Life Extension Magazine®

Issue: Jun 2012

Testosterone

The cosmetic treatment of wrinkles.

Wrinkles now have a greater social impact because people live longer. Science and hedonism overlap in the search for causes, treatments and prevention of wrinkles. The cosmetic approach to wrinkles includes: i. Cleansing ii. Photoprotection iii. Active ingredients. Active ingredients go well beyond simple moisturisers and exert a more complex activity in protecting skin from external injuries, nourishing it and removing its superficial layers. Transport systems and excipients are increasingly effective. Functional agents currently include alpha hydroxy acids (AHAs), poly-AHAs, complex poly-AHAs, retinoids, fish polysaccharides, anti-enzymatic agents, antioxidants (including ascorbic acid, pycnogenol, ursolic acid, vegetable isoflavones, vitamin E, coenzyme Q10, lipoic acid, resveratorol, l-carnosine, and taurine) as well as agaricic acid and various plant extracts. All are reviewed in this text. Most are topical, some can be given by mouth, even as food supplements. Cosmetics are becoming closer to drugs in preventing and treating wrinkles. Included amongst the cosmeceuticals are the anti-wrinkle agents described herein.

J Cosmet Dermatol. 2004 Jan;3(1):26-34

Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment.

OBJECTIVE: To observe the efficacy of topical application of 0.1% hyaluronan formulations of different molecular weights (MW) (50, 130, 300, 800, and 2000 kDa, respectively) in the periocular area as anti-wrinkle treatment. MATERIAL AND METHODS: Seventy-six female subjects between 30 and 60 years of age with clinical signs of periocular wrinkles applied one of the formulations twice-daily to the area of interest in a randomized fashion for 60 days. Around the other eye, a vehicle control cream was applied. Measurements of skin hydration and skin elasticity were performed before treatment, 30 and 60 days thereafter. At similar time points negative replicas were taken and evaluated by semi-automated morphometry. RESULTS: All HA-based creams utilized in this study demonstrated a significant improvement in skin hydration and overall elasticity values (R2) when compared to placebo. Measurements of wrinkle depth using mean roughness (Ra) and maximum roughness (Rz) values revealed significant improvement in the 130 and the 50 kDa HA group after 60 days of treatment compared to placebo-treated area. CONCLUSION: Topical application of all 0.1% HA formulations used in this study led to significant improvement in skin hydration and elasticity. Application of low-molecular-weight (LMW) HA was associated with significant reduction of wrinkle depth, which may be due to better penetration abilities of LMW HA.

J Drugs Dermatol. 2011 Sep 1;10(9):990-1000

Effects of topical application of inorganic polyphosphate on tissue remodeling in rat inflamed gingiva.

BACKGROUND AND OBJECTIVE: Inorganic polyphosphate [poly(P)] is a biopolymer found in almost all cells and tissues, and which promotes tissue remodeling. However, there is limited information on how poly(P) affects the connective tissue in inflamed gingiva. This study examined the effects of topical application of poly(P) on gingival connective tissue and its remodeling in a rat periodontitis model.MATERIAL AND METHODS: Male Wistar rats (n = 36, 8 wk of age) were used in this 6-wk study. The rats were divided into six groups of six rats each. The control group received no treatment. In the other groups, periodontitis was ligature-induced for 4 wk. After 4 wk, the rats with periodontitis were further divided into five groups, and were left untreated (periodontitis group) or subjected to topical application of oral rinses containing 0, 0.1, 1, or 5% poly(P) for 2 wk. RESULTS: The periodontitis and 0% poly(P) groups showed a higher density of polymorphonuclear leukocytes and a lower density of collagen in gingival tissue than the control group (p < 0.05). In contrast, groups treated with more than 1% poly(P) exhibited a lower density of polymorphonuclear leukocytes (p < 0.05) and a higher density of collagen than the periodontitis and 0% poly(P) groups (p < 0.05). A higher expression of fibroblast growth factor-2 was observed in the gingiva of rats treated with 1% poly(P) than in those treated with 0% poly(P) (p < 0.05). CONCLUSION: Topical application of poly(P) may induce connective tissue remodeling, contributing to improvement of inflamed gingiva in rats.

J Periodontal Res. 2012 Apr;47(2):159-64

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend life span, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV’s effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

Cell. 2006 Dec 15;127(6):1109-22

Modern approach to topical treatment of aging skin.

The main processes involved in skin aging are intrinsic and extrinsic. Apart from them, so called stochastic aging connotes cell damage caused by metabolic processes, free radicals and cosmic irradiation. The clinical expression of intrinsic aging include smooth, dry, and thinned skin with accentuated expression lines. It is inevitable and time dependent. Extrinsically aged skin shows signs of photodamage which include appearance of wrinkles, pigmented lesions, actinic keratoses and patchy hypopigmentations. Therapeutic modalities imply photoprotection with sunscreens that prevent sunburns and block ultraviolet irradiation. Other modalities include use of retinoids which regulate gene transcription with subsequent cellular differentiation and proliferation. The topical and peroral administration of network antioxidants, such as vitamin E and C, coenzyme Q10, alpha-lipoic acid and glutathione, enhance antiaging effect. The other antioxidants such as green tea, dehydroepiandrosterone, melatonin, selenium and resveratrol, have also antiaging and anti-inflammatory effects. Topical bleaching agents such as hydroquinone, kojic acid and azelaic acid can reduce signs of aging. Studies confirm the efficacy of these topical agents in combination with superficial and/or medium depth or deep peeling agents for photodamaged skin treatment. Indications for type of chemical peels according to various clinical diagnosis are done, as well as advantages and disadvantages of different types of chemical peels.

Coll Antropol. 2010 Sep;34(3):1145-53

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

Science. 1997 Jan 10;275(5297):218-20

In vivo skin effects of a dimethylaminoethanol (DMAE) based formulation.

Dimethylaminoethanol (DMAE) has been used in anti-aging formulations but few scientifically based data address its efficacy. The aim of this study was to evaluate the effects of DMAE-based formulations on hairless mice and human skin. Formulations containing with or without DMAE were applied to the dorsum of hairless mice. Histopathological and histometric evaluations were carried out after seven days. Formulations were also applied to the ventral forearm and the lateral periocular area of human volunteers. Stratum corneum water content and skin mechanical properties were analyzed using Corneometer and Cutometer, before and after a single and repeated application. Histometric evaluations showed that formulations with or without DMAE increased the viable epidermis thickness, but only the DMAE-supplemented formulation led to increased dermal thickness. DMAE also induced increase in collagen fiber thickness, which was observed in the histopathological study. After the single and the 8-week period application on human skin, formulations with and without DMAE enhanced the stratum corneum water content in the forearm skin. Mechanical properties were not significantly modified. So, we can suggest that DMAE action is related to its effects on the dermis as observed in the histopathological and histometric studies and showed hydration effects on skin.

Pharmazie. 2009 Dec;64(12):818-22

The role of dimethylaminoethanol in cosmetic dermatology.

Skincare formulations for the improvement of aging skin are increasingly important consumer products. Here, we review available data on one such agent - 2-dimethylaminoethanol (DMAE) or deanol - that has recently been evaluated in a placebo-controlled trial. DMAE is an analog of the B vitamin choline and is a precursor of acetylcholine. Although the role of acetylcholine as a neurotransmitter is well known, growing evidence points to acetylcholine as a ubiquitous cytokine-like molecule that regulates basic cellular processes such as proliferation, differentiation, locomotion, and secretion in a paracrine and autocrine fashion. Indeed, this modulatory role may contribute to the cutaneous activity of DMAE. In a randomized clinical study, 3% DMAE facial gel applied daily for 16 weeks has been shown to be safe and efficacious (p < 0.05) in the mitigation of forehead lines and periorbital fine wrinkles, and in improving lip shape and fullness and the overall appearance of aging skin. These effects did not regress during a 2-week cessation of application. Beneficial trends (p > 0.05 but

Am J Clin Dermatol. 2005;6(1):39-47

Dimethylaminoethanol affects the viability of human cultured fibroblasts.

BACKGROUND: In clinical practice, dimethylaminoethanol (DMAE) has been used in the fight against wrinkles and flaccidity in the cervicofacial region. The firming action of DMAE is explained by the fact that its molecule, considered to be a precursor of acetylcholine, alters muscle contraction. However, no experimental studies have confirmed this theory. Because the actual mechanism of DMAE action was not defined and there were no references in the literature regarding its direct action on fibroblasts, this study was performed to evaluate the direct action of DMAE on cultured human fibroblasts. METHODS: Human fibroblasts obtained from discarded fragments of total skin from patients undergoing plastic or reconstructive surgical procedures performed within the Plastic Surgery Division at the Federal University of São Paulo were used for this study. The explant technique was used. The culture medium was supplemented with different concentrations of DMAE on the fourth cell passage, and the cell proliferation rate, cytosolic calcium levels, and cell cycle were evaluated. Statistical analysis was performed using analysis of variance (ANOVA) followed by a Newman-Keuls test for multiple comparisons. RESULTS: A decrease in fibroblast proliferation was associated with an increase in DMAE concentration. A longer treatment time with trypsin was required for the groups treated with DMAE in a dose-dependent manner. In the presence of DMAE, cytosolic calcium increased in a dose-dependent manner. Apoptosis also increased in groups treated with DMAE. CONCLUSION: Dimethylaminoethanol reduced the proliferation of fibroblasts, increased cytosolic calcium, and changed the cell cycle, causing an increase in apoptosis in cultured human fibroblasts.

Aesthetic Plast Surg. 2007 Nov-Dec;31(6):711-8

Split face study on the cutaneous tensile effect of 2-dimethylaminoethanol (deanol) gel.

BACKGROUND/AIMS: Beyond subjective assessments, the effect of skin tensors is difficult to assess. The present 2-phase randomized double-blind split face study was designed to compare the effect of a gel containing 3% 2-dimethylaminoethanol (deanol, DMAE) with the same formulation without DMAE. METHODS: In a first pilot study, sensorial assessments and measures of the skin distension under suction were performed in eight volunteers. In a second study conducted in 30 volunteers, shear wave propagation was measured. RESULTS: Large interindividual variations precluded any significant finding in the first study. The DMAE formulation showed, however, a significant effect characterized by increased shear wave velocity in the direction where the mechanical anisotropy of skin showed looseness. CONCLUSION: The DMAE formulation under investigation increased skin firmness.

Skin Res Technol. 2002 Aug;8(3):164-7

Carnosine in patients with type I diabetes mellitus.

Examination of carnosine in patients with diabetes mellitus type I, showed that the plasma levels of carnitine were non significantly increased compared to the levels in healthy population, while the levels in red cells were decreased Lowered levels of carnosine in red cells could point out similar deficit in other cells. Due to low levels in cells carnosine is less available for metabolic processes, like antioxidant reactions and its participation in antioxidants defense reactions is limited non-enzymatic glycosylation of proteins. Therefore it should be supplemented.

Bratisl Lek Listy. 1999 Sep;100(9):500-2

Retardation of the senescence of cultured human diploid fibroblasts by carnosine.

We have examined the effects of the naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) on the growth, morphology, and life span of cultured human diploid fibroblasts. With human foreskin cells, HFF-1, and fetal lung cells, MRC-5, we have shown that carnosine at high concentrations (20-50 mM) in standard medium retards senescence and rejuvenates senescent cultures. These late-passage cultures preserve a nonsenescent morphology in the presence of carnosine, in comparison to the senescent morphology first described by Hayflick and Moorhead. Transfer of these late-passage cells in medium containing carnosine to unsupplemented normal medium results in the appearance of the senescent phenotype. The serial subculture of cells in the presence of carnosine does not prevent the Hayflick limit to growth, although the life span in population doublings as well as chronological age is often increased. This effect is obscured by the normal variability of human fibroblast life spans, which we have confirmed. Transfer of cells approaching senescence in normal medium to medium supplemented with carnosine rejuvenates the cells but the extension in life span is variable. Neither D-carnosine, (beta-alanyl-D-histidine), homocarnosine, anserine, nor beta-alanine had the same effects as carnosine on human fibroblasts. Carnosine is an antioxidant, but it is more likely that it preserves cellular integrity by its effects on protein metabolism.

Exp Cell Res. 1994 Jun;212(2):167-75

Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts.

We have confirmed and extended previous results on the beneficial effects of L-carnosine on growth, morphology, and longevity of cultured human fibroblasts, strains MRC-5 and HFF-1. We have shown that late-passage HFF-1 cells retain a juvenile appearance in medium containing 50 mM carnosine, and revert to a senescent phenotype when carnosine is removed. Switching cells between medium with and without carnosine also switches their phenotype from senescent to juvenile, and the reverse. The exact calculation of fibroblast life spans in population doublings (PDs) depends on the proportion of inoculated cells that attach to their substrate and the final yield of cells in each subculture. We have shown that carnosine does not affect cell attachment, but does increase longevity in PDs. However, the plating efficiency of MRC-5 cells seeded at low density is strongly increased in young and senescent cells by carnosine, as shown by the growth of individual colonies. We have also demonstrated that very late-passage MRC-5 cells (with weekly change of medium without subculture) remain attached to their substrate much longer in medium containing carnosine in comparison to control cultures, and also retain a much more normal phenotype. Carnosine is a naturally occurring dipeptide present at high concentration in a range of human tissues. We suggest it has an important role in cellular homeostasis and maintenance.

Exp Gerontol. 1999 Jan;34(1):35-45

Effect of carnosine on Drosophila melanogaster life span.

A positive dose-dependent effect of carnosine (beta-alanyl-L-histidine) on the life span of male Drosophila melanogaster flies was shown. The mean life span of male flies receiving 200 mg/liter carnosine approached that of females. At the same time carnosine had no effect on the life span of female flies. This positive effect of carnosine probably reflects its protective action against age-related accumulation of free radicals and did not depend on carnosine metabolism in the body. Addition of 200 mg/liter histidine and beta-alanine (separately or in combination) had no effect on the mean life span of flies.

Bull Exp Biol Med. 2002 Jun;133(6):559-61

Effect of carnosine and its Trolox-modified derivatives on life span of Drosophila melanogaster.

This study investigated the effect of antioxidants, i.e., carnosine and its Trolox- (water-soluble analog of alpha-tocopherol) acylated derivatives (S,S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (S,S-Trolox-carnosine, STC) and (R,S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (R,S-Trolox-carnosine, RTC) on the life span of the fruit fly Drosophila melanogaster. Adding carnosine to foodstuff was accompanied and followed by a 20% increase in the average life span of males, but it did not influence the average life span of females. At the same time, adding STC to foodstuff prolonged average longevity both in males (by 16%) and females (by 36%), but the addition of RTC to foodstuff had no influence upon the average life span of insects of either gender. The compounds studied have previously been shown to protect neurons of the rat brain from oxidative stress in the descending order of efficiency: RTC > STC > carnosine. The finding obtained in the present study suggests another order of efficacy regarding the effect on life span in male insects: STC > carnosine > RTC (inefficient). No correlation between antioxidant protection of rat neurons and the effect on life span of the fruit fly makes it possible to suppose the presence of additional cellular targets to be acted upon by exposure of D. melanogaster to these compounds.

Rejuvenation Res. 2010 Aug;13(4):453-7

Carnosine, the protective, anti-aging peptide.

Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes.

Biosci Rep. 1999 Dec;19(6):581-7

Carnosine as a potential anti-senescence drug.

The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) has been found to exert an anti-senescence effect when used as a dietary supplement. Carnosine clearly improved the external appearance of experimental animals and provided beneficial physiological effects, thus maintaining the animals in better condition than control animals receiving no carnosine or a mixture of beta-alanine and L-histidine.

Biochemistry (Mosc). 2000 Jul;65(7):866-8

Carnosine is neuroprotective against permanent focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: Carnosine is a naturally occurring dipeptide with multiple neuroprotective properties. In addition, it is well tolerated in high doses with minimal side effects. The purposes of this study were to determine whether carnosine is neuroprotective in permanent focal cerebral ischemia and to determine potential mechanisms of neuroprotection.METHODS: We investigated the efficacy of carnosine in a mouse model of permanent focal cerebral ischemia. The effects of carnosine were investigated with respect to neuronal damage and infarct formation, endogenous antioxidant status, and matrix metalloproteinase activity. RESULTS: Carnosine significantly decreased infarct size and neuronal damage when administered at time points both before and after the induction of ischemia. Carnosine also decreased reactive oxygen species levels in the ischemic brain, preserved normal glutathione levels, and decreased matrix metalloproteinase protein levels and activity. CONCLUSIONS: Carnosine is neuroprotective in focal cerebral ischemia and appears to influence deleterious pathological processes that are activated after the onset of ischemia.

Stroke. 2007 Nov;38(11):3023-31

Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells.

Malondialdehyde (MDA) is a deleterious end-product of lipid peroxidation. The naturally-occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in brain and innervated tissues at concentrations up to 20 mM. Recent studies have shown that carnosine can protect proteins against cross-linking mediated by aldehyde-containing sugars and glycolytic intermediates. Here we have investigated whether carnosine is protective against malondialdehyde-induced protein damage and cellular toxicity. The results show that carnosine can (1) protect cultured rat brain endothelial cells against MDA-induced toxicity and (2) inhibit MDA-induced protein modification (formation of cross-links and carbonyl groups).

Neurosci Lett. 1997 Dec 5;238(3):135-8

Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro.

Glycation of low-density lipoprotein (LDL) by reactive aldehydes, such as glycolaldehyde, can result in the cellular accumulation of cholesterol in macrophages. In this study, it is shown that carnosine, or its constituent amino acids beta-alanine and l-histidine, can inhibit the modification of LDL by glycolaldehyde when present at equimolar concentrations to the modifying agent. This protective effect was accompanied by inhibition of cholesterol and cholesteryl ester accumulation in human monocyte-derived macrophages incubated with the glycated LDL. Thus, carnosine and its constituent amino acids may have therapeutic potential in preventing diabetes-induced atherosclerosis.

FEBS Lett. 2007 Mar 6;581(5):1067-70

Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide.

Pomegranate juice (PJ), which is a rich source of potent flavonoid antioxidants, was tested for its capacity to protect nitric oxide (NO) against oxidative destruction and enhance the biological actions of NO. Employing chemiluminescence headspace analysis, PJ was found to be a potent inhibitor of superoxide anion-mediated disappearance of NO. PJ was much more potent than Concord grape juice, blueberry juice, red wine, ascorbic acid, and DL-alpha-tocopherol. As little as 3 microl of a 6-fold dilution of PJ, in a reaction volume of 5,000 microl, produced a marked antioxidant effect, whereas 300 microl of undiluted blueberry juice or nearly 1,000 microl of undiluted Concord grape juice were required to produce similar effects. PJ and other antioxidant-containing products were found to augment the anti-proliferative action of NO (DETA/NO) on vascular smooth muscle cell (rat aorta) proliferation. PJ was much more effective than the other products tested and elicited no effects when tested alone in the absence of added NO. Similarly, neither PJ nor the other products enhanced the anti-proliferative action of alpha-difluoromethylornithine, a stable substance that inhibits cell growth by NO-independent mechanisms. In order to determine whether PJ is capable of increasing the production of NO by vascular endothelial cells, PJ was tested for its capacity to upregulate and/or activate endothelial NO synthase (eNOS) in bovine pulmonary artery endothelial cells. PJ elicited no effects on eNOS protein expression or catalytic activity. Moreover, PJ did not enhance promoter activity in the eNOS gene (COS-7 cells transfected with eNOS). These observations indicate that PJ possesses potent antioxidant activity that results in marked protection of NO against oxidative destruction, thereby resulting in augmentation of the biological actions of NO.

Nitric Oxide. 2006 Sep;15(2):93-102

Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease.

Pomegranate juice contains antioxidants such as soluble polyphenols, tannins, and anthocyanins and may have antiatherosclerotic properties. However, no study has investigated the effects of pomegranate juice on patients who have ischemic coronary heart disease (CHD). We investigated whether daily consumption of pomegranate juice for 3 months would affect myocardial perfusion in 45 patients who had CHD and myocardial ischemia in a randomized, placebo-controlled, double-blind study. Patients were randomly assigned into 1 of 2 groups: a pomegranate juice group (240 ml/day) or a placebo group that drank a beverage of similar caloric content, amount, flavor, and color. Participants underwent electrocardiographic-gated myocardial perfusion single-photon emission computed tomographic technetium-99m tetrofosmin scintigraphy at rest and during stress at baseline and 3 months. Visual scoring of images using standardized segmentation and nomenclature (17 segments, scale 0 to 4) was performed by a blinded independent nuclear cardiologist. To assess the amount of inducible ischemia, the summed difference score (SDS) was calculated by subtracting the summed score at rest from the summed stress score. The experimental and control groups showed similar levels of stress-induced ischemia (SDS) at baseline (p >0.05). After 3 months, the extent of stress-induced ischemia decreased in the pomegranate group (SDS -0.8 +/- 2.7) but increased in the control group (SDS 1.2 +/- 3.1, p <0.05). This benefit was observed without changes in cardiac medications, blood sugar, hemoglobin A1c, weight, or blood pressure in either group. In conclusion, daily consumption of pomegranate juice may improve stress-induced myocardial ischemia in patients who have CHD.

Am J Cardiol. 2005 Sep 15;96(6):810-4

Cardioprotective effect of whole fruit extract of pomegranate on doxorubicin-induced toxicity in rat.

CONTEXT: Cardioprotective effects of various plants are generally attributed to their antioxidant activity. The whole fruit extract of pomegranate (WFEP), Punica granatum L. (Punicaceae), has a potent antioxidant activity. Objective: To investigate cardioprotective effect of WFEP against doxorubicin (Dox)-induced cardiotoxicity in rats. MATERIALS AND METHODS: Male Wistar rats were divided randomly into three groups of eight rats each: control (water, 5 mL/kg); Dox (10 mg/kg i.v.) and WFEP (100 mg/kg). Dox was administered in Dox and WFEP groups. After anesthetizing the animals on the last day, electrocardiogram was recorded and blood was analyzed for creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activities. Determinations of superoxide dismutase (SOD), reduced glutathione (GSH), lipid peroxidation (LPO) and histopathology of the heart tissues were carried out. RESULTS: The WFEP group showed decreased QT and increase in heart rate (p < 0.05) compared to the Dox group. Significant decrease in CK-MB (p < 0.01), LDH (p < 0.05) and no such significant decrease in AST were observed as compared to the Dox group. There was significant increase in the level of GSH (p < 0.05), whereas inhibition of LPO and increase in SOD concentration was not significant in the WFEP group compared to the Dox group. Histopathological study of the WFEP-treated group showed slight protection against myocardial toxicity induced by Dox. CONCLUSION: Results indicate that WFEP has cardioprotective effect against Dox-induced cardiotoxicity in rats.

Pharm Biol. 2011 Apr;49(4):377-82

Acute and long term effects of grape and pomegranate juice consumption on endothelial dysfunction in pediatric metabolic syndrome.

BACKGROUND: This study aimed to determine the short- and long-term effects of consumption of grape and pomegranate juices on markers of endothelial function and inflammation in adolescents with metabolic syndrome (MetS). METHODS: In a non-pharmacologic randomized controlled trial, 30 individuals were randomly assigned to two groups of drinking natural grape or pomegranate juice for 1 month. Measurements of inflammatory factors [Hs-CRP, sE-selectin, sICAM-1, sVCAM, and interleukin 6 (IL-6)] and flow-mediated dilation (FMD) were made at baseline, 4 hours after first juice consumption and after one month of juice consumption. RESULTS: The percent changes of FMD were significant in both groups in the short- and long-term. Hs-CRP had a nonsignificant decrease. sE selectin had a significant decrease after 4 hours in total and in the pomegranate juice group, followed by a significant decrease after 1 month in both groups. After 4 hours, sICAM-1 significantly decreased in the pomegranate juice group, and after 1 month it decreased in total and pomegranate juice group. Interleulkin-6 (IL-6) had a significant constant decrease at 4-hour and 1-month measurements after drinking pomegranate juice, and in both groups after 1 month. Significant negative correlations of changes in sICAM-1 and sE-selectin with changes in FMD were found in both periods of follow-up; and at 1 month for IL-6. CONCLUSIONS: Decline in inflammation was associated with improvement in FMD without changes in conventional risk factors. Daily consumption of natural antioxidants may improve endothelial function in adolescents with MetS.

J Res Med Sci. 2011 Mar;16(3):245-53

Acute and long-term effects of grape and pomegranate juice consumption on vascular reactivity in paediatric metabolic syndrome.

OBJECTIVES: This study, which to the best of our knowledge is the first of its kind, aimed to determine the acute and long-term effects of the consumption of grape and pomegranate juices on endothelium function in adolescents with metabolic syndrome, and to compare the effects of these two kinds of juices. METHODS: This randomised controlled clinical trial was conducted in 2008 among 30 adolescents, aged 12-15 years, with metabolic syndrome. Participants were randomly assigned to two groups of equal number; one group was asked to drink 18 millilitre per kilogram per day of natural grape juice and the other group was asked to drink 240 millilitre per day of natural pomegranate juice once daily for 1 month. Juices were homemade without any added sweetener. Basal brachial artery dimension and flow-mediated dilation as an index of endothelial function and endothelial-dependent dilation after receiving nitoglycerin spray were evaluated by high-resolution B mode ultrasonography before juice consumption, 4 hours and 30 days after regular daily consumption. RESULTS: Flow-mediated dilation at 90 seconds and after nitoglycerin significantly improved at 4 hours and at 1 month after drinking both kinds of juices, without significant difference between the two groups. The change at 1 month versus 4 hours was significant only in the grape juice group. CONCLUSION: Daily consumption of diets rich in antioxidants might improve endothelial function in adolescents with metabolic syndrome. These effects began as soon as 4 hours after juice consumption. Such beneficial effects should be considered in dietary recommendations for the paediatric age group, notably in obese individuals.

Cardiol Young. 2010 Feb;20(1):73-7

Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease.

This randomized, double-blind, parallel trial assessed the influence of pomegranate juice consumption on anterior and posterior carotid intima-media thickness (CIMT) progression rates in subjects at moderate risk for coronary heart disease. Subjects were men (45 to 74 years old) and women (55 to 74 years old) with > or =1 major coronary heart disease risk factor and baseline posterior wall CIMT 0.7 to 2.0 mm, without significant stenosis. Participants consumed 240 ml/day of pomegranate juice (n = 146) or a control beverage (n = 143) for up to 18 months. No significant difference in overall CIMT progression rate was observed between pomegranate juice and control treatments. In exploratory analyses, in subjects in the most adverse tertiles for baseline serum lipid peroxides, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, TGs/HDL cholesterol, total cholesterol/HDL cholesterol, and apolipoprotein-B100, those in the pomegranate juice group had significantly less anterior wall and/or composite CIMT progression versus control subjects. In conclusion, these results suggest that in subjects at moderate coronary heart disease risk, pomegranate juice consumption had no significant effect on overall CIMT progression rate but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein/HDL axis.

Am J Cardiol. 2009 Oct 1;104(7):936-42

Effects of pomegranate juice and extract polyphenols on platelet function.

Several studies have shown that polyphenols reduce cardiovascular accidents in high-risk patients; in particular, the inhibition of platelet function may be responsible for part of this benefit. This research studied the antiplatelet effect of Wonderful variety pomegranate (Punica granatum) products, which contain primarily hydrolyzed tannins such as ellagitannins. We have investigated in vitro the effects of treatment with either pomegranate juice (PJ) or the polyphenol-rich extract from pomegranate fruit (POMx) on platelet aggregation, calcium mobilization, thromboxane A(2) production, and hydrogen peroxide formation, induced by collagen and arachidonic acid. PJ and POMx reduce all the platelet responses studied. POMx showed a stronger action in reducing platelet activation; moreover, POMx is active at the concentration that it is possible to obtain after polyphenol-rich food intake (2 microM). These results demonstrated that the cardiovascular health benefits of pomegranate may in part be related to the ability of polyphenols to inhibit platelet function. In fact, PJ and pomegranate extract have similar effects at concentrations expected for normal intake.

J Med Food. 2009 Apr;12(2):334-9

Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice.

BACKGROUND: Pomegranate seed oil has been shown to protect against diet induced obesity and insulin resistance. OBJECTIVE: To characterize the metabolic effects of punicic acid on high fat diet induced obesity and insulin resistance. DESIGN: High-fat diet or high-fat diet with 1% Pomegranate seed oil (PUA) was fed for 12 weeks to induce obesity and insulin resistance. We assessed body weight and composition (pSABRE DEXA-scan), energy expenditure (Columbus Instruments) and insulin sensitivity at the end of the 12 weeks. RESULTS: PSO intake resulted in a lower body weight, 30.5±2.9 vs 33.8±3.2 g PSO vs HFD respectively, p=0.02, without affecting food intake or energy expenditure. The lower body weight was fully explained by a decreased body fat mass, 3.3±2.3 vs 6.7±2.7 g for PSO and HFD fed mice, respectively, p=0.02. Insulin clamps showed that PSO did not affect liver insulin sensitivity but clearly improved peripheral insulin sensitivity, 164±52% vs 92±24% for PSO and HFD fed mice respectively, p=0.01. CONCLUSIONS: We conclude that dietary PSO ameliorates high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure.

Food Chem Toxicol. 2011 Jun;49(6):1426-30

Obesity: The preventive role of the pomegranate (Punica granatum).

Obesity represents a rapidly growing threat to the health of populations in an increasing number of countries. Diet intervention has been proposed as one of the strategies for weight loss and weight maintenance. Traditionally, the pomegranate, including its roots, tree bark, fruit juice, leaves, and flowers, has been used to treat some conditions such as diarrhea, hemorrhage, acidosis, and microbial infections. Pomegranate extracts have been found to have strong anti-inflammatory, antioxidant, and even antitumor properties in vivo and in vitro. More recently, positive effects on fat reduction have been shown using the pomegranate and its extracts. Many of the beneficial effects are related to the presence of anthocyanins, tannins, and very high levels of antioxidants, including polyphenols and flavonoids. Many studies have explored the effects of the pomegranate in obesity, and various mechanisms have been proposed as to how these different extracts help in fat reduction. This article provides an overview of the work done addressing the potential benefits of the pomegranate on obesity and assesses the efficacy of intervention by means of the pomegranate and its extracts. Human studies in this field are still limited and need more attention that would help in understanding the preventive and protective roles pomegranate extracts have on obesity.

Nutrition. 2012 Feb 16

Short telomeres in depression and the general population are associated with a hypocortisolemic state.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls. METHODS: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires. RESULTS: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (r(s) = -.258, p = .003). CONCLUSIONS: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population.

Biol Psychiatry. 2012 Feb 15;71(4):294-300

Telomere shortening in chronic obstructive pulmonary disease.

Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p

Respir Med. 2009 Feb;103(2):230-6

Study of telomere length and different markers of oxidative stress in patients with Parkinson’s disease.

BACKGROUND: Many studies have shown that short telomere length (TL) is associated with high oxidative stress and various age-related diseases. Parkinson’s disease (PD) is an age-related disease, and although its pathogenic mechanism is uncertain, oxidative stress is believed to be implicated in this pathology. The aim of this case-control study was to assess both TL and the different markers of oxidative stress in elderly patients with PD compared to age control subjects. METHODS: 20 PD patients and 15 age-matched controls, >65 years were studied. TL was measured by Southern blotting from DNA samples extracted from white blood cells. Superoxide dismutase (SOD) activity and plasma levels of total glutathione and protein carbonyls were determined. RESULTS: There was a trend for lower TL in PD patients: 6.06 ± 0.81 kb in PD versus 6.45 ± 0.73 kb in controls (p = 0.08). No significant difference was found between the two groups in terms of oxidative stress markers. In controls, age was the main determinant of telomere shortening (r = -0.547; p = 0.03) whereas, in PD patients, telomere shortening was mainly dependent on plasmatic concentrations of carbonyl proteins (r= -0.544; p=0.044). In PD patients, a negative association was observed between plasma carbonyl protein levels and SOD activity (r= -0.622, p=0.004). CONCLUSIONS: In PD, TL is shorter in presence of high oxidative stress as measured by carbonyl protein levels. The absence of telomere attrition with age among patients with PD could reflect a telomere regulation by mechanisms other than age.

J Nutr Health Aging. 2011 Apr;15(4):277-81

Telomeres, telomerase, and aging: origin of the theory.

In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.

Exp Gerontol. 1996 Jul-Aug;31(4):443-8

Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans.

OBJECTIVE: Life stress is hypothesized to alter the dynamic regulation of the autonomic, neuroendocrine, and immune systems. This study examined the effects of antecedent chronic life stress on psychological and physiological responsivity after acute challenge with a psychological stressor. METHOD: Using a within-subject mixed design, male volunteers with (N = 12) and without chronic life stress (N = 11) were administered a 12-minute laboratory stressor (mental arithmetic) vs a video control. RESULTS: Acute psychological stress induced subjective distress, increases of circulating concentrations of epinephrine, norepinephrine, beta-endorphin, adrenocorticotropic hormone (ACTH), and cortisol, and a selective redistribution of natural killer (NK) cells into the peripheral blood as compared with the video control condition. Although the two groups were almost identical at baseline in psychological, sympathetic, neuroendocrine, and immune domains, the chronic stress group showed greater subjective distress, higher peak levels of epinephrine, lower peak levels of beta-endorphin and of NK cell lysis, and a more pronounced redistribution of NK cells in response to the acute psychological challenge than the controls. Furthermore, the acute stressor induced a protracted decline in NK lysis per NK cell in the chronic stress group but had no effect in the controls. CONCLUSIONS: In summary, when persons who are undergoing chronic life stress are confronted with an acute psychological challenge, an exaggerated psychologic and peak sympathomedullary reactivity occurs that is associated with decrements in individual NK cell function and is protracted beyond termination of the stressor and sympathomedullary recovery.

Psychosom Med. 1997 Jul-Aug;59(4):447-57

Neural correlates of epigenesis.

The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals’ level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.

Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16033-8

Mechanism of anti-stress activity of Ocimum sanctum Linn, eugenol and Tinospora malabarica in experimental animals.

Effects of restraint stress (RS) and its modulation by O. sanctum (Os), eugenol and T. malabarica (Tm) were evaluated on some biochemical and biophysical parameters in rats. RS induced elevations in blood glucose and urea levels, were unaffected by either Os, eugenol or Tm pretreatment. However, both Os and eugenol lowered RS-induced cholesterol levels. RS also caused a generalized increase in enzyme activity and Os, eugenol or Tm effectively lowered the RS-induced elevations in lactate dehydrogenase (LDH) and alkaline phosphatase. RS also induced (a) increased membrane protein clusterization, (b) increased membrane fluidity and (c) reduced membrane thickness--in RBC membrane, whereas, the effects on the synaptosomal membrane were less marked. The RS-induced changes in RBC membrane dynamics were attenuated/reversed by Os, eugenol or Tm, in a differential manner. These biochemical and membrane changes during Rs and their modulation by the adaptogens are discussed in light of the possible mechanisms of action of these agents, during such aversive stimuli.

Indian J Exp Biol. 1992 Jul;30(7):592-6

Circadian rhythm of hormones is extinguished during prolonged physical stress, sleep and energy deficiency in young men.

The circadian rhythm of hormones (N = 10) and mental performance (N = 18) was investigated in male cadets during a 5-day military training course with continuous heavy physical activities corresponding to 35% of the maximal oxygen uptake, with almost total lack of food and sleep. The 24-h means for androstenedione, dihydroepiandrosterone (DHEA), 17 alpha-hydroxyprogesterone, testosterone and thyroid-stimulating hormone decreased strongly during the course, and the circadian rhythm was extinguished below the minimum levels measured during the control experiment. The 24-h means for cortisol, dihydroepiandrosterone sulfate (DHEA-S) and progesterone increased during the course, and the circadian rhythm was abolished above the maximum levels of the control experiment. A gradual increase was found in thyroxine, free thyroxine and triiodothyronine during the first 12 h of activities, followed by a constant decrease for the rest of the course. Mental performance decreased during the course and the amplitude of its circadian rhythm increased from +/- 10% to +/- 30% of the 24-h mean. The circadian rhythms investigated were almost normalized after 4-5 days of rest. However, the nocturnal rise for cortisol, androstenedione and DHEA appeared earlier, and the plasma levels of thyroid hormones, estradiol and DHEA-S were lower during the recovery experiment than in the control experiment. The responses to stress of the circadian rhythm for mental performance and steroid hormones during the course indicate a differential regulation.

Eur J Endocrinol. 1994 Jul;131(1):56-66

Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency.

The objective of this study was to assess the effects of oral testosterone supplementation therapy on glucose homeostasis, obesity and sexual function in middle-aged men with type 2 diabetes and mild androgen deficiency. Forty-eight middle-aged men, with type 2 diabetes, (visceral) obesity and symptoms of androgen deficiency, were included in this open-label study. Twenty-four subjects received testosterone undecanoate (TU; 120 mg daily, for 3 months); 24 subjects received no treatment. Body composition was analyzed by bio-impedance. Parameters of metabolic control were determined. Symptoms of androgen deficiency and erectile dysfunction were scored by self-administered questionnaires. TU had a positive effect on (visceral) obesity: statistically significant reduction in body weight (2.66%), waist-hip ratio (-3.96%) and body fat (-5.65%); negligible changes were found in the control group. TU significantly improved metabolic control: decrease in blood glucose values and mean glycated hemoglobin (HbA1c) (from 10.4 to 8.6%). TU treatment significantly improved symptoms of androgen deficiency (including erectile dysfunction), with virtually no change in the control group. There were no adverse effects on blood pressure or hematological, biochemical and lipid parameters, and no adverse events. Oral TU treatment of type 2 diabetic men with androgen deficiency improves glucose homeostasis and body composition (decrease in visceral obesity), and improves symptoms of androgen deficiency (including erectile dysfunction). In these men, the benefit of testosterone supplementation therapy exceeds the correction of symptoms of androgen deficiency and also includes glucose homeostasis and metabolic control.

Aging Male. 2003 Mar;6(1):1-7

Low testosterone levels are common and associated with insulin resistance in men with diabetes.

CONTEXT: Low testosterone levels are common in men with type 2 diabetes and may be associated with insulin resistance. OBJECTIVE: We investigated prevalence of testosterone eficiency and the relationship between testosterone and insulin resistance in a large cohort of men with type 2 and type 1 diabetes. DESIGN: The study was a cross-sectional survey of 580 men with type 2 diabetes and 69 men with type 1 diabetes. A subgroup of 262 men with type 2 diabetes was then reassessed after a median of 6 months. RESULTS: Forty-three percent of men with type 2 diabetes had a reduced total testosterone, and 57% had a reduced calculated free testosterone. Only 7% of men with type 1 diabetes had low total testosterone. By contrast, 20.3% of men with type 1 diabetes had low calculated free testosterone, similar to that observed in type 2 diabetes (age-body mass index adjusted odds ratio = 1.4; 95% confidence interval = 0.7-2.9). Low testosterone levels were independently associated with insulin resistance in men with type 1 diabetes as well as type 2 diabetes. Serial measurements also revealed an inverse relationship between changes in testosterone levels and insulin resistance. CONCLUSIONS: Testosterone deficiency is common in men with diabetes, regardless of the type. Testosterone levels are partly influenced by insulin resistance, which may represent an important avenue for intervention, whereas the utility of testosterone replacement remains to be established in prospective trials.

J Clin Endocrinol Metab. 2008 May;93(5):1834-40

The dark side of testosterone deficiency: III. Cardiovascular disease.

A considerable body of evidence exists suggesting that androgen deficiency contributes to the onset, progression, or both of cardiovascular disease (CVD). The aim of this review is to evaluate the relationships between testosterone (T) deficiency and risk factors of CVD and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. The relationship between androgen deficiency and endothelial function, lipid profiles, inflammatory responses, altered vascular smooth muscle reactivity, and hypertension are discussed with regard to CVD. A comprehensive literature search was carried out with the use of Pub Med from 1980 through 2009, and relevant articles pertinent to androgen deficiency and vascular disease were evaluated and discussed. Low T, whether attributed to hypogonadism or androgen deprivation therapy, in men with prostate carcinoma, produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. Testosterone supplementation restores arterial vasoreactivity; reduces proinflammatory cytokines, total cholesterol, and triglyceride levels; and improves endothelial function but also might reduce high-density lipoprotein levels. Testosterone is an anabolic hormone with a wide range of beneficial effects on men’s health. The therapeutic role of T in men’s health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for CVD, androgen replacement therapy could potentially reduce CVD risk in hypogonadal men. It should be emphasized, however, that androgen replacement therapy should be done with very thorough and careful monitoring for prostate diseases.

J Androl. 2009 Sep-Oct;30(5):477-94

Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study.

In both men and women, circulating androgen levels decline with advancing age. Until now, results of several small studies on the relationship between endogenous androgen levels and atherosclerosis have been inconsistent. In the population-based Rotterdam Study, we investigated the association of levels of dehydroepiandrosterone sulfate (DHEAS) and total and bioavailable testosterone with aortic atherosclerosis among 1,032 nonsmoking men and women aged 55 yr and over. Aortic atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta, which have been shown to reflect intimal atherosclerosis. Relative to men with levels of total and bioavailable testosterone in the lowest tertile, men with levels of these hormones in the highest tertile had age-adjusted relative risks of 0.4 [95% confidence interval (CI), 0.2-0.9] and 0.2 (CI, 0.1-0.7), respectively, for the presence of severe aortic atherosclerosis. The corresponding relative risks for women were 3.7 (CI, 1.2-11.6) and 2.3 (CI, 0.7-7.8). Additional adjustment for cardiovascular disease risk factors did not materially affect the results in men, whereas in women the associations diluted. Men with levels of total and bioavailable testosterone in subsequent tertiles were also protected against progression of aortic atherosclerosis measured after 6.5 yr (SD +/- 0.5 yr) of follow-up (P for trend = 0.02). No clear association between levels of DHEAS and presence of severe aortic atherosclerosis was found, either in men or in women. In men, a protective effect of higher levels of DHEAS against progression of aortic atherosclerosis was suggested, but the corresponding test for trend did not reach statistical significance. In conclusion, we found an independent inverse association between levels of testosterone and aortic atherosclerosis in men. In women, positive associations between levels of testosterone and aortic atherosclerosis were largely due to adverse cardiovascular disease risk factors.

J Clin Endocrinol Metab. 2002 Aug;87(8):3632-9

Testosterone and atherosclerosis in aging men: purported association and clinical implications.

Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.

Am J Cardiovasc Drugs. 2005;5(3):141-54

Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages.

By lowering high density lipoprotein (HDL) cholesterol, testosterone contributes to the gender difference in HDL cholesterol and has been accused to be pro-atherogenic. The mechanism by which testosterone influences HDL cholesterol is little understood. We therefore investigated the effect of testosterone on the gene expression of apolipoprotein A-I (apoA-I), hepatic lipase (HL), scavenger receptor B1 (SR-BI), and the ATP binding cassette transporter A1 (ABCA1), all of which are important regulators of HDL metabolism. In both cultivated HepG2 hepatocytes and primary human monocyte-derived macrophages, testosterone led to a dose-dependent up-regulation of SR-BI, which was assessed on both the mRNA and the protein levels. As a functional consequence, we observed an increased HDL(3)-induced cholesterol efflux from macrophages. At supraphysiological dosages, testosterone also increased the expression of HL in HepG2 cells. Testosterone had no effect on the expression of apoA-I in HepG2 cells and ABCA1 in either HepG2 cells or macrophages. These data suggest that testosterone, despite lowering HDL cholesterol, intensifies reverse cholesterol transport and thereby exerts an anti-atherogenic rather than a pro-atherogenic effect.

Biochem Biophys Res Commun. 2002 Sep 6;296(5):1051-7

Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk.

Testosterone administration to men is known to decrease high-density lipoprotein cholesterol (HDL-C) and the subclasses HDL(2) and HDL(3). It also might increase the number of small, dense, low-density lipoprotein cholesterol (LDL-C) particles in hypogonadal men. The decrease in HDL-C and in LDL-C size is potentially mediated by hepatic lipase activity, which hydrolyzes lipoprotein phospholipids and triacylglycerol. To determine how HDL-C and LDL-C particles are affected by testosterone administration to eugonadal men, testosterone was administered as a supraphysiological dose (600 mg/wk) for 3 wk to elderly, obese, eugonadal men before elective hip or knee surgery, and lipids were measured by routine methods and by density gradient ultracentrifugation. Hepatic lipase activity increased >60% above baseline levels, and HDL-C, HDL(2), and HDL(3) significantly declined in 3 wk. In addition, the LDL-C peak particle density and the amount of LDL-C significantly increased. Testosterone is therefore a potent stimulator of hepatic lipase activity, decreasing HDL-C, HDL(2), and HDL(3) as well as increasing LDL particle density changes, all associated with increased cardiovascular risk.

Am J Physiol Endocrinol Metab. 2003 Jun;284(6):E1112-8

Serum testosterone level and related metabolic factors in men over 70 years old.

BACKGROUND: Sex hormone decline remarkably decreases metabolic function in elderly men. Many degenerative diseases may relate to testosterone deficiency. OBJECTIVE: To evaluate the serum testosterone concentration in elderly men, its related metabolic and inflammatory factors, and the relationship of metabolic syndrome to testosterone levels. METHODS: 381 elderly men (78.8+/-4.1 yr old) residing in a veterans’ nursing home were enrolled. We measured body height and weight, waist and hip circumferences, body fat, blood pressure, blood glucose and insulin, glycosylated hemoglobin (HbA1c), lipid profile, complete blood count, high sensitivity C-reactive protein (hsCRP), total testosterone, and SHBG. Free testosterone was calculated by Nanjee-Wheeler’s method. RESULTS: Serum total testosterone levels were 0.20-15.74 ng/ml (free testosterone 11.78-478.31 pmol/l). Total testosterone correlated negatively with body mass index (BMI), waist-hip ratio, body fat, blood glucose, blood insulin, HbA1c, serum triglyceride, white blood cell (WBC) count and hsCRP; but positively with HDL-cholesterol (HDL-C) and hemoglobin. Multiple regression stepwise forward analysis revealed that BMI values, fasting blood glucose, WBC count, fasting hsCRP and hemoglobin were independent factors related to total testosterone. Furthermore, total testosterone is lower in elderly men with metabolic syndrome, according to National Cholesterol Education Program criteria with a modification of waist circumference. However, free testosterone plays a small role in association with metabolic factors in this elderly men’s population. CONCLUSION: Total testosterone level is significantly related to metabolic and inflammatory factors in elderly men. Low total testosterone may be a significant indicator for development of metabolic syndrome in elderly men.

J Endocrinol Invest. 2007 Jun;30(6):451-8

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