritional assessment techniques: Third National Health and Nutrition Examination Survey (NHANES III).

OBJECTIVES: The objective of this study was to investigate the association of body composition (obesity) and periodontal disease using simple, inexpensive nutritional assessment techniques available in the Third National Health and Nutrition Examination Survey (NHANES III). MATERIAL AND METHODS: Caucasian subjects, aged 18 years and above, participating in NHANES III, were used for this study. Weight, height, waist circumference, hip circumference, skinfold thickness (S), and bioelectrical impedance analysis measurements were performed and used in the calculation of body mass index (BMI), waist-to-hip ratio (WHR) (visceral fat), log sum of S (subcutaneous fat), and fat-free mass (FFM). Data were analyzed using SPSS. One-way, factorial ANOVA, multivariate analyses, and regression curve analyses were performed. p<0.05 was used to reject the null hypothesis. RESULTS: Adjusting for age, gender, history of diabetes, current smoking, and socioeconomic status, statistically significant correlations were found between periodontitis and WHR, BMI, FFM, and in some instances S. CONCLUSION: This study, indicating significant correlations between body composition and periodontal disease (with WHR being the most significant, followed by BMI, FFM, and S), showed similarities to those observed in other obesity-related health problems. This strengthened arguments that periodontal disease and certain obesity-related systemic illnesses are related, with abnormal fat metabolism possibly being an important factor.

J Clin Periodontol. 2003 Apr;30(4):321-7.