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Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in C. elegans. Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.

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Papaya leaves are used frequently for curing scores of ailments. The medicinal properties of papaya leaves are due to presence of certain bioactive/pharmacological compounds. However, the papaya leaf curl virus (PaLCuV), a geminivirus, is a major threat to papaya cultivation globally. During the present investigation, we observed that PaLCuV infection significantly altered the anatomy, physiology, and bioactive properties of papaya leaves. As compared to healthy leaves, the PaLCuV-infected leaves were found to have reduced stomatal density (76.83%), stomatal conductance (78.34%), photosynthesis rate (74.87%), water use efficiency (82.51%), chlorophyll (72.88%), carotenoid (46.63%), osmolality (48.55%), and soluble sugars (70.37%). We also found lower enzymatic activity (superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT)-56.88%, 85.27%, and 74.49%, respectively). It was found that the size of guard cells (50%), transpiration rate (45.05%), intercellular CO2 concentration (47.81%), anthocyanin (27.47%), proline content (74.17%), malondialdehyde (MDA) (106.65%), and electrolyte leakage (75.38%) was elevated in PaLCuV-infected leaves. The chlorophyll fluorescence analysis showed that the infected plant leaves had a significantly lower value of maximal quantum yield of photosystem II (PSII (Fv/Fm), photochemical quantum yield of photosystem I (PSI (Y(I)), and effective quantum yield of PSII (Y(II)). However, in non-photochemical quenching mechanisms, the proportion of energy dissipated in heat form (Y(NPQ)) was found to be significantly higher. We also tested the bioactivity of infected and healthy papaya leaf extracts on a Caenorhabditis elegans (C. elegans) model system. It was found that the crude extract of papaya leaves significantly enhanced the life span of C. elegans (29.7%) in comparison to virus-infected leaves (18.4%) on application of 100 µg/mL dose of the crude extract. Our research indicates that the PaLCuV-infected leaves not only had anatomical and physiological losses, but that pharmacological potential was also significantly decreased.

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Terpenes and their derivatives have been used conventionally as potential dietary supplements to boost the nutritional value of endless food products. Several plant-based complex terpenoid and their derivatives have been reported for a wide range of medicinal and nutritional properties. However, their simple counterparts, whose production is relatively easy, sustainable, and economic from food-grade microbial sources, have not been studied yet for any such biological activities. The present study aimed to investigate the longevity-promoting property and neuromodulatory effects of 3,3-dimethylallyl alcohol (Prenol), one of the simplest forms of terpenoid and a constituent of fruit aroma, in the animal model Caenorhabditis elegans. Prenol supplementation (0.25 mM) augmented the lifespan of wild-type nematodes by 22.8% over the non-treated worms. Moreover, a suspended amyloid-ß induced paralysis and reduced α-synuclein aggregation were observed in Prenol-treated worms. The lifespan extending properties of Prenol were correlated with ameliorated physiological parameters and increased stress (heat and oxidative) tolerance in C. elegans. In silico and gene-specific mutant studies showed that pro-longevity transcription factors DAF-16, HSF-1, and SKN-1 were involved in the improved lifespan and health-span of Prenol-treated worms. Transgenic green fluorescent protein-reporter gene expression analysis and relative mRNA quantification (using real-time PCR) demonstrated an increase in the expression of DAF-16, HSF-1, and SKN-1 transcription factors and their downstream target genes in Prenol-treated worms. Together, the findings suggest that small molecules, like Prenol, could be explored as a potential alternate to develop therapeutics against aging and age-related ailments.

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Among the fascinating adaptations to limiting oxygen conditions (hypoxia) is the suppression of food intake and weight loss. In humans, this phenomenon is called high-altitude anorexia and is observed in people suffering from acute mountain syndrome. The high-altitude anorexia appears to be conserved in evolution and has been seen in species across the animal kingdom. However, the mechanism underlying the recovery of eating behavior after hypoxia is still not known. Here, we show that the phosphatidylinositol transfer protein PITP-1 is essential for the fast recovery of eating behavior after hypoxia in the nematode Caenorhabditis elegans. Unlike the neuroglobin GLB-5 that accelerates the recovery of eating behavior through its function in the oxygen (O2 )-sensing neurons, PITP-1 appears to act downstream, in neurons that express the mod-1 serotonin receptor. Indeed, pitp-1 mutants display wild-type-like O2 -evoked-calcium responses in the URX O2 -sensing neuron. Intriguingly, loss-of-function of protein kinase C 1 (PKC-1) rescues pitp-1 mutants' recovery after hypoxia. Increased diacylglycerol (DAG), which activates PKC-1, attenuates the recovery of wild-type worms. Together, these data suggest that PITP-1 enables rapid recovery of eating behavior after hypoxia by limiting DAG's availability, thereby limiting PKC activity in mod-1-expressing neurons.

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The present investigation demonstrates the longevity-promoting effects of 3-methyl-3-buten-1-ol (isoprenol) in the animal model Caenorhabditis elegans that might be served as a lead nutraceutical in geriatric research. Our results showed that 0.5 mM isoprenol extended the mean lifespan of worms by 25% in comparison to control worms. Isoprenol also significantly enhanced survival of the worms under various stress conditions. It was found that the longevity-promoting effects of isoprenol were associated with improved age-associated physiological behaviour and reduced intracellular reactive oxygen species (ROS) accumulation. Finally, studies with gene-specific mutants revealed the involvement of pro-longevity transcription factors (TFs) DAF-16 and SKN-1 with simultaneous over-expression of GST-4 and SOD-3 in isoprenol treated worms. In silico analysis revealed the binding affinity of isoprenol with DAF-16 and SKN-1 TFs. Together, the findings suggest that isoprenol is able to enhance the lifespan of C. elegans and embarks its potential in the developments of formulations for age-related ailments.

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BACKGROUND: Bacopa monnieri (L.) Pennell, commonly known as Brahmi is an important medicinal plant traditionally used as memory enhancer and antiepileptic agent. OBJECTIVE: The present study investigated antioxidant and stress resistance potentials of B. monnieri aqueous extract (BMW) using Caenorhabditis elegans animal model system. MATERIALS AND METHODS: The antioxidant activity of the BMW was measured using in vitro (DPPH, reducing power and total polyphenol content) and in vivo (DCF-DA assay) assays. The antistress potential of BMW (0.1, 0.01, and 0.001 mg/ml) was evaluated through thermal stress (37°C) and oxidative stress (10 mM paraquat) using C. elegans. Quantification of the HSP-16.2 level was done using CL2070 transgenic worms. RESULTS: Present study reveals that BMW possess in vitro and in vivo antioxidant activities. BMW significantly enhanced stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress, although it did not extend lifespan at 20°C and attenuated age dependent decline in physiological behaviors. Moreover, it was shown that BMW was able to up-regulate expression of stress associated gene hsp-16.2, which significantly (P < 0.001) extends the mean lifespan of worms under stress conditions. CONCLUSION: The study strongly suggests that BMW acts as an antistressor and potent reactive oxygen species scavenger which enhances the survival of the worms in different stress conditions.

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Despite the vast exploration of rhizospheric microbial wealth for crop yield enhancement, knowledge about the efficacy of microbial agents as biocontrol weapons against root-knot disease is scarce, especially in medicinal plants, viz., Bacopa monnieri. In the present investigation, rhizospheric microbes, viz., Bacillus megaterium, Glomus intraradices, Trichoderma harzianum ThU, and their combinations were evaluated for the management of Meloidogyne incognita (Kofoid and White) Chitwood and bacoside content enhancement in B. monnieri var CIM-Jagriti. A novel validated method Fourier transform near infrared was used for rapid estimation of total bacoside content. A significant reduction (2.75-fold) in root-knot indices was observed in the combined treatment of B. megaterium and T. harzianum ThU in comparison to untreated control plants. The same treatment also showed significant enhancement (1.40-fold) in total bacoside contents (plant active molecule) content using Fourier transform near-infrared (FT-NIR) method that analyses samples rapidly in an hour without solvent usage and provides ample scope for natural product studies.

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Beta-caryophyllene (BCP) is a natural bicyclic sesquiterpene and is a FDA approved food additive, found as an active ingredient in essential oils of numerous edible plants. It possesses a wide range of biological activities including anti-oxidant, anti-inflammatory, anti-cancerous and local anesthetic actions. We used the well established Caenorhabditis elegans model system to elucidate the stress modulatory and lifespan prolonging action of BCP. The present study for the first time reports the lifespan extension and stress modulation potential of BCP in C. elegans. Upon evaluation, it was found that 50µM dose of BCP increased the lifespan of C. elegans by over 22% (P≤0.0001) and significantly reduced intracellular free radical levels, maintaining cellular redox homeostasis. Moreover, the results suggest that BCP modulates feeding behavior, pharyngeal pumping and body size effectively. Further, this compound also exhibited significant reduction in intestinal lipofuscin levels. In the present investigation, we have predicted possible biological molecular targets for BCP using molecular docking approaches and BCP was found to have interaction with SIR-2.1, SKN-1 and DAF-16. The prediction was further validated in vivo using mutants and transgenic strains unraveling underlying genetic mechanism. It was observed that BCP increased lifespan of mev-1 and daf-16 but failed to augment lifespan in eat-2, sir-2.1 and skn-1 mutants. Relative quantification of mRNA demonstrated that several genes regulating oxidative stress, xenobiotic detoxification and longevity were modulated by BCP treatment. The study unravels the involvement of multiple signaling pathways in BCP mediated lifespan extension.

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Since aging is the most important risk factor for variety of diseases, the discovery of a wide range of chemical modulators of aging in model organisms encourages new strategies for targeting age associated diseases. Simple genetic manipulation leads to long-lived and healthy animals, so any compound which could have similar effect would prove a boon to mankind. In the present study, effect of different pharmacological doses (1.0, 0.1, 0.01 and 0.001 mg/mL) of O. sanctum crude extract were used to determine their impact on life span, thermotolerance and ROS scavenging activities in C. elegans. The results revealed that 1 mg/mL of O. sanctum extract significantly extended the life span of C. elegans. The extract also proved to be a strong free radical scavenger and increased resistance against thermal stress. It is also suggested that the protective and life span extending action of the crude extract is not only due to its antioxidant capacity but may also be mediated by modulation of some signaling pathways. Thus, in addition to all the known medicinal property of Ocimum, it is capable of increasing stress tolerance and life span in C. elegans.

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Aging, the major cause of several ailments has led to intense exploration of potential drugs that delay aging and its associated effects. We mined the information on traditional Indian medicines and identified an iridoid, 10-O-trans-p-Coumaroylcatalpol (OCC), a major ingredient of Premna integrifolia Linn. (syn: Premna serratifolia). OCC forms an important constituent of famous herbal formulation 'Dashmula', a ten herb formulation, commonly used for its various medicinal properties. Employing model system C. elegans, the effect of OCC on life span, stress resistance, chemotaxis, the content of reactive oxygen species (ROS) and on the aggregation of alpha synuclein was studied. OCC extended the mean life span of nematodes, increased their tolerance against chemical induced stress, improved the chemotaxis index and reduced the ROS content. Further, the aggregation of Parkinson's disease (PD) associated protein, alpha synuclein (asyn), was decreased when transgenic a-syn expressing worms were raised on OCC mixed diet. We extended the studies further to explore the possible genetic mechanism that mediates the observed effects of OCC. Employing the genetic knockout mutants TK22 [mev-1(kn1)III]; GR1307 [daf-16(mgDf50)I]; VC199 [sir-2.1(ok434)IV] and transgenic GFP expressing strain TJ356 [zls356; DAF-16::GFP], our studies revealed that the effects were mediated by daf-16 and not by sir-2.1 or mev-1. Our results indicate that OCC has the ability to ameliorate a-syn aggregation, reduce oxidative stress and promote longevity in C. elegans via activation of longevity promoting transcription factor DAF-16. Thus, OCC may serve as a lead compound of plant origin for important nutraceutical intervention against aging and age associated PD.

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In modern times, there has been a major increase in the use of plants or herbal constituents for the prevention of age-related disorders. 4-Hydroxy-E-globularinin (4-HEG) is an iridoid and a major component of Premna integrifolia. This investigation represents a breakthrough in geriatrics by showing the longevity-promoting activity of 4-HEG in the animal model Caenorhabditis elegans. 4-HEG (20µM) enhanced the mean life span of worms by over 18.8% under normal culture conditions and also enhanced their survival under oxidative stress. The longevity-promoting activity was associated with reduced reactive oxygen species (ROS) levels and fat accumulation in the worms. Gene-specific mutant studies verified the role of ROS detoxification pathways and simultaneous nuclear translocation of DAF-16 in the 4-HEG-mediated effects. Quantitative real-time PCR estimations and observations of transcriptional reporters indicated that 4-HEG was able to upregulate stress-inducible genes, viz., hsp-16.2 and sod-3. Thus, 4-HEG may serve as a lead compound of plant origin for the development of important nutraceuticals superseding the aging process.

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BACKGROUND: The concept of DNA barcoding for species identification has gained considerable momentum in animals because of fairly successful species identification using cytochrome oxidase I (COI). In plants, matK and rbcL have been proposed as standard barcodes. However, barcoding in complex genera is a challenging task. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the species discriminatory power of four reportedly most promising plant DNA barcoding loci (one from nuclear genome--ITS, and three from plastid genome--trnH-psbA, rbcL and matK) in species of Indian Berberis L. (Berberidaceae) and two other genera, Ficus L. (Moraceae) and Gossypium L. (Malvaceae). Berberis species were delineated using morphological characters. These characters resulted in a well resolved species tree. Applying both nucleotide distance and nucleotide character-based approaches, we found that none of the loci, either singly or in combinations, could discriminate the species of Berberis. ITS resolved all the tested species of Ficus and Gossypium and trnH-psbA resolved 82% of the tested species in Ficus. The highly regarded matK and rbcL could not resolve all the species. Finally, we employed amplified fragment length polymorphism test in species of Berberis to determine their relationships. Using ten primer pair combinations in AFLP, the data demonstrated incomplete species resolution. Further, AFLP analysis showed that there was a tendency of the Berberis accessions to cluster according to their geographic origin rather than species affiliation. CONCLUSIONS/SIGNIFICANCE: We reconfirm the earlier reports that the concept of universal barcode in plants may not work in a number of genera. Our results also suggest that the matK and rbcL, recommended as universal barcode loci for plants, may not work in all the genera of land plants. Morphological, geographical and molecular data analyses of Indian species of Berberis suggest probable reticulate evolution and thus barcode markers may not work in this case.

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BACKGROUND: DNA barcoding refers to the use of short DNA sequences for rapid identification of species. Genetic distance or character attributes of a particular barcode locus discriminate the species. We report an efficient approach to analyze short sequence data for discrimination between species. METHODOLOGY AND PRINCIPAL FINDINGS: A new approach, Oligonucleotide Frequency Range (OFR) of barcode loci for species discrimination is proposed. OFR of the loci that discriminates between species was characteristic of a species, i.e., the maxima and minima within a species did not overlap with that of other species. We compared the species resolution ability of different barcode loci using p-distance, Euclidean distance of oligonucleotide frequencies, nucleotide-character based approach and OFR method. The species resolution by OFR was either higher or comparable to the other methods. A short fragment of 126 bp of internal transcribed spacer region in ribosomal RNA gene was sufficient to discriminate a majority of the species using OFR. CONCLUSIONS/SIGNIFICANCE: Oligonucleotide frequency range of a barcode locus can discriminate between species. Ability to discriminate species using very short DNA fragments may have wider applications in forensic and conservation studies.

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