Lifespan-extending Effect Research Articles

The natural phytochemical trans‐communic acid inhibits cellular senescence and pigmentation through FoxO3a activation

Ageing is characterized by the accumulation of chronic and irreversible oxidative damage, chronic inflammation and organ dysfunction. To attenuate these ageing-related changes, various natural phytochemicals are often applied. Trans-communic acid (TCA), an active component of brown pine leaf extract, has antimicrobial and cancer chemopreventive activity and inhibits ultraviolet B (UVB)-induced MMP-1 expression. To determine whether the phytochemical TCA could affect the lifespan of an ageing model, Caenorhabditis elegans prevent ageing-related phenotypes of the skin. Caenorhabditis elegans (C.elegans) wild-type N2 and mutant strains were used in this study to explore the lifespan extension effect of TCA and its mechanism. We estimated lipofuscin accumulation and melanin levels, which are closely associated with skin senescence. Moreover, we explored the mechanism of action associated with ageing attenuation. We performed oxidative stress resistance and thermotolerance assays in C.elegans and surface plasmon resonance analysis of TCA binding with the forkhead box-O3a (FoxO3a) protein. TCA, which is the active component in Korean red pine (Pinus densiflora), attenuated ageing-related changes in skin cells. TCA lowered lipofuscin accumulation in fibroblasts and decreased melanin levels in melanocytes. These protective effects were mediated by activation of the representative longevity gene FoxO3a, which was induced by direct binding with TCA. Interestingly, TCA extended the lifespan of C.elegans, although it did not affect stress resistance, oxidative stress or thermotolerance. These results strongly suggest that TCA prevents the senescent phenotype of model organisms and exhibits beneficial effects on ageing-related skin phenotypes through direct FoxO3a activation.

Phosphatidylcholine Extends Lifespan via DAF-16 and Reduces Amyloid-Beta-Induced Toxicity in Caenorhabditis elegans.

Phosphatidylcholine is one of the major phospholipids comprising cellular membrane and is known to have several health-promoting activities, including the improvement of brain function and liver repair. In this paper, we examine the in vivo effect of dietary supplementation with phosphatidylcholine on the response to environmental stressors and aging in C. elegans. Treatment with phosphatidylcholine significantly increased the survival of worms under oxidative stress conditions. However, there was no significant difference in response to stresses caused by heat shock or ultraviolet irradiation. Oxidative stress is believed to be one of the major causal factors of aging. Then, we examined the effect of phosphatidylcholine on lifespan and age-related physiological changes. Phosphatidylcholine showed a lifespan-extending effect and a reduction in fertility, possibly as a tradeoff for long lifespan. Age-related decline of motility was also significantly delayed by supplementation with phosphatidylcholine. Interestingly, the expressions of well-known longevity-assuring genes, hsp-16.2 and sod-3, were significantly upregulated by dietary intervention with phosphatidylcholine. DAF-16, a transcription factor modulating stress response genes, was accumulated in the nucleus by phosphatidylcholine treatment. Increase of the ROS level with phosphatidylcholine suggests that the antioxidant and lifespan-extending effects are due to the hormetic effect of phosphatidylcholine. Phosphatidylcholine also showed a protective effect against amyloid beta-induced toxicity in Alzheimer's disease model animals. Experiments with long-lived mutants revealed that the lifespan-extending effect of phosphatidylcholine specifically overlapped with that of reduced insulin/IGF-1-like signaling and required DAF-16. These findings showed the antioxidant and antiaging activities of phosphatidylcholine for the first time in vivo. Further studies focusing on the identification of underlying cellular mechanisms involved in the antiaging effect will increase the possibility of using phosphatidylcholine for the development of antiaging therapeutics.

Effect of tranexamic acid in improving the lifespan of naturally aging mice.

An effective method to improve lifespan is not known. Therefore, in this study, we examined the lifespan-extending effect of tranexamic acid in normal mice. We bred hairless mice without exposure to ultraviolet radiation and psychical stress until they died naturally. During the study period, the mice were orally administered tranexamic acid (12mg/kg/day) three times weekly. An increase in the lifespan of mice was observed by tranexamic acid administration. Furthermore, age-related diseases of the skin were ameliorated by tranexamic acid administration. Moreover, the blood level of tumor necrosis factor-α, interleukin-6, reactive oxygen species (ROS), and matrix metalloproteinase (MMP)-9 was decreased by tranexamic acid administration. These results indicate that tranexamic acid suppresses the secretion of inflammatory cytokines, MMP-9, and ROS induced by natural aging, ameliorating age-related diseases, and, consequently, extending the lifespan.

Resource recovery potentials by landfill mining and reclamation in South Korea

In the existing paradigm for waste management, landfills are the final disposal site for waste with no control over the waste being sent to the sites. However, the expanding number of landfills that are at the end of their lifespans and the increasing amount of waste disposed of to landfills have presented a growing need for a shift in this paradigm, which can be achieved by the active promotion of landfill mining and resource recovery. In this study, we analyze the landfill resource recovery potentials to understand the effects on landfill lifespan extension, reduction in landfill disposal rate, energy saving, and reduction in greenhouse gas (GHG) emissions. Simulations based on material flow analysis were conducted on existing landfills, which were categorized into four different types based on their remaining capacities and availability of nearby incineration or SRF facilities. The resource recovery potentials, GHG reduction effect, and energy saving effect were higher for Type 2-1 and Type 2-2 landfills with higher ratios of combustible waste. The landfill lifespan extension effect was the highest for Type 2-2 landfill which receives a relatively smaller amount of waste than the other landfills. The reduction in landfill disposal rate was highest for Type 3, which does not have an incinerator or SRF facilities nearby. On the other hand, the overall effects, including the effect on reducing the landfill disposal rate, are the lowest for Type 1 because the chosen landfill only covers a significantly small proportion of the total waste generated in the city compared to the other landfills. The findings of this study suggest that appropriate landfill mining and reclamation operations are integral to prolonging the lifespans of existing landfills and present insights for building future landfill management strategies.

Pro-oxidant and lifespan extension effects of caffeine and related methylxanthines in Caenorhabditis elegans

Caffeine and related purine alkaloids are common ingredients of many stimulating drinks. Studies have shown that lower concentrations of caffeine have a protective role in aging-related disorders. However, the associated mode of action of caffeine and its related methylxanthines is still not clear. In this study, we demonstrated that caffeine and theophylline promote longevity in Caenorhabditis elegans. Lifespan studies with the wild type, DAF-16 and SKN-1 mutant strains indicated that the methylxanthines-mediated lifespan extension in C. elegans was independent of DAF-16/FOXO and SKN-1. All the tested methylxanthines could protect C. elegans against acute oxidative stress. At early stages of life, an increase of ROS (reactive oxygen species) induced the translocation of DAF-16 and SKN-1, resulting in upregulation of several antioxidant genes, for example, sod-3p::GFP, gst-4p::GFP, gcs-1p::GFP; and downregulation of hsp-16.2p::GFP. RT-PCR corroborates the upregulation of gst-4 and skn-1 genes. The expression of DAF-16 decreased although its nuclear translocation was induced.

Antioxidant and anti-aging activities and structural elucidation of polysaccharides from Panax notoginseng root

Abstract Two novel polysaccharides, MRP5 and MRP5A, were obtained from the root of Panax notoginseng using column chromatography. Structure characterization suggested that MRP5A, with an average molecular weight of 11.38 × 104 Da, was composed of rhamnose (7.7%), arabinose (6.6%), glucose (69.8%) and galactose (15.9%). MRP5 had an average molecular weight of 9.16 × 104 Da and consisted of rhamnose (3.6%), arabinose (14.5%), glucose (51.2%) and galactose (29.7%). The results of methylation analysis and one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectra reveal that MRP5 contains repeating units of →3)-β-Glcp-(1→, →6)-β-Glcp-(1→, →3, 6)-Glcp-(1→, β-Glcp-(1→, →3)-β-Galp-(1→, →3, 6)-β-Galp-(1→, →3)-α-Rhap-(1→, →3)-α-Araf-(1→, and α-Araf-(1→ residues. MRP5 and MRP5A exhibited relatively low antioxidant abilities in vitro, but strongly protective effects against oxidative stress and lifespan extension effects in C. elegans. Overall, the present study indicated that MRP5 could be further investigated as a functional food for promoting healthspan.

DDS promotes longevity through a microbiome-mediated starvation signal

The antibiotic diaminodiphenyl sulfone (DDS) is used in combination with other antibiotics as a first line treatment for leprosy. DDS has been previously reported to extend lifespan in Caenorhabditis elegans through inhibition of pyruvate kinase and decreased mitochondrial function. Here we report an alternative mechanism of action by which DDS promotes longevity in C. elegans by reducing folate production by the microbiome. This results in altered methionine cycle metabolite levels mimicking the effects of metformin and lifespan extension that is dependent on the starvation- and hypoxia-induced flavin containing monoxygenase, FMO-2.

Longevity Effect of Liuwei Dihuang in Both Caenorhabditis Elegans and Aged Mice.

Liuwei Dihuang (LWDH), a famous traditional Chinese medicine, is widely used in the clinical treatment of aging-related diseases in China. However, its pharmacological mechanisms are not clear. In the present study, we evaluated the lifespan extension effect of LWDH in C. elegans and mice and revealed its underlying mechanisms. The results showed that LWDH significantly extended the lifespan of C. elegans in a dose-dependent manner. LWDH also conferred protection to nematodes against oxidative stress and reduced their fat storage. Genetics analysis and microarray data showed that the longevity effect of LWDH was attributed to the regulation of the innate immune response, proteolysis, lipid metabolism, and the oxidation-reduction process and was dependent on daf-16. Among the six herbs in the formula, Radix Rehmanniae Preparata and Fructus Macrocarpii contributed most to the longevity effect of this medicine, while the other four components had a synergistic effect on the longevity effect of the prescription. The lack of any single herb reduced the efficacy of the complete formula. LWDH also extended the lifespan and reduced both the weight and oxidant stress status in aged mice. Taken together, these results suggested that LWDH might function in a multi-target manner to extend the lifespan in both C. elegans and aged mice, and the best effect was achieved with the complete formula.

Anti-Parkinson activity of bioactive substances extracted from Holothuria leucospilota

Parkinson’s disease (PD) is a well-known neurodegenerative disorder characterized by dopaminergic (DA) neuron loss and α-synuclein aggregation. Recent study revealed that the extracts from sea cucumber, Holothuroidea spp., exhibited neuroprotective and lifespan extension effects in Caenorhabditis elegans model. Interestingly, the black sea cucumber, Holothuria leucospilota, possesses body wall and a specialized organ called cuvierian tubules containing high amount of bioactive compounds. In this study, the neuroprotective effects of the body wall (BW) and cuvierian tubules (CT) from this sea cucumber against PD were evaluated using C. elegans as a model. H. leucospilota were extracted using ethanol (ET), ethyl acetate (EA), butanol (BU) and aqueous (AQ) fractions. Extracts from these fractions were used to treat the 6-OHDA-induced BZ555 and α-synuclein expressing NL5901 strains of C. elegans. Treatment with ET, EA, BU and AQ fractions of H. leucospilota extracts could significantly prevent degeneration of DA neurons in 6-OHDA-induced worms, improve food-sensing behavior mediated by DA neurons, and up-regulate cat-2 and sod-3 gene expressions. These results indicate the neuroprotective activity of the extracts which may be attributed to the anti-oxidant activity of the bioactive compounds. Moreover, α-synuclein aggregation was significantly reduced together with the recovery of lipid deposition upon the treatment with H. leucospilota extracts. In addition, treatment with H. leucospilota extracts was able to increase the lifespan of 6-OHDA-induced N2. NMR analysis revealed the major chemical components in the effective EA fractions were terpenoids, steroids, saponins, and glycosides. In summary, H. leucospilota extracts exhibited anti-Parkinson effect in both toxin-induced and transgenic C. elegans models of PD. Further study will be performed to elucidate the most effective anti-PD molecules which will lead to the development of anti-PD drug.

REGULATION OF LIFESPAN BY DSIRT6 IN DROSOPHILA MELANOGASTER

Sirtuins (SIRT1-7 in mammals) are a family of NAD+ dependent deacylases which regulate multiple cellular pathways involved in the aging process. SIRT6, in particular, has emerged as a key regulator of longevity, with roles in DNA repair, metabolism, and chromatin modification. Sirt6 knockout mice are short lived, while overexpression of Sirt6 extends lifespan in male mice. Despite its involvement in many age-related pathways, the precise molecular mechanisms by which SIRT6 extends lifespan are not known. Here, we use the powerful genetic tools of Drosophila melanogaster to investigate the role of SIRT6 (dSirt6 in Drosophila) in regulating lifespan. We find whole-body overexpression of dSirt6 extends lifespan in flies, up to 38% in males and 39% in females. This lifespan-extending effect is repeatable in multiple overexpression systems, including both constitutive and inducible driver lines. dSirt6 overexpressing flies exhibit reduced expression of H3K9 and H3K56 acetylation at both young and old ages. dSirt6 overexpression also extends survival of flies treated with paraquat, an inducer of DNA damage, in young and aged flies. Finally, RNA-sequencing experiments indicate that dSirt6 overexpression is associated with differential expression of several hundred genes in the brain and fat body, in both young and aged flies. Together, these data suggest that dSirt6 overexpression robustly extends lifespan in Drosophila and may promote longevity via both epigenetic mechanisms and through enhancing DNA repair.

Lifespan-extending property of 6-shogaol from Zingiber officinale Roscoe in Caenorhabditis elegans.

Aging is a key risk factor for many diseases, understanding the mechanism of which is becoming more important for drug development given the fast-growing aging population. In the course of our continued efforts to discover anti-aging natural products, the active constituent 6-shogaol was isolated from Zingiber officinale Roscoe. The chemical structure of 6-shogaol was identified by comparison of its NMR data with literature values. The lifespan-extending effect of 6-shogaol was observed in a dose-dependent manner in Caenorhabditis elegans that has been widely used as a model organism for human aging studies. Mechanism of such action was investigated using C. elegans models, suggesting that 6-shogaol is capable of increasing stress tolerances via enzyme induction. The proposed mechanism was further supported by observation of the increase in SOD and HSP expressions upon treatment with 6-shogaol in transgenic strains of C. elegans which contain GFP-based reporters. In addition, the mechanism was elaborated by confirming that the effect observed for 6-shogaol is independent from other aging-related factors that are known to affect the aging process of C. elegans.

Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster

1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) is a neurotoxin that causes Parkinson's disease in animals via mechanisms linked with oxidative stress and inflammation. Resveratrol is a natural polyphenol and a phytoalexin with antioxidative and antiinflammatory properties. Here, we investigated the rescue role of resveratrol on MPTP-triggered toxicity in Drosophila melanogaster for the first time. D. melanogaster (Harwich strain, 1-to 3- days old) were first orally exposed to resveratrol (0, 7.5, 15, 30, 60 and 120 mg/kg diet) and MPTP (0, 250, 500, 1000, 2000, and 3000 μM) for longevity and 7 days survival assays respectively. Consequently, we selected resveratrol (30 and 60 mg/kg diet) to evaluate its rescue role on MPTP (250 and 500 μM)-induced toxicity in D. melanogaster after 3 days of oral treatment. Specifically, we evaluated markers of neurotoxicity (acetylcholinesterase and negative geotaxis), inflammation (nitric oxide), oxidative stress-antioxidant status (hydrogen peroxide, total thiol, catalase and glutathione-S-transferase), cell viability and fecundity. The data showed that resveratrol increased lifespan of D. melanogaster in a dose-dependent manner up to 60 mg/kg diet. Further, resveratrol restored MPTP-induced inhibition of catalase, glutathione-S-transferase and acetylcholinesterase activities in D. melanogaster. Moreover, resveratrol ameliorated MPTP-triggered cell death, histological alterations, behavioural deficits and accumulation of nitric oxide and hydrogen peroxide levels in flies (p < 0.05). Conclusively, the lifespan extension effects of resveratrol and its rescue role on MPTP- mediated toxicity in the flies may be due to its antioxidant and anti-inflammatory properties.

Evaluation of the lifespan extension effects of several Turkish medicinal plants in Caenorhabditis elegans.

Research on longevity is important to both prolong lifespan and support healthy aging. Natural products are widely being utilized and used as new resources for drug molecules. Caenorhabditis elegans is an advantageous organism for longevity research and age-related diseases. In this study, we tested a number of plant extracts for their effects on C. elegans longevity. In lifespan assays, agesynchronized wild-type C. elegans specimens were treated with different concentrations of plant extracts. Plant extracts were prepared as either infusions or decoctions, similar to their traditional utilization. Hedera helix L. (Araliaceae) extended lifespan in worms in a concentration-dependent manner. The mean survival rates in the H. helix-treated groups were significantly higher, by 23.7% when applied at 1000 µg/mL, 16% when applied at 500 µg/mL, and 16% when applied at 250 µg/mL, compared to the control group. HPLC analysis identified chlorogenic acid as the major component of H. helix. Salvia verticillata L. (Lamiaceae) and Myrtus communis L. (Myrtaceae) treatments resulted in median lifespan extension. Maximum lifespan was extended in worms by Rubus sanctus Schreb. (Rosaceae) treatment. This study provided the first evidence demonstrating the possible lifespan-extending effects of a group of Turkish medicinal plants in an in vivo model, C. elegans.

The Drosophila TGF-beta/Activin-like ligands Dawdle and Myoglianin appear to modulate adult lifespan through regulation of 26S proteasome function in adult muscle.

ABSTRACTThe Drosophila Activin signaling pathway employs at least three separate ligands – Activin-β (Actβ), Dawdle (Daw), and Myoglianin (Myo) – to regulate several general aspects of fruit fly larval development, including cell proliferation, neuronal remodeling, and metabolism. Here we provide experimental evidence indicating that both Daw and Myo are anti-ageing factors in adult fruit flies. Knockdown of Myo or Daw in adult fruit flies reduced mean lifespan, while overexpression of either ligand in adult muscle tissues but not in adipose tissues enhanced mean lifespan. An examination of ubiquitinated protein aggregates in adult muscles revealed a strong inverse correlation between Myo- or Daw-initiated Activin signaling and the amount of ubiquitinated protein aggregates. We show that this correlation has important functional implications by demonstrating that the lifespan extension effect caused by overexpression of wild-type Daw or Myo in adult muscle tissues can be completely abrogated by knockdown of a 26S proteasome regulatory subunit Rpn1 in adult fly muscle, and that the prolonged lifespan caused by overexpression of Daw or Myo in adult muscle could be due to enhanced protein levels of the key subunits of 26S proteasome. Overall, our data suggest that Activin signaling initiated by Myo and Daw in adult Drosophila muscles influences lifespan, in part, by modulation of protein homeostasis through either direct or indirect regulation of the 26S proteasome levels. Since Myo is closely related to the vertebrate muscle mass regulator Myostatin (GDF8) and the Myostatin paralog GDF11, our observations may offer a new experimental model for probing the roles of GDF11/8 in ageing regulation in vertebrates.This article has an associated First Person interview with the first author of the paper.

Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy

Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex–fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13+ cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer.

Metformin extends C. elegans lifespan through lysosomal pathway.

Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin. Elucidating the molecular mechanism of metformin regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.

Transcription factors CEP‐1/p53 and CEH‐23 collaborate with AAK‐2/AMPK to modulate longevity in Caenorhabditis elegans.

SummaryA decline in mitochondrial electron transport chain (ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP‐1/p53 and CEH‐23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK‐2/AMP kinase (AMPK) signaling. Further functional analyses suggested that CEP‐1/p53 and CEH‐23 act downstream of AAK‐2/AMPK signaling and CRTC‐1 transcriptional coactivator to promote stress resistance and lifespan. As AAK‐2, CEP‐1, and CEH‐23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human.

Coelomocytes are required for lifespan extension via different methods of dietary restriction in C. elegans

Dietary restriction has been shown to have a lifespan-extending effect in various model organisms, from yeast to mice. The nematode C. elegans is widely used as a model organism for researches on dietary restriction due to various dietary restriction methods developed in C. elegans. Previous study showed that coelomocyte-specific cup-4 and cup-5 genes are necessary for dietary-restriction-induced longevity in C. elegans. We examined the effect of coelomocyte knockout on lifespan extension by different methods of dietary restriction. The extension of both mean and maximum lifespan by bacterial dilution was completely abolished by genetic ablation of coelomocytes. Knockout of coelomocytes also blocked the lifespan extension conferred by food deprivation or removal of peptone in culture media. These findings indicate that coelomocytes are required for lifespan extension by different methods of dietary restriction, and suggest that the activation of coelomocytes may be a common underlying mechanism involved in dietary-restriction-induced longevity in C. elegans.

Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic.

Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s - 1990s, China is rapidly becoming an aging society. Therefore, the investigation of healthspan-extending drugs becomes more urgent. Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects. A proprietary extract of the dried root of Astragalus membranaceus, called TA-65, was associated with a significant age-reversal effect in the immune system. Our review focuses on the function and the underlying mechanisms of Astragalus membranaceus in lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer effects, based on experimental and clinical studies.

Screening lifespan-extending drugs in Caenorhabditis elegans via label propagation on drug-protein networks.

BackgroundOne of the most challenging tasks in the exploration of anti-aging is to discover drugs that can promote longevity and delay the incidence of age-associated diseases of human. Up to date, a number of drugs, including some antioxidants, metabolites and synthetic compounds, have been found to effectively delay the aging of nematodes and insects.ResultsWe proposed a label propagation algorithm on drug-protein network to infer drugs that can extend the lifespan of C. elegans. We collected a set of drugs of which functions on lifespan extension of C. elegans have been reliably determined, and then built a large-scale drug-protein network by collecting a set of high-confidence drugprotein interactions. A label propagation algorithm was run on the drug-protein bipartite network to predict new drugs with lifespan-extending effect on C. elegans. We calibrated the performance of the proposed method by conducting performance comparison with two classical models, kNN and SVM. We also showed that the screened drugs significantly mediate in the aging-related pathways, and have higher chemical similarities to the effective drugs than ineffective drugs in promoting longevity of C. elegans. Moreover, we carried out wet-lab experiments to verify a screened drugs, 2- Bromo-4’-nitroacetophenone, and found that it can effectively extend the lifespan of C. elegans. These results showed that our method is effective in screening lifespanextending drugs in C. elegans.ConclusionsIn this paper, we proposed a semi-supervised algorithm to predict drugs with lifespan-extending effects on C. elegans. In silico empirical evaluations and in vivo experiments in C. elegans have demonstrated that our method can effectively narrow down the scope of candidate drugs needed to be verified by wet lab experiments.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0362-4) contains supplementary material, which is available to authorized users.