Mahtab Jafari

Curcumin Extends Life Span, Improves Health Span, and Modulates the Expression of Age-Associated Aging Genes in Drosophila melanogaster

BACKGROUND Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been widely used as a spice and herbal medicine in Asia. It has been suggested to have many biological activities, such as antioxidative, antiinflammatory, anticancer, chemopreventive, and antineurodegenerative properties. We evaluated the impact of curcumin on life span, fecundity, feeding rate, oxidative stress, locomotion, and gene expression in two different wild-type Drosophila melanogaster strains, Canton-S and Ives, under two different experimental conditions. RESULTS We report that curcumin extended the life span of two different strains of D. melanogaster, an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects. Life span extension was gender and genotype specific. Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK. CONCLUSIONS The observed positive effects of curcumin on life span and health span in two different D. melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals. The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span-extending effects.

Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy

The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti‐aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti‐aging effects in Drosophila. We demonstrated that a R. rosea extract and one of its bioactive components, salidroside, inhibited the growth of bladder cancer cell lines with a minimal effect on nonmalignant bladder epithelial cells TEU‐2. Interestingly, the R. rosea extract and salidroside component exhibited a selective ability to inhibit the growth of p53 knockout primary mouse embryo fibroblasts (p53−/− MEFs) compared to their wild‐type counterparts. The growth inhibitory effects of the R. rosea extract and salidroside were, however, attenuated in TSC2 and p53 double knock MEFs (TSC2−/−, p53−/− MEFs), suggesting that TSC2 protein is, at least in part, required for the growth inhibitory effects of the R. rosea extract and salidroside. The R. rosea extract and salidroside treatment of UMUC3 cells resulted in an increase of AMP‐activated protein kinase (AMPK)‐α phosphorylation and a decrease of 4E‐BP1 phosphorylation, leading to increased binding of 4E‐BP1 to m7 GTP. These results indicate that the R. rosea extract and salidroside inhibit translation initiation. Furthermore, both the R. rosea extract and salidroside treatment of UMUC3 cells caused a significant percentage of cells undergoing autophagy. Therefore, the R. rosea extract and salidroside deserve further study as novel agents for chemoprevention of bladder carcinogenesis.

Efficacy of Alternate-Day Dosing Versus Daily Dosing of Atorvastatin

Background: Atorvastatin is a synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In placebo-controlled trials, it has been shown to achieve significant dose-dependent reductions in low-density lipoprotein cholesterol, total cholesterol, and triglycerides. This trial compared the efficacy of daily atorvastatin administration with that of alternate-day dosing.Methods: This was a randomized, prospective, nonblinded, controlled clinical trial. Fiftyfour patients with low-density lipoprotein cholesterol of 100 to 200 mg/dL were enrolled. Baseline fasting lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), liver function tests (aspartate transaminase and alanine aminotransferase), and creatine kinase were drawn. Patients were randomized to three atorvastatin dose groups. Group I received 10 mg of atorvastatin every day, Group II received 10 mg every other day, and Group III received 20 mg every other day. After 6 weeks of treatment with atorvastatin, fasting lipid profiles, liver function tests, and creatine kinase concentrations were redrawn. Compliance to treatment was assessed at each visit.Results: Of the 54 patients enrolled, 46 completed the study. All three regimens significantly reduced total cholesterol and low-density lipoprotein cholesterol compared to baseline. No statistically significant differences existed between the three groups in regards to total, or a percentage, decrease in total cholesterol and low-density lipoprotein cholesterol at 6 weeks compared to baseline. All regimens were well tolerated and none of the patients had a significant elevation of liver enzymes or creatine kinase during the course of the study.Conclusion: Alternate-day dosing of atorvastatin is an efficacious and safe alternative to daily dosing.

Decreased mitochondrial superoxide levels and enhanced protection against paraquat in Drosophila melanogaster supplemented with Rhodiola rosea

The root extract from Rhodiola rosea has been reported to have numerous health benefits in human and animal studies. Its molecular mechanism is currently unknown; however, it has been suggested to act as an antioxidant. This study found that a formulation of R. rosea extract, SHR-5, from the Swedish Herbal Institute (SHI) could extend both mean (24% in both sexes) and maximum (16% in males and 31% in females) life span in Drosophila melanogaster when compared to controls. It also found that it lowered mitochondrial superoxide levels and afforded elevated protection against the superoxide generator paraquat in both sexes. The extract SHR-5 did not alter the activities of the major antioxidant enzymes, the superoxide dismutases or catalase, nor did it afford protection against H2O2 or soluble iron. These results present a decrease in endogenous superoxide levels as a possible mode of action for the root extract of R. rosea.

Rosa damascena Decreased Mortality in Adult Drosophila

The effects of a rose-flower extract, Rosa damascena, on the mortality rate of Drosophila melanogaster was evaluated in this study. R. damascena is a potent antioxidant that has many therapeutic uses in addition to its perfuming effects. Supplementing Drosophila with this rose extract resulted in a statistically significant decrease in mortality rate in male and female flies. Moreover, the observed anti-aging effects were not associated with common confounds of anti-aging properties, such as a decrease in fecundity or metabolic rate.

Protection of human cultured cells against oxidative stress by Rhodiola rosea without activation of antioxidant defenses.

Rhodiola rosea root has been long used in traditional medical systems in Europe and Asia as an adaptogen to increase an organisms resistance to physical stress. Recent research has demonstrated its ability to improve mental and physical stamina, to improve mood, and to help alleviate high-altitude sickness. We have also recently found that R. rosea is able to extend the life span of Drosophila melanogaster. The mode of action of R. rosea is currently unknown; it has been suggested by some to act as an antioxidant, whereas others have argued that it may actually be a pro-oxidant and act through a hormetic mechanism. We found that R. rosea supplementation could protect cultured cells against ultraviolet light, paraquat, and H(2)O(2). However, it did not alter the levels of the major antioxidant defenses nor did it markedly activate the antioxidant response element or modulate heme-oxygenase-1 expression levels at relevant concentrations. In addition, R. rosea extract was not able to significantly degrade H(2)O(2) in vitro. These results suggest that in human cultured cells R. rosea does not act as an antioxidant and that its mode of action cannot be sufficiently explained through a pro-oxidant hormetic mechanism.

Can Drosophila melanogaster represent a model system for the detection of reproductive adverse drug reactions

Once a molecule is identified as a potential drug, the detection of adverse drug reactions is one of the key components of its development and the FDA approval process. We propose using Drosophila melanogaster to screen for reproductive adverse drug reactions in the early stages of drug development. Compared with other non-mammalian models, D. melanogaster has many similarities to the mammalian reproductive system, including putative sex hormones and conserved proteins involved in genitourinary development. Furthermore, the D. melanogaster model would present significant advantages in time efficiency and cost-effectiveness compared with mammalian models. We present data on methotrexate (MTX) reproductive adverse events in multiple animal models, including fruit flies, as proof-of-concept for the use of the D. melanogaster model.

Lifespan extension and delay of age-related functional decline caused by Rhodiola rosea depends on dietary macronutrient balance

BackgroundThis study was conducted to evaluate the effects of rhizome powder from the herb Rhodiola rosea, a traditional Western Ukraine medicinal adaptogen, on lifespan and age-related physiological functions of the fruit fly Drosophila melanogaster.ResultsFlies fed food supplemented with 5.0 mg/ml and 10.0 mg/ml of R. rosea rhizome powder had a 14% to 17% higher median lifespan, whereas at 30.0 mg/ml lifespan was decreased by 9% to 12%. The preparation did not decrease fly fecundity.The effect of R. rosea supplement on lifespan was dependent on diet composition. Lifespan extension by 15% to 21% was observed only for diets with protein-to-carbohydrate ratios less than 1. Lifespan extension was also dependent on total concentration of macronutrients. Thus, for the diet with 15% yeast and 15% sucrose there was no lifespan extension, while for the diet with protein-to-carbohydrate ratio 20:1 R. rosea decreased lifespan by about 10%.Flies fed Rhodiola preparation were physically more active, less sensitive to the redox-cycling compound menadione and had a longer time of heat coma onset compared with controls. Positive effects of Rhodiola rhizome on stress resistance and locomotor activity were highest at the ‘middle age’.ConclusionsThe present data show that long-term food supplementation with R. rosea rhizome not only increases D. melanogaster lifespan, but also delays age-related decline of physical activity and increases stress resistance, what depends on protein-to-carbohydrate ratio of the diet.

Pioglitazone: an anti-diabetic compound with anti-aging properties

Insulin and Insulin-Growth-Factor-like (IGF) signaling pathways are well known longevity pathways in nematodes, insects and mammals. To our knowledge, there are no systematic pharmacological studies evaluating the anti-aging properties of medications that target this pathway in Drosophila. Although there are no published data implicating an anti-aging role for these compounds in Drosophila, we hypothesized that their promising pharmacological profile might decrease mortality. However, the decrease in mortality could be due to a number of potential artifacts and confounds such as fecundity depression, decrease in metabolic rate, or CNS depression. Therefore, the mere finding that a compound decreases mortality does not qualify it as an anti-aging compound. In this study, we evaluated the anti-aging properties of four compounds that might target the insulin signaling pathway in Drosophila. Once it was established that the compound decreased mortality, we proceeded to evaluate possible confounding factors that could have contributed to the mortality reduction. We show that only piolglitazone displayed anti-aging properties. At present, we do not have a mechanistic explanation for this pharmacological disparity.

Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster

The discovery of life extension in Caenorhabditis elegans treated with anticonvulsant medications has raised the question whether these drugs are prospective anti-aging candidate compounds. The impact of these compounds on neural modulation suggests that they might influence the chronic diseases of aging as well. Lamotrigine is a commonly used anticonvulsant with a relatively good adverse-effects profile. In this study, we evaluated the interaction between the impacts of lamotrigine on mortality rate, lifespan, metabolic rate and locomotion. It has been proposed in a wide range of animal models that there is an inverse relationship between longevity, metabolic rate, and locomotion. We hypothesized that the survival benefits displayed by this compound would be associated with deleterious effects on health span, such as depression of locomotion. Using Drosophila as our model system, we found that lamotrigine decreased mortality and increased lifespan in parallel with a reduction in locomotor activity and a trend towards metabolic rate depression. Our findings underscore the view that assessing health span is critical in the pursuit of useful anti-aging compounds.