Increase In Mean Life Span Research Articles

Characterization of Effects of mTOR Inhibitors on Aging in Caenorhabditis elegans.

Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from Day 16 (or ~70 years in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.

Phenolic-rich lees from Philippine rice wine (tapuy) increases Caenorhabditis elegans lifespan in spite of having low antioxidant activity

Tapuy is an indigenous wine produced in the Philippines. Rice wine fermentation produces a by-product of rice leftover and microbial biomass, collectively called lees, which usually is discarded as a waste product. However, studies have shown the potential value of lees as a healthy food source. We wanted to determine the nutritional profile of tapuy wine and its lees and their abilities to extend lifespan in Caenorhabditis elegans. Tapuy lees (7.65 g/100 g dry weight) was 18.5-fold greater in protein content compared to tapuy wine. Its sugar content (27.66 g/100 g dry weight) is similar to the tapuy wine’s sugar content (23.465 g/100 g dry weight). Through LC–MS/MS, 18.75% and 12.39% of spectral peaks in tapuy wine and lees were matched, respectively, to specific compounds, and several of them are associated with beneficial health effects. Furthermore, the phenolic content in tapuy lees (19,475.526 Gallic Acid Equivalent) is 6.5-fold greater compared to tapuy wine. Surprisingly, the DPPH and FRAP antioxidant assays show that tapuy lees had a lesser antioxidant ability compared to tapuy wine. However, C. elegans fed with supplementation of tapuy lees extract showed a 16.24% increase in mean lifespan, which is higher compared to the 6.10% increase in mean lifespan when supplemented with tapuy wine. Taking all these findings together, our study revealed that tapuy lees has a greater nutritional value than tapuy wine, and this underutilized and wastefully discarded product can be repurposed as a potential functional food.Graphical

Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.

Aging results in the progressive decline of muscle strength. Interventions to maintain muscle strength may mitigate the age-related loss of physical function, thus maximizing health span. The work on environmental enrichment (EE), an experimental paradigm recapitulating aspects of an active lifestyle, has revealed EE-induced metabolic benefits mediated by a brain-fat axis across the lifespan of mice. EE initiated at 18-month of age shows a trend toward an increased mean lifespan. While previous work described EE's influences on the aging dynamics of several central-peripheral processes, its influence on muscle remained understudied. Here, the impact of EE is investigated on motor function, neuromuscular physiology, and the skeletal muscle transcriptome. EE is initiated in 20-month-old mice for a five-month period. EE mice exhibit greater relative lean mass that is associated with improved mobility and hindlimb grip strength. Transcriptomic profiling of muscle tissue reveals an EE-associated enrichment of gene expression within several metabolic pathways related to oxidative phosphorylation and the TCA cycle. Many mitochondrial-related genes-several of which participate in the electron transport chain-are upregulated. Stress-responsive signaling pathways are downregulated because of EE. The results suggest that EE improves motor function-possibly through preservation of mitochondrial function-even late in life.

How size and genetic diversity shape lifespan across breeds of purebred dogs.

While the lifespan advantage of small body size and mixed breed status has been documented repeatedly, evidence for an effect of genetic diversity across dog breeds is equivocal. We hypothesized that this might be due to a strong right-censoring bias in available breed-specific lifespan estimates where early-dying dogs from birth cohorts that have not died off completely at the time of data collection are sampled disproportionately, especially in breeds with rapidly growing populations. We took advantage of data on owner reported lifespan and cause of death from a large public database to quantify the effect of size and genetic diversity (heterozygosity) on mortality patterns across 118 breeds based on more than 40,000 dogs. After documenting and removing the right-censoring bias from the breed-specific lifespan estimates by including only completed birth cohorts in our analyses, we show that small size and genetic diversity are both linked to a significant increase in mean lifespan across breeds. To better understand the proximate mechanisms underlying these patterns, we then investigated two major mortality causes in dogs - the cumulative pathophysiologies of old age and cancer. Old age lifespan, as well as the percentage of old age mortality, decreased with increasing body size and increased with increasing genetic diversity. The lifespan of dogs dying of cancer followed the same patterns, but while large size significantly increased proportional cancer mortality, we could not detect a significant signal for lowered cancer mortality with increasing diversity. Our findings suggest that outcross programs will be beneficial for breed health and longevity. They also emphasize the need for high-quality mortality data for veterinary epidemiology as well as for developing the dog as a translational model for human geroscience.

Rapamycin Supplementation: Effect on Longevity in Drosophila melanogaster

Target of rapamycin (TOR) regulates a number of cellular responses, including autophagy. The purpose of this study was to investigate the effect on life span of supplementation with rapamycin dissolved in either dimethylsulfoxide (DMSO) or ethanol, in male and female flies of three strains of Drosophila melanogaster: Oregon R, w1118, and y w. The hypothesis was that longevity would be decreased regardless of strain, sex or solvent, consistent with an unpublished prior study using y w males in this laboratory, or alternatively that it would be increased as in publications from other laboratories. Flies were exposed to food supplemented with 200 µM rapamycin dissolved in one of the two solvents before being mixed into a standard agar‐yeast‐cornmeal‐sucrose medium. Supplementation was continuous beginning 2 d posteclosion. The mean life span of Oregon R females was diminished by rapamycin in both ethanol and DMSO solvents, by 17% and 13%, respectively (P < 0.0005). Oregon R males also exhibited a shortened mean life span, which was significant in DMSO (8%, P = 0.008) but not ethanol (3%, P = 0.9). In contrast, w1118 female flies had a 4% increase in mean life span with rapamycin dissolved in ethanol (P < 0.0005) but not DMSO (1% increase, P = 0.2). Rapamycin decreased life span in w1118 males, but the effect was significant only in DMSO (22%, P = 0.002), not ethanol (10%, P = 0.6). It decreased longevity significantly in y wflies of both sexes on both solvents, by 9% in females and 7‐12% in males (all P < 0.0005 except male/DMSO P = 0.04). Notably, the life spans of control flies differed significantly between the solvents, being longer with ethanol for y w of both sexes and longer with DMSO for Oregon R males and w1118 males. In conclusion, these results show that effects of rapamycin on life span of Drosophila are sex‐, strain‐ and solvent‐dependent.

An extract of Rosaceae,\xa0Solanaceae and Zingiberaceae increases health span and mobility in Caenorhabditis elegans

BackgroundMembers of the Rosaceae, Solanaceae and Zingiberaceae families which include fruits such as cherries, tomatoes and ginger are known to have health promoting effects. There is growing interest in consuming these “functional foods” as a means to increase health and healthy ageing. However, many studies explore the effect of these foods in isolation, not as a blend of multiple functional foods.MethodsIn this study, an extract containing the dried berries, fruits, and roots of members of these families was prepared, which we called Bioact®180. The nematode Caenorhabditis elegans was used to evaluate the effects of Bioact®180 on lifespan and health endpoints, including muscle and mitochondria structure and locomotion.ResultsExposure to the 1000 µg/mL of Bioact®180 extract, containing 4% total phenols, were healthier, as observed by an increase in mean lifespan with and small but significant increase in maximal lifespan. Nematodes exposed to Bioact®180 displayed better mobility in mid-life stages as well as enhanced mitochondrial morphology, which was more comparable to younger animals, suggesting that these worms are protected to some degree from sarcopenia.ConclusionsTogether, our findings reveal that Bioact®180, a blend of fruits and roots from Rosaceae, Solanaceae and Zingiberaceae family members has anti-aging effects. Bioact®180 promotes health and lifespan extension in C. elegans, corresponding to functional improvements in mobility.

Antioxidant and Anti-Atherogenic Properties of Hawthorn Vinegar in Drosophila melanogaster Fed a High-Fat Diet

Consumption of vinegar has been associated with protection against hyperglycemia, dyslipidemia, and hypertension. Hawthorn is a medicinal plant with hypolipidemic, anti-inflammatory, digestive modulator, antimicrobial, antioxidant, cardiac stimulant, and hypotensive properties. Therefore, Hawthorn vinegar rich in bioactives (epicatechin, triterpene, saponins, oligomeric procyanidins, chlorogenic acid, and flavonoids) may present a greater value as a functional food for the management of lifestyle diseases. Drosophila melanogaster, when placed on a high-fat diet, exhibit decreased life span and increased antioxidant enzymes. In this high-fat diet fly model, the Hawthorn vinegar led to a significant increase in mean life span, antioxidant enzyme activities, and reduction in malonyldialdehyde level. Furthermore, in vitro studies showed inhibition of α-glucosidase and α-amylase, and angiotensin-converting enzyme II activities, the measures of antiglycemic and antihypertensive potentials, respectively.

Lactobacillus gastricus BTM 7 prevents intestinal colonization by biofilm forming Cronobacter sakazakii in Caenorhabditis elegans model host.

The study reports protective role of potential probiotic cultures against infection by biofilm forming Cronobacter sakazakii in Caenorhabditis elegans model system. Among the fifteen indigenous potential probiotics, the cell free supernatant of Lactobacillus gastricus BTM7 possessed highest antimicrobial action and biofilm inhibition against C. sakazakii. The competitive exclusion assays revealed that preconditioning with probiotics resulted in increased mean life span of the nematode to 12-13days as compared to 5-6days when the pathogen was administered alone. Enhanced expression of the marker genes (pmk-1, daf-16 and skn-1) was observed during the administration of probiotic cultures. The highest expression of pmk-1 (2.5 folds) was observed with administration of L. gastricus BTM7. The principal component analysis on selected variables revealed that L. gastricus BTM7 has the potential to limit the infection of C. sakazakii in C. elegans and enhance the expression of key genes involved in extending life span of the worm.

Cyanobacterial pigment protein allophycocyanin exhibits longevity and reduces Aβ-mediated paralysis in C. elegans: complicity of FOXO and NRF2ortholog DAF-16 and SKN-1.

The allophycocyanin (APC) protein purified from Phormidium sp. A09DM was investigated for its in vivo antioxidant and anti-aging potential in Caenorhabditis elegans. An increased mean lifespan of APC-treated (100μg/ml) worms (wild type) were observed from 16 ± 0.2days (control) to 20 ± 0.1days (treated). APC-treated worms also showed improved physiological marker of aging such as the rate of pharyngeal pumping and higher rate of survival against oxidative and thermal stress. Furthermore, APC was found to moderate the expression of human amyloid beta (Aβ1-42) as well as associated Aβ-induced paralysis in the transgenic C. elegans CL4176 upon increase in temperature. Furthermore, RNA interference (RNAi)-mediated studies revealed the dependence of downstream regulator daf-16, independent of stress-induced resistance gene skn-1 in the APCtreated C. elegans. In the present study, we tried to demonstrate the anti-aging activity, longevity and protective effects of APC against cellular stress in C. elegans, which can lead to the use of this biomolecule in drug development for age-related disorders.

Loss of proteasome subunit RPN-12 causes an increased mean lifespan at a higher temperature in C. elegans.

Loss of proteasome subunit RPN-12 causes an increased mean lifespan at a higher temperature in C. elegans.

SENESCENCE-ASSOCIATED SECRETOME COMPONENTS AS BIOMARKERS FOR AGING

Cellular senescence is a state of stable growth arrest in response to stress, which is a fundamental process of biological aging. They secrete products, the Senescence-Associated Secretory Phenotype (SASP), which consists of inflammatory cytokines, chemokines, growth factors and matrix remodeling proteins. Senescent cells accumulate with advancing age and partial elimination of senescent cells can reverse age-related dysfunction and increase mean lifespan in mice. However, it is not clear whether components of the SASP can be measured in human plasma and serve as aging biomarkers. Here we generated a candidate panel of senescence markers based on a multiplexed bead-based assay of proteins secreted by senescent preadipocytes, endothelial cells, fibroblasts, myoblasts, preadipocytes, and epithelial cells compared to non-senescent controls. The SASP undoubtedly varies by cell type; however, we observed that multiple components of the SASP are conserved. We then assessed circulating SASP components in human plasma samples from Mayo Clinic Biobank participants (n=280, 20 male and 20 female per decade, age 20-90) using the same method. We confirmed that components of the SASP can be quantified in human plasma with the multiplexed bead-based assay and observed several SASP components robustly increase with chronological age in humans. Our study illustrates that senescence-associated secretome components are detectable in human plasma and could potentially serve as biomarkers of systemic aging and senescent cell burden.

Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster.

Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.

Probiotic mediated colonization resistance against E.coli infection in experimentally challenged Caenorhabditis elegans

This study investigates the antimicrobial potential of sixteen indigenous probiotic bacteria in Caenorhabditis elegans infected with different serotypes of clinical Escherichia coli isolates. The probiotic cultures exhibited varying degree of antimicrobial activity against the pathogenic strains. The Cell Free Supernatant (CFS) of Lactobacillus plantarum K90 exhibited maximum antimicrobial activity against all indicator strains. Further, the pathogenic potential of the clinical strains was determined using liquid killing assay in C. elegans, where the pathogenic strains resulted in complete killing of the worm in 5 days as compared to 60% survival of worms fed with standard food of E. coli OP50. The clinical strains also resulted in impaired pharynx and internal hatching of the eggs in the worms. The protective effects of probiotics against the pathogenic strains was determined via competition, exclusion and displacement assays with different stages of intervention of probiotic culture. No significant increase in mean life span (MLS) of the worm was observed in competition and displacement assay. Among the tested strains in exclusion assay, a pretreatment with L. gastricus BTM 7 was found to result in better protection of the worm against infection with pathogenic E. coli strains by extending its life by three days and no other adverse effect on physiology and morphology of the worm. The results suggest that preconditioning with probiotic strains can be used as an effective way to reduce the invasion and colonization by the pathogens.

Effects of livestock exclusion on density, survival and biomass of the perennial sagebrush grass Hymenachne pernambucense (Poaceae) from a temperate fluvial wetland

In Argentina, the intensification of soybean production has displaced a substantial proportion of cattle ranching to fluvial wetlands such as those in the Delta of the Paraná River. Cattle grazing affects structure and dynamics of native forage plants but there is little information on this impact in populations from fluvial wetlands. This study addresses the effect of cattle ranching on density, survival, mean life-span and aerial biomass of Hymenachne pernambucense (Poaceae), an important forage species in the region. The study was carried out monthly for one year in permanents plots subject to continuous grazing and plots excluded from grazing in the Middle Delta of the Paraná River. In plots excluded from grazing, tillers showed significantly higher population density and survival, and a two-fold increase in mean life-span, while continuous grazing decreased survival of cohorts. The largest contribution to tiller density in ungrazed and grazed populations was made by spring and summer cohorts, respectively. Total and green biomass were significantly higher in the ungrazed population, with highest differences in late spring-early summer. Cattle grazing affected the relationship between tiller density and green biomass suggesting that cattle prefer sprouts because they are more palatable and nutritious than older tissue.

Epidemiology of diabetes mellitus in Russian Federation: clinical and statistical report according to the federal diabetes registry

Aim. We analysed the main epidemiological characteristics of diabetes mellitus (DM) in the Russian Federation (prevalence, incidence, mortality and mean life span), degree of diabetes control, and prevalence of diabetic complications (retinopathy, nephropathy, and diabetic foot syndrome and macrovascular pathology) according to the federal DM registry.
 Materials and methods. The database of the federal DM registry of 79 regions was included using the online system until 31.12.2016.
 Results. TThe total number of patients with DM in the Russian Federation on 31.12.2016 was 4.348 million (2.97% of the population), comprising 4 million patients with DM2 (92%), 255,000 with type 1 diabetes (T1DM) (6%), and 75,000 with other types of DM (2%). DM prevalence per 100,000 population was as follows: T1DM, 164.19/100,000; type 2 diabetes (T2DM), 2637.17/100,000; and other types of DM, 50.62/100. The incidence per 100,000 population was as follows: T1DM, 16.15/100,000; T2DM, 154.9/100,000; and other types of DM, 8.65/100,000. Mortality per 100,000 population was as follows: T1DM, 2.1/100,000; T2DM, 60.29/100,000; and other types of DM, 0.57/100,000. Mortality decreased in patients with T1DM by 6.6% and with T2DM by 3.6%. Mean life span in patients with T1DM was 50.3 years for men and 58.5 years for women. Mean life span in patients with T2DM was 70.1 years for men and 75.5 years for women. Glycated haemoglobin A1c (HbA1c) levels in T1DM was 7% in 33.4%, 7%7.9% in 28.3%, 8%8.9% in 16.2%, and 9.0% in 22.1% of patients. HbA1c levels in T2DM was 7% in 52.1%, 7%7.9% in 29.1%, 8%8.9% in 10%, and 9.0% in 8.7% of patients.
 Conclusions. This study evaluated the increase in DM prevalence in the Russian Federation in 2016 and in the dynamics of 20132016, which was mainly due to T2DM. An increase in patients with a target HbA1c level 7% and a decrease in the proportion of patients with severe uncontrolled DM was observed; however, the treatment effectiveness of this key indicator was unsatisfactory, i.e. less than a third of the patients with DM. In the dynamics of 20132016, an increase in mean life span for patients with T2DM and mortality reduction in patients with T1DM and T2DM was observed. The frequency of diabetic complications varied widely, which may reflect differences in the quality of specialised care in different regions.

Bulbophyllum sterile petroleum ether fraction induces apoptosis in vitro and ameliorates tumor progression in vivo.

Orchids of the genus Bulbophyllum have been reported to possess antitumor activity. Present study investigated the possible antitumor activity of the active fraction of bulb and root of Bulbophyllum sterile. Alcoholic extract along with petroleum ether, dichloromethane and ethyl acetate fractions were subjected to SRB assay in HCT-116, MDA-MB-231 and A549 cell lines. The active fractions were further evaluated for apoptosis, expression of apoptotic signaling proteins, comet assay and cell cycle analysis. Furthermore, they were assessed for in vivo antitumor activity in Ehrlich ascites carcinoma model. Petroleum fraction of bulbs (PFB) and roots (PFR) was found to be most active in HCT-116 cell lines with IC50 value of 94.2±6.0 and 75.7±9.8, respectively. Apoptosis was evident from acridine orange/ethidium bromide staining along with the expression of phospho-p53 and phospho-Bad. Both PFB and PFR arrested G2/M phase of the cell cycle with 32.6% and 49.4% arrest, respectively compared to 17.5% arrest with control. An increase in mean life span and hepatic antioxidant levels was observed with PFB and PFR treatment in EAC inoculated mice. The results suggested that the active fractions of bulbs and roots possess anticancer activity likely by inducing apoptosis through phospho-p53 dependent pathway.

Lower Doses of Fructose Extend Lifespan in Caenorhabditis elegans

ABSTRACTEpidemiological studies indicate that the increased consumption of sugars including sucrose and fructose in beverages correlate with the prevalence of obesity, type-2 diabetes, insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension in humans. A few reports suggest that fructose extends lifespan in Saccharomyces cerevisiae. In Anopheles gambiae, fructose, glucose, or glucose plus fructose also extended lifespan. New results presented here suggest that fructose extends lifespan in Caenorhabditis elegans (C. elegans) wild type (N2). C. elegans were fed standard laboratory food source (E. coli OP50), maintained in liquid culture. Experimental groups received additional glucose (111 mM), fructose (55 mM, 111 mM, or 555 mM), sucrose (55 mM, 111 mM, or 555 mM), glucose (167 mM) plus fructose (167 mM) (G&F), or high fructose corn syrup (HFCS, 333 mM). In four replicate experiments, fructose dose-dependently increased mean lifespan at 55 mM or 111 m Min N2, but decreased lifespan at 555 mM (P < 0.001). Sucrose did not affect the lifespan. Glucose reduced lifespan (P < 0.001). Equal amount of G&F or HFCS reduced lifespan (P < 0.0001). Intestinal fat deposition (IFD) was increased at a higher dose of fructose (555 mM), glucose (111 mM), and sucrose (55 mM, 111 mM, and 555 mM). Here we report a biphasic effect of fructose increasing lifespan at lower doses and shortening lifespan at higher doses with an inverse effect on IFD. In view of reports that fructose increases lifespan in yeast, mosquitoes and now nematodes, while decreasing fat deposition (in nematodes) at lower concentrations, further research into the relationship of fructose to lifespan and fat accumulation in vertebrates and mammals is indicated.

Polyphenolic drug composition based on benzenepolycarboxylic acids (BP-C3) increases life span and inhibits spontaneous tumorigenesis in female SHR mice

Effects of long-term application of novel polyphenolic composition BP-C3, containing polyphenolic benzenepolycarboxylic acids, vitamins and minerals on some biomarkers of aging, life span and spontaneous tumorigenesis has been studied in female SHR mice. Administration of BP-C3 with drinking water (0.005%) did not exert any toxic effect (did not have effect on general condition of animals, weight dynamics and consumption of food), postponed age-related switch-off of estrous function, caused slight reduction of body temperature. An increased survival was observed in mice treated with BP-C3 (p=0.00164, log rank test). BP-C3 increased mean lifespan – by 8.4%, lifespan of the last 10% of animals – by 12.4%, and life span of tumor-free mice – by 11.6%. A tendency in ability of BP-C3 to inhibit development of spontaneous tumors in mice was detected, though it did not reach the level of statistical significance (p=0.166, log rank test). The number of malignant mammary tumors was 1.5 times less and total number of tumors of various localizations was 1.6 times less in BP-C3 treated animals. Multiple tumors were registered in 8% of mice in the control group and no cases – in BP-C3 treated group. Thus, BP-C3 demonstrated some anti-carcinogenic and a pronounced geroprotective activity.

Supplementation with Major Royal-Jelly Proteins Increases Lifespan, Feeding, and Fecundity in Drosophila.

The major royal-jelly proteins (MRJPs) are the main constituents responsible for the specific physiological role of royal jelly (RJ) in honeybees. Male and female Drosophila flies were fed diets containing either no MRJPs (A) or casein (B) at 1.25% (w/w) of diet or MRJPs at 1.25% (C), 2.50% (D), or 5.00% (E). Diets B, C, D, and E increased mean lifespan by 4.3%, 9.0%, 12.4%, and 13.9% in males and by 5.8%, 9.7%, 20.0%, and 11.8% in females in comparison to results from diet A, respectively. The diet supplemented with 2.50% MRJPs seems to have the optimal dose to improve both physiological and biochemical measures related to aging in both sexes. Interestingly, lifespan extension by MRJPs in Drosophila was positively associated with feeding and fecundity and up-regulation of copper and zinc-superoxide dismutase (CuZn-SOD) and the Egfr-mediated signaling pathway. This study provides strong evidence that MRJPs are important components of RJ for prolonging lifespan in Drosophila.

The aryl hydrocarbon receptor promotes aging phenotypes across species

The ubiquitously expressed aryl hydrocarbon receptor (AhR) induces drug metabolizing enzymes as well as regulators of cell growth, differentiation and apoptosis. Certain AhR ligands promote atherosclerosis, an age-associated vascular disease. Therefore, we investigated the role of AhR in vascular functionality and aging. We report a lower pulse wave velocity in young and old AhR-deficient mice, indicative of enhanced vessel elasticity. Moreover, endothelial nitric oxide synthase (eNOS) showed increased activity in the aortas of these animals, which was reflected in increased NO production. Ex vivo, AhR activation reduced the migratory capacity of primary human endothelial cells. AhR overexpression as well as treatment with a receptor ligand, impaired eNOS activation and reduced S-NO content. All three are signs of endothelial dysfunction. Furthermore, AhR expression in blood cells of healthy human volunteers positively correlated with vessel stiffness. In the aging model Caenorhabditis elegans, AhR-deficiency resulted in increased mean life span, motility, pharynx pumping and heat shock resistance, suggesting healthier aging. Thus, AhR seems to have a negative impact on vascular and organismal aging. Finally, our data from human subjects suggest that AhR expression levels could serve as an additional, new predictor of vessel aging.