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Ageing is a progressive deterioration in functional and structural well-being of the body, accompanied with age-associated neurological disorders such as Parkinson's disease (PD), Alzheimer's disease and Huntington's disease. PD is marked with motor function decline, progressive neurodegeneration due to aggregation of insoluble α-synuclein in the dopaminergic neuron. Here we investigated the effect of tambulin (3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl) chromen-4-one), a hydroxy substituted flavanol isolated from fruits of Zanthoxyllum armatum DC (Family-Rutaceae) for its longevity promoting and neuromodulatory activities using Caenorhabditis elegans model system. Our results show that tambulin treatment significantly enhance lifespan and stress tolerance in worms, along with mitigation of ageing biomarkers like lipofuscin and protein carbonyl. In line with the alleviated ROS levels, tambulin treatment led to upregulated mRNA expression of ROS scavenging genes viz., sod-1, sod-3, and ctl-2. Upregulation in daf-16 gene indicates the involvement of insulin signaling pathway in tambulin mediated longevity. Tambulin treatment exhibited curtailed PD manifestations in terms of reduced α-synuclein levels, lipid accumulation, improved locomotary behavior and dopamine levels. Altogether, our data suggest that tambulin mediated alleviation of PD manifestations possibly involved PD counter protective machinery as evident through upregulated mRNA expression of lagr-1, ymel-1, pdr-1, ubc-12, and lrk-1. Our studies present tambulin as a potential molecule for its properties against ageing and Parkinson's disease. Further studies are speculated to realize the mechanistic and pharmacological aspects of tambulin., (Copyright © 2019. Published by Elsevier Inc.)

The advancements in the field of gerontology have unraveled the signaling pathways that regulate life span, suggesting that it might be feasible to modulate aging. To this end, we isolated a novel phytomolecule Acacetin 7-O-α-l-rhamnopyranosyl (1-2) β-D-xylopyranoside (ARX) from Premna integrifolia and evaluated its antiaging effects in Caenorhabditis elegans The spectral data analysis revealed the occurrence of a new compound ARX. Out of the three tested pharmacological doses of ARX, viz. 5, 25, and 50 µM, the 25-µM dose was able to extend life span in C. elegans by more than 39%. The present study suggests that ARX affects bacterial metabolism, which in turn leads to dietary restriction (DR)-like effects in the worms. The effect of ARX on worms with mutations (mev-1, eat-2, sir-2.1, skn-1, daf-16, and hsf-1) indicates that ARX-mediated life-span extension involves mechanisms associated with DR and maintenance of cellular redox homeostasis. This study is the first time report on longevity-promoting activity of ARX in C. elegans mediated by stress and DR-regulating genes. This novel phytomolecule can contribute in designing therapeutics for managing aging and age-related diseases., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The progression in lifespan has been associated with elevated intracellular reactive oxygen species (ROS) and oxidative stress level which contributes to development of age related disorders. The discovery of lifespan modulating phytomolecules may promote development of natural therapies against age related afflictions. Acacetin (5,7-dihydroxy-4-methoxyflavone), is a naturally occurring flavonoid known to possess therapeutic properties. To this end, the present study evaluates effect of acacetin (AC) on lifespan, stress and neurotoxicity for the first time by using well-established free living, multicellular Caenorhabditis elegans model system. The 25 μM dose of AC significantly prolonged the mean lifespan of worms by 27.31% in comparison to untreated control and other tested doses of AC. Additionally, AC enhanced stress resistance against oxidative and thermal stress in worms. Furthermore, AC attenuated age related intracellular ROS level, aggregation of age pigment lipofuscin and increased the mean survival in stress hypersensitive mev-1 mutant by 40.5%. AC supplementation also reduced the alpha synuclein aggregation in transgenic worm model of Parkinson's disease. The enhanced stress resistance, lifespan and alleviation of age related pathology can be attributed to increment in stress modulatory enzymes like superoxide dismutase (SOD) and catalase (CAT) level. Altogether the results suggest AC exposure maintains stress level, health span and extends mean lifespan of C. elegans. The longevity promoting and neuromodulatory effects of AC are mediated by up regulation of the stress response genes sod-3 and gst-4. The present finding gives new insights of natural remedies and their future prospects in developing therapeutic interventions for managing age related diseases.

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments., Competing Interests: The authors declare that they have no competing interests.

An endophytic fungus was isolated from the rhizomes of Curcuma amada (Zingiberaceae), which was identified as Fusarium oxysporum on the basis of its morphological and molecular characters. Chromatographic separation and spectroscopic analysis of the fungal metabolite (chloroform extract) led to the identification of one pure compound having molecular formula C5H12O2, i.e., 2,3-pentanediol (1). Activity analysis of compound 1 demonstrated improved antiaging (antioxidant, thermotolerance) properties against Caenorhabditis elegans, in comparison to a similar, commercially available molecule i.e., 1,5-pentanediol (2). The effective (lower) concentration of 1 significantly showed (28.6%) higher survival percentage of the worms under thermal stress (37 ºC) compared to its higher concentration (25.3%), while similar trends were followed in oxidative stress where (22.2%) higher survival percentage was recorded in comparison to untreated control. The compound 1, however, lacked potential antimicrobial activity, indicating the plausible ramification of the position of OH group in such bioactive molecules. In silico evaluation of these molecules against common as well as unique targets corroborated better antiaging potential of 1 in comparison to that of 2. The results for the first time indicated that the utilization of the endophytic fungi of C. amada could, thus, be a possible source for obtaining non-plant-based bioactive compounds having broader therapeutic applications pertaining to age-related progressions.

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.

Shatavarin IV (SIV), a steroidal saponin, is a major bioactive phytomolecule present in roots of Asparagus racemosus (Liliaceae) known for its anticancer activity. Age-associated neurodegenerative Parkinson's disease (PD) is characterised by alpha-synuclein aggregation in dopaminergic neuron resulting in neurodegeneration. The invention of bioactive molecules that delay aging and age-associated disorders endorses development of natural phytomolecule as a therapeutic agent for curing age-related diseases. Therefore, the present study for the first time explores the potential of SIV against aging and Parkinsonism utilising Caenorhabditis elegans model system. SIV significantly attenuated oxidative stress in terms of intracellular reactive oxygen species (ROS) as well as oxidative damage including protein carbonylation and also promotes longevity. SIV also significantly increased the mRNA expression of stress responsive genes namely sod-1, sod-2, sod-3, gst-4, gst-7 and ctl-2 suggesting its anti-oxidant property that might be contributed in the modulation of oxidative stress and promoting lifespan. Additionally, SIV improved PD symptoms by reducing the alpha-synuclein aggregation, lipid accumulation and enhancing dopamine level. Altogether, present findings indicate that SIV possibly utilising ubiquitin-mediated proteasomal system and attenuating oxidative stress by up-regulating PD-associated genes pdr-1, ubc-12 and pink-1. Therefore, this study is a forward step in exploring the anti-aging and anti-Parkinsonism potential of bioactive compound SIV in C. elegans. [ABSTRACT FROM AUTHOR]

Species from lower invertebrates to a spectrum of mammals show antiaging health benefits of phytochemical(s). Here, we explored the pro-longevity effects of a natural triterpenoid, ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) in Caenorhabditis elegans with maximal life span being evident at 25 µM UA. Similar to eat-2 mutants, UA uptake by worm results in reduced fat storage and attenuation of reactive oxygen species (ROS), independent of superoxide dismutase(s) activation. The genetic requirements for UA-mediated longevity are quite similar to dietary restriction (DR) achieved through SKN-1/NRF-2 exhibiting upregulation of downstream target genes gcs-1 and daf-9. Longevity mechanism was independent of PHA-4/FOXA and attributed to partial dependence on sir-2.1. Altogether, our study suggests differential use of UA-elicited signaling cascades in nutrient sensing for longevity. Both the redox state and the proteostasis of an organism play critical role in aging and disease resistance. Interestingly, we observed a reduction of toxic protein aggregation in transgenic polyglutamine (polyQ) C. elegans model and UA-mediated JNK-1 (c-Jun-NH2-terminal kinase) activation in wild-type animals. Thus, our study demonstrates a small extent of prevention against proteotoxic stress by UA coupled with positive aspects of DR-mediated longevity. [ABSTRACT FROM AUTHOR]

Aging is an unavoidable phenomenon, often afflicting structure and functionality of body, marked with onset of age associated manifestations. Parkinson's disease (PD), the second most common form of dementia is manifested with Lewy body formation and dopaminergic dysfunction. Present study explores silymarin, a known hepatoprotective regimen for its efficacy in Aging and PD using Caenorhabditis elegans . Silymarin positively modulated longevity, reduced oxidative stress, independent of feeding behaviour. Up-regulation of longevity and stress related genes daf-16, sod-3, gst-4 and skn-1 indicate the possible involvement of these genes for regulating longevity. In-addition silymarin alleviated PD symptoms by reducing α-synuclein levels, lipid accumulation and enhanced dopamine function. Silymarin executes its beneficial effects through mitigation of free radicals, while achieving alleviation in Parkinsonism possibly through pdr-1 mediated recruitment of ubiquitin proteasome system as evident from qPCR studies. Altogether, silymarin emerged as a potent molecule for investigation in Aging and age related disorders. [ABSTRACT FROM AUTHOR]

Remarkably the c-Jun-NH2-terminal kinase (JNK) pathway is all evolutionarily conserved across species. In view of the hypothesis that increased stress resistance subdue aging, we investigated the role of ursolic acid (3β-Hydroxy-urs-12-en-28-oic acid; UA) in the pioneering aging model Caenorhabditis elegans with an increase in mean and maximum lifespan by up to 30%. Our genetic study unravelled the underlying pathway where JNK-1 is acting independently of insulin-IGF-1 signalling (IIS) pathway to modulate longevity. In support of in vivo results in silico docking study of UA with C. elegans JNK-1 ATP-binding site suggested promising binding affinity exhibiting binding energy of −8.11 kcalmol −1 . UA induced JNK-1 activation in wild-type animals underlie the importance of pharmacological interventions in the delineation of molecular targets for aging and associated pathologies. [ABSTRACT FROM AUTHOR]

Withanolide A (steroidal lactone) forms the major constituent of the most popular herbal drug in Ayurvedic medicine, Ashwagandha. It has been used since ancient times as an alternative medicine for the treatment of a variety of age related disorders. Here we provide multiple lines of evidence indicating that Withanolide A improves healthspan, delays age-associated physiological changes and also extends the lifespan of Caenorhabditis elegans . We also report several neuroprotective benefits of this natural product, including its anti-amyloidogenic effects, alleviation of α-synuclein aggregation and neuroprotection through modulation of neural mediators like acetylcholine. We observed that Withanolide A mediates lifespan extension and promotes stress resistance via insulin/insulin-like growth factor signaling pathway. Such findings could be helpful to develop a therapeutic medicine from this natural product for the prevention or reversal of age-related ailments and to improve the survival of patients suffering from Alzheimer's or Parkinson's disease. [ABSTRACT FROM AUTHOR]

The ever increasing popularity of herbal supplements modulating aging has shifted focus towards development of natural therapeutics for curing age related afflictions in living organisms. The progression in age is correlated with elevation in oxidative stress. The increment in oxidative stress ultimately affects human health, which led to search for new stress alleviating compounds, but very few bioactive molecules are available presently. To this end, we evaluated the effect of three aqueous extract viz. Ocimum basilicum (OCW), Premna integrifolia (PSW) and mixture of both herbs (OPW) on Caenorhabditis elegans . The present study delineates effect of OPW, PSW and OCW on lifespan using survival and stress assays. The maximal lifespan extension was observed in OPW (50 μg/ml) 32% ( P < 0.0001) followed by 27.9% ( P < 0.0001) in PSW (50 μg/ml) and 18.39% ( P < 0.0001) in OCW (50 μg/ml). Furthermore, all the three extracts were able to modulate both the oxidative as well as thermal stress. Altogether, OPW mediates maximal lifespan extension in the worm which can be attributed to modulation of stress level to a greater extent. These results may provide insights for designing evidence-based herbal therapy in future. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]