Life Extension Magazine

Life Extension Magazine December 2008

Abstracts

Super MiraForte™

Effects of Marapuama in the chronic mild stress model: further indication of antidepressant properties.

ETHNOPHARMACOLOGY RELEVANCE: Ptychopetalum olacoides Bentham (PO) (Olacaceae), known as Marapuama, is regarded as a “nerve tonic” in the Amazon. Traditional uses include states of lassitude with noticeable lack of desire/motivation, and to manage particularly stressful (physical and/or psychological) circumstances. Suggestive of antidepressant activity, we have established that a specific PO ethanol extract (POEE) significantly decreases immobility in the tail suspension and forced swimming tests. AIM OF THE STUDY: The aim of this study was to verify the effects of POEE in the unpredictable chronic mild stress (UCMS) depression model in mice, given the construct and face values of the UCMS as an experimental model of depression and the traditional use of this species. MATERIALS AND METHODS: Over 6 weeks BALB/c mice were subjected to the UCMS protocol. The effects of POEE (50, 100, 300 mg/kg, p.o.) and imipramine (20 mg/kg, i.p.) were evaluated in relation to coat state, splash-test grooming, and corticosterone levels. RESULTS: The coat state degradation, decreased grooming and increased serum corticosterone induced by UCMS were prevented by POEE and imipramine treatments. CONCLUSION: In addition to supporting traditional claims and previously reported antidepressant properties for POEE, this study shows that POEE prevents stress-induced HPA hyperactivity.

J Ethnopharmacol. 2008 Jul 23;118(2):300-4

Interest of lignans in prevention and treatment of cancers.

Lignans are diphenolic compounds widely distributed in the plant kingdom. They are mainly localised in lignified tissues, seeds and roots. These molecules are involved in plant defence mechanisms, but are also interesting for human health. Flax lignans belonging to the phytoestrogens are metabolised after ingestion into enterolignans that may offer a protection against the onset and development of hormono-dependant cancers. In vitro studies based on mammalian cellular models tend to confirm their beneficial effects observed during epidemiological studies and give us insights about their mechanisms of action. The most studied lignan, podophyllotoxin, and its semi-synthetic derivatives (etoposide, teniposide, etoposide phosphate), are particularly interesting at a curative level due to their cytotoxic properties. These semi-synthetic derivatives are used in chemotherapy of lung cancer for example. However, the extensive use of these anticancer drugs will lead to the problem of podophyllotoxin supply. This molecule is currently extracted from the rhizomes and roots of an Indian species Podophyllum hexandrum which has subsequently become endangered. Strategies are investigated to obtain economically viable alternative sources of Podophyllotoxin from plants and in vitro cultures of several species. Among them, north american Podophyllum peltatum, Linum wild species, Hyptis, Anthriscus, Juniperus or Dysosma species which accumulate Podophyllotoxin or closely related derivatives, are good candidates. double dagger.

Med Sci (Paris). 2008 May;24(5):511-9

Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice.

The plants from the Lepidium gender have demonstrated to have effect on the size of the prostate. Lepidium meyenii (Maca) is a Peruvian plant that grows exclusively over 4000 m above sea level. The present study was designed to determine the effect of red maca (RM) in the prostate hyperplasia induced with testosterone enanthate (TE) in adult mice. Prostate hyperplasia was induced by administering TE, and then these animals (n = 6, each group) were treated with RM or Finasteride (positive control) for 21 days. There was an additional group without prostate hyperplasia (vehicle). Mice were killed on days 7, 14 and 21 after treatment with RM. Testosterone and oestradiol levels were measured on the last day of treatment. Prostatic stroma, epithelium and acini were measured histologically. RM reduced prostate weight at 21 days of treatment. Weights of seminal vesicles, testis and epididymis were not affected by RM treatment. The reduction in prostate size by RM was 1.59 times. Histological analysis showed that TE increased 2-fold the acinar area, effect prevented in the groups receiving TE + RM for 14 (P < 0.05) and 21 (P < 0.05) days and the group receiving TE + Finasteride for 21 days (P < 0.05). TE increased prostatic stroma area and this effect was prevented by treatment with RM since 7 days of treatment or Finasteride. The reduction in prostatic stroma area by RM was 1.42 times. RM has an anti-hyperplastic effect on the prostate of adult mice when hyperplasia was induced with TE acting first at prostatic stromal level.

Andrologia. 2008 Jun;40(3):179-85

A double-blind, randomized, pilot dose-finding study of maca root (L. Meyenii) for the management of SSRI-induced sexual dysfunction.

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P<0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

CNS Neurosci Ther. 2008 Fall;14(3):182-91

Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content.

OBJECTIVE: To examine the estrogenic and androgenic activity of Lepidium meyenii (Maca) and its effect on the hormonal profile and symptoms in postmenopausal women. DESIGN: Fourteen postmenopausal women completed a randomized, double-blind, placebo-controlled, crossover trial. They received 3.5 g/day of powered Maca for 6 weeks and matching placebo for 6 weeks, in either order, over a total of 12 weeks. At baseline and weeks 6 and 12 blood samples were collected for the measurement of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin, and the women completed the Greene Climacteric Scale to assess the severity of menopausal symptoms. In addition, aqueous and methanolic Maca extracts were tested for androgenic and estrogenic activity using a yeast-based hormone-dependent reporter assay. RESULTS: No differences were seen in serum concentrations of estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin between baseline, Maca treatment, and placebo (P > 0.05). The Greene Climacteric Scale revealed a significant reduction in scores in the areas of psychological symptoms, including the subscales for anxiety and depression and sexual dysfunction after Maca consumption compared with both baseline and placebo (P < 0.05). These findings did not correlate with androgenic or alpha-estrogenic activity present in the Maca as no physiologically significant activity was observed in yeast-based assays employing up to 4 mg/mL Maca extract (equivalent to 200 mg/mL Maca). CONCLUSIONS: Preliminary findings show that Lepidium meyenii (Maca) (3.5 g/d) reduces psychological symptoms, including anxiety and depression, and lowers measures of sexual dysfunction in postmenopausal women independent of estrogenic and androgenic activity.

Menopause. 2008 Sep 6

Changes in sexual hormones in a male population over 50 years of age. Frequency of low testosterone levels and risk factors.

OBJECTIVES: To investigate the changes in sexual hormones in a selected male population older than 50 years of age. To assess the frequency of biochemical hypogonadism and which factors are related to testosterone levels. PATIENTS AND METHODS: A Cross-sectional study was carried out on 230 Spanish men older than 50 years of age. Blood tests were performed including: total testosterone, SHBG, calculated free testosterone, dehidroepiandrosterone sulfate, androstendione, estradiol, bioavailable estradiol, FSH, LH, and prolactin. Clinical and socio-demographic backgrounds were investigated. The frequency of biochemical hypogonadism was established using total and free testosterone levels as diagnostic criteria. Factors that may influence testosterone levels were evaluated by univariate and multivariate statistical analysis, and a logistic regression model was used to determine which factors can predict biochemical hypogonadism according to free testosterone levels. RESULTS: Age was associated with a significant decrease (p < 0.05) in total testosterone (0.6% per year), free testosterone (1.3% per year), dehydroepiandrosterone sulfate (1.8% per year) and bioavailable estradiol (0.69% per year). Moreover, an increase in SHBG, LH, and FSH was observed (p < 0.05). According to total testosterone levels, 4.8% of the men were hypogonadal, whereas 24.8% were hypogonadal when free testosterone was considered. In the univariate analysis, obesity, diabetes mellitus and hyperlipemia were related to lower total testosterone levels, while free testosterone levels were lower in men with sedentary life, lower levels of education, obesity or diabetes mellitus. In the multivariate analysis age, diabetes mellitus and obesity were inversely related to total and free testosterone levels. Free testosterone was also inversely related to hyperlipemia. For biochemical hypogonadism, simple logistic regression analysis selected age, sedentary life, obesity and diabetes mellitus. In the multivariate analysis age, obesity and diabetes mellitus had significant independent prognostic value. CONCLUSIONS: Starting from 50 years of age, a significant age-related decrease in total testosterone, free testosterone, dehydroepiandrosterone sulfate and bioavailable estradiol is observed. The frequency of biochemical hypogonadism is higher when free testosterone levels are used for diagnosis. Total testosterone levels were related to age, diabetes mellitus and obesity. Free testosterone was related to age. diabetes mellitus, obesity and hyperlipemia. The probability of suffering low free testosterone levels increases with age, diabetes mellitus and/or obesity.

Actas Urol Esp. 2008 Jun;32(6):603-10

Free testosterone levels and implications on clinical outcomes in elderly men.

BACKGROUND AND AIMS: Aging is accompanied by a progressive decline in serum testosterone. Evidence concerning the clinical manifestations of low serum testosterone levels is contradictory. We aimed to examine the age-related decline in testosterone and the possible clinical outcomes, including erectile dysfunction, prostatism, cognitive function, daily life activities, depression, and osteoporosis. METHODS: One hundred and twenty men underwent comprehensive geriatric assessment. Testosterone and free testosterone levels were measured, geriatric assessment scales, International Index of Erectile Function (IIEF) and International Prostate Symptom Scale (IPSS) were performed, and bone mineral densities were determined. RESULTS: The mean age of the 120 men was 73.8+/-5.90. A significant decrease in testosterone and free testosterone levels with increasing age was determined (p=0.021). It was also found that erectile dysfunction, as determined by IIEF (r=0.66, p<0.001), and symptoms of prostatism determined by IPSS (r=-0.23, p=0.016), were significantly associated with low free testosterone levels. Laboratory parameters, obesity, osteoporosis, cognitive function, daily life activities, and cardiovascular diseases were not significantly different between groups with low and normal free testosterone levels. CONCLUSION: Age-related decrease in free testosterone may lead to erectile dysfunction and symptoms of prostatism in elderly men.

Aging Clin Exp Res. 2008 Jun;20(3):201-6

New steroidal aromatase inhibitors: suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death.

BACKGROUND: Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. RESULTS: The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. CONCLUSION: Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

BMC Cell Biol. 2008 Jul 24;9:41

Effects of aromatase inhibition in hypogonadal older men: a randomized, double-blind, placebo-controlled trial.

Objective: To assess the effects of sustained aromatase inhibition in older hypogonadal men. Design and patients: In a 1-year randomized, double-blind, placebo-controlled trial, 88 men, aged 60 and older with testosterone levels between 5.2 and 10.4 nmol/L on a single measure or between 10.4 and 12.1 nmol/L on two consecutive measures, and symptoms of hypogonadism were recruited. Subjects received either anastrozole 1 mg daily or placebo. Measurements: Changes in gonadal steroid hormone levels, body composition (by computerized tomography (CT) and dual x-ray absorptiometry (DXA)), strength, prostate specific antigen (PSA), symptoms of benign prostatic hypertrophy (BPH), hematocrit and lipid levels were assessed. Results: Testosterone levels increased from 11.2 +/- 3.3 nmol/L at baseline to 18.2 +/- 4.8 nmol/L at month 3 (p < 0.0001 vs. placebo) while bioavailable testosterone levels increased from 2.7 +/- 0.8 nmol/L at baseline to 5.4 +/- 1.7 nmol/L at month 3 (p < 0.0001 vs. placebo). Testosterone and biotestosterone levels peaked at month 3 and then declined by month 12 (though they remained significantly higher than baseline and greater than placebo). Estradiol levels decreased from 55.8 +/- 15.4 pmol/L at baseline to 42.2 +/- 13.6 pmol/L at month 3 and then remained stable (p < 0.0001). Body composition and strength did not change, nor did PSA, BPH symptoms, hematocrit or lipid levels. Conclusions: Anastrozole administration normalized androgen production in older hypogonadal men and decreased estradiol production modestly. These alterations did not improve body composition or strength.

Clin Endocrinol (Oxf). 2008 Jun 25

Enterolactone restricts the proliferation of the LNCaP human prostate cancer cell line in vitro.

Ecological data suggest a long-term diet high in plant material rich in biologically active compounds, such as the lignans, can significantly influence the development of prostate cancer over the lifetime of an individual. The capacity of a pure mammalian lignan, enterolactone (ENL), to influence the proliferation of the LNCaP human prostate cancer cell line was investigated as a function of cell density, metabolic activity, expression and secretion of prostate specific antigen (PSA), cell cycle profile, and the expression of genes involved in development and progression of prostate cancer. Treatment with a subcytotoxic concentration of ENL (60 muM for 72 h) was found to reduce: cell density (57.5%, SD 7.23, p < 0.001), metabolic activity (55%, SD 0.03, p < 0.001), secretion of PSA (48.50% SD 4.74, p = 0.05) and induce apoptosis (8.33-fold SD 0.04, p = 0.001) compared to untreated cells. Cotreatment with 10 muM etoposide was found to increase apoptosis by 50.17% (SD 0.02, p < 0.001). Additionally, several key genes (e. g. MCMs, survivin and CDKs) were beneficially regulated by ENL treatment (p < 0.05). The data suggest that the antiproliferative activity of ENL is a consequence of altered expression of cell cycle associated genes and provides novel molecular evidence for the antiproliferative properties of a pure lignan in prostate cancer.

Mol Nutr Food Res. 2008 May;52(5):567-80

Aromatase inhibition by synthetic lactones and flavonoids in human placental microsomes and breast fibroblasts--a comparative study.

Interference of exogenous chemicals with the aromatase enzyme can be useful as a tool to identify chemicals that could act either chemopreventive for hormone-dependent cancer or adverse endocrine disruptive. Aromatase is the key enzyme in the biosynthesis of steroids, as it converts androgens to estrogens. Certain flavonoids, plant derived chemicals, are known catalytic aromatase inhibitors. Various systems are in use to test aromatase inhibitory properties of compounds. Commonly used are microsomes derived from ovary or placental tissue characterized by high aromatase activity. To a lesser extent whole cell systems are used and specifically cell systems that are potential target tissue in breast cancer development. In this study aromatase inhibitory properties of fadrozole, 8-prenylnaringenin and a synthetic lactone (TM-7) were determined in human placental microsomes and in human primary breast fibroblasts. In addition, apigenin, chrysin, naringenin and two synthetic lactones (TM-8 and TM-9) were tested in human microsomes only. Comparison of the aromatase inhibitory potencies of these compounds between the two test systems showed that the measurement of aromatase inhibition in human placental microsomes is a good predictor of aromatase inhibition in human breast fibroblasts.

Toxicol Appl Pharmacol. 2008 May 1;228(3):269-76

In vitro and in vivo modulation of testosterone mediated alterations in apoptosis related proteins by [6]-gingerol.

Ginger (Zingiber officinale, Zingiberaceae) has been widely used as a dietary spice, and as a traditional oriental medicine. The rhizome of ginger contains pungent vanillyl ketones, including [6]-gingerol and [6]-paradol, and have been credited with therapeutic and preventive health benefits, including anti-cancer activity. Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. Here we are reporting the modulatory effects of [6]-gingerol on testosterone-induced alterations on apoptosis related proteins in both in vitro, androgen sensitive LNCaP cells and in vivo, ventral prostate of Swiss albino mice. [6]-gingerol treatment resulted apoptosis in LNCaP cells, as indicated by depolarization of mitochondrial membrane potential, increase in sub G1 cell population by flow cytometry and the appearance of DNA laddering pattern in agarose gel electrophoresis. Results of western blot analysis showed that [6]-gingerol upregulated the testosterone depleted levels of p53 in mouse prostate and upregulated its downstream regulator Bax and further activated Caspase-9 and Caspase-3 in both LNCaP cells and in mouse prostate. We also found downregulation of testosterone induced antiapoptotic proteins, Bcl-2 and Survivin expression by [6]-gingerol in both LNCaP cells and in mouse ventral prostate. Thus, [6]-gingerol shows its protective effects in both in vivo and in vitro prostate cancer models by modulation of proteins involved in apoptosis pathway.

Mol Nutr Food Res. 2007 Dec;51(12):1492-502

Dose-response effect of Red Maca (Lepidium meyenii) on benign prostatic hyperplasia induced by testosterone enanthate.

The main goal of this study was to determine the effect of a freeze-dried aqueous extract of the red variety of Lepidium meyenii (Red Maca) on testosterone-induced benign prostatic hyperplasia (BPH) in adult rats of the Holtzman strain. Rats were treated with freeze-dried aqueous extract of Red Maca at doses of 0, 0.01, 0.05, 0.1, and 0.5 g/kg body wt. A positive control group received Finasteride (0.6 mg/kg body wt.). After treatment, the animals were sacrificed, and the ventral prostate was extracted, and weighed. HPLC was used to determine the presence of glucosinolates in Red Maca. The prostate weight diminished in a dose-dependent fashion in rats treated with Red Maca. The effect of Red Maca was better than that observed with Finasteride. Finasteride, but not Red Maca, reduced seminal vesicles weight. Analysis of the HPLC indicated the presence of benzyl glucosinolate (Glucotropaeolin) with a content of 0.639%. Serum testosterone levels were not affected by Red Maca. Moreover, serum testosterone levels were not related to prostate or seminal vesicles weight in rats treated with vehicle and Red Maca. In conclusion, Red Maca administered orally in rats seems to exert an inhibitory effect at a level post DHT conversion, on the BPH-induced experimentally, although a direct measure of reductase action would still be required.

Phytomedicine. 2007 Aug;14(7-8):460-4

Testosterone and the brain.

Gender differences in spatial recognition, and age-related declines in cognition and mood, point towards testosterone as an important modulator of cerebral functions. Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men. In addition, reduced testosterone is associated with depressive disorders. The relationship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the patient, and in appropriate patients with low testosterone levels, testosterone substitution can increase positive mood and decrease negative mood. The much publicized link between testosterone and aggression is probably only of importance in athletes who supplement their testosterone levels to excessively high levels, whereas in hypogonadal men, testosterone supplementation only enhances the positive aspects of aggression such as vigour and energy. Current data suggest that testosterone supplementation in hypogonadal men of all ages will enhance many aspects of mood and cognition.

Aging Male. 2006 Dec;9(4):195-9

In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study.

OBJECTIVE: An age-related decline in serum total and free testosterone concentration may contribute to ill health in men, but limited data are available for men > 70 years of age. We sought to determine the distribution and associations of reduced testosterone concentrations in older men. DESIGN: The Health in Men Study is a community-representative prospective cohort investigation of 4,263 men aged > or = 70 years. Cross-sectional hormone data from 3,645 men were analysed. METHODS: Early morning sera were assayed for total testosterone, sex hormone binding globulin (SHBG) and LH. Free testosterone was calculated using the Vermeulen method. RESULTS: Mean (+/- s.d.) serum total testosterone was 15.4 +/- 5.6 nmol/l (444 +/- 162 ng/dl), SHBG 42.4 +/- 16.7 nmol/l and free testosterone 278 +/- 96 pmol/l (8.01 +/- 2.78 ng/dl). Total testosterone correlated with SHBG (Spearman’s r = 0.6, P < 0.0001). LH and SHBG increased with age (r = 0.2, P < 0.0001 for both). Instead of declining, total testosterone increased marginally (r = 0.04, P = 0.007) whilst free testosterone declined with age (r = -0.1, P < 0.0001). Free testosterone was inversely correlated with LH (r = -0.1, P < 0.0001). In multivariate analyses, increasing age, body mass index (BMI) and LH were associated with lower free testosterone. CONCLUSIONS: In men aged 70-89 years, modulation of androgen action may occur via an age-related increase in SHBG and reduction in free testosterone without a decline in total testosterone concentration. Increasing age, BMI and LH are independently associated with lower free testosterone. Further investigation would be required to assess the clinical consequences of low serum free testosterone, particularly in older men in whom total testosterone may be preserved.

Eur J Endocrinol. 2007 May;156(5):585-94