Model organism life extending therapeutics modulate diverse nodes in the drug-gene-microbe tripartite human longevity interactome.

Advances in antiaging drug/lead discovery in animal models constitute a large body of literature on novel senotherapeutics and geroprotectives. However, with little direct evidence or mechanism of action in humans-these drugs are utilized as nutraceuticals or repurposed supplements without proper testing directions, appropriate biomarkers, or consistent in-vivo models. In this study, we take previously identified drug candidates that have significant evidence of prolonging lifespan and promoting healthy aging in model organisms, and simulate them in human metabolic interactome networks. Screening for drug-likeness, toxicity, and KEGG network correlation scores, we generated a library of 285 safe and bioavailable compounds. We interrogated this library to present computational modeling-derived estimations of a tripartite interaction map of animal geroprotective compounds in the human molecular interactome extracted from longevity, senescence, and dietary restriction-associated genes. Our findings reflect previous studies in aging-associated metabolic disorders, and predict 25 best-connected drug interactors including Resveratrol, EGCG, Metformin, Trichostatin A, Caffeic Acid and Quercetin as direct modulators of lifespan and healthspan-associated pathways. We further clustered these compounds and the functionally enriched subnetworks therewith to identify longevity-exclusive, senescence-exclusive, pseudo-omniregulators and omniregulators within the set of interactome hub genes. Additionally, serum markers for drug-interactions, and interactions with potentially geroprotective gut microbial species distinguish the current study and present a holistic depiction of optimum gut microbial alteration by candidate drugs. These findings provide a systems level model of animal life-extending therapeutics in human systems, and act as precursors for expediting the ongoing global effort to find effective antiaging pharmacological interventions.Communicated by Ramaswamy H. Sarma.

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence.

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC50 of 311.31 µg/ml as compared to standard ascorbic acid with an IC50 of 130.53 µg/ml. In reducing power assay, the EC50 value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC50 = 33.83 µg/ml). The IC50 value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC50 of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC50 of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC50 of 505.81 µg/ml (IC50 of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.

Computational screening of natural MtbDXR inhibitors for novel anti-tuberculosis compound discovery.

DXR (1-deoxy-d-xylulose-5-phosphate reductoisomerase) is an essential enzyme in the Methylerythritol 4-phosphate (MEP) pathway, which is used by M. tuberculosis and a few other pathogens. This essential enzyme in the isoprenoid synthesis pathway has been previously reported as an important target for antibiotic drug design. However, till now, there is no record of any drug-like safe molecule to inhibit MtbDXR. Numerous plant species have been traditionally used for tuberculosis therapies. In this study, we selected six plant species with anti-tubercular properties. The chemoinformatic screening was performed on 352 phytochemicals from those plants against the MtbDXR protein. After molecular docking analysis, we filtered the top five compounds, CID: 5280443 (Apigenin), CID: 3220 (Emodin), CID: 5280863 (Kaempferol), CID: 5280445 (Luteolin), and CID: 6101979 (beta-Hydroxychalcone), based on binding affinity. Molecular dynamics simulations disclosed the stability of the compounds at the active site of the proteins. Finally, in silico ADME and toxicity evaluations confirmed the compounds to be effective and safe for oral administration. Thus, our findings identified three drug-like safe molecules- Apigenin, Kaempferol, and beta-Hydroxychalcone, that showed good stability in the protein's active site. The results of this computational approach may act as an initial instruction for future in vitro and in vivo testing to identify natural drug-like compounds to treat tuberculosis.Communicated by Ramaswamy H. Sarma.

Not young but still immature: a HIF-1α-mediated maturation checkpoint in regenerating muscle.

Muscle fibers express particular isoforms of contractile proteins, depending on the fiber's function and the organism's developmental stage. In the adult, after a muscle injury, newly generated fibers transition through embryonic and neonatal myosins, prior to selecting their distinctive adult myosin isoform. In this issue of the JCI, Wang et al. discover a checkpoint that regulates the neonatal-to-adult myosin isoform transition. They found that HIF-1α regulated this checkpoint, with elevated HIF-1α levels blocking progression, while HIF-1α knockout accelerated the transition. They further related these findings to centronuclear myopathy, a disease in which HIF-1α is similarly elevated and neonatal myosin expression is maintained. These findings highlight a maturation checkpoint that impacts the skeletal muscle regeneration following ischemic injury, providing a pharmacologically accessible pathway in injury and diseases such as centronuclear myopathy.

Lipid oxidation in pathophysiology of atherosclerosis: Current understanding and therapeutic strategies.

A marked increase in the global prevalence of ischemic heart disease demands focused research for novel and more effective therapeutic strategies. At present, atherosclerotic cardiovascular disease (ACVD) is the leading cause of the global incidence of heart attacks and a major contributor to many peripheral cardiac diseases. Decades of research have unearthed the complex and multidimensional pathophysiology of ACVD encompassing oxidative stress, redox imbalance, lipid peroxidation, pro-inflammatory signaling, hyperglycemic stress and diabetes mellitus, chronic low-grade inflammation and aging, immune dysregulation, vascular dysfunction, loss of hemostasis, thrombosis, and fluid shear stress. However, the scientific basis of therapeutic interventions using conventional understandings of the disease mechanisms has been subject to renewed scrutiny with novel findings in recent years. This critical review attempts to revise the pathophysiological mechanisms of atherosclerosis using a recent body of literature, with a focus on lipid metabolism and associated cellular and biochemical processes. The comprehensive study encompasses different molecular perspectives in the development and progression of coronary atherosclerosis. The review also summarizes currently prescribed small molecule therapeutics in inflammation and ACVD, and overviews prospective management measures under development including peptides and microRNA therapeutics. The study provides updated insights into the current knowledge of coronary atherosclerosis, and highlights the need for effective prevention, management and development of novel intervention approaches to overcome this chronic epidemic.

Predicting multi-enzyme inhibition in the arachidonic acid metabolic network by Heritiera fomes extracts.

Heritiera fomes is a mangrove plant with a rich history of ethnomedicinal usage against chronic inflammation. Biochemical analyses of H. fomes have exposed a plethora of bioactive phytochemicals that contribute to this therapeutic effect by perturbing enzymes of a complex inflammatory network mediated by arachidonic acid (AA) metabolism. This study is the first instance of utilizing cheminformatic approaches to elucidate a molecular linkage between these phytochemical interventions and the multi-enzyme AA metabolic network regulation. Analysis of the simulations reflects H. fomes as a functional reservoir of multiple safe and potent natural anti-inflammatory compounds. The investigation suggests two phytocompounds extracted from the plant: a sesquiterpene lactone and a flavone glycoside, as candidate inhibitors of multiple catalytic checkpoints of the inflammatory network. The outcomes of this research act as a primary guideline for future laboratory and clinical testing of anti-inflammatory potentials of H. fomes as an exploitable source of safe and potent drug-like molecules.Communicated by Ramaswamy H. Sarma.

In-silico screening of bioactive phytopeptides for novel anti-ageing therapeutics.

A metabolic network of energy-sensing molecular pathways drives the biological ageing process. Regulating certain network elements can help decelerate the ageing process and ameliorate ageing associated disorders. Bioactive phytopeptides are a prospective avenue for anti-ageing therapeutics and rejuvenation biotechnology. The present study investigates the potential of therapeutic plant peptides against cellular senescence by targeting three key proteins in the ageing network - target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). This investigation screened a library of reported bioactive peptides using standard cheminformatic methods including in-silico ADMET, molecular docking, molecular dynamics simulation and molecular mechanics calculation. The retrieved simulation data predict 25 diverse phytopeptides as potential safe and drug-like anti-ageing biologics with half-lives >20 h and bioavailability scores >0.40. The best docked peptide, Cycloleonuripeptide B, exhibited strong binding affinity and stable complex formation with mTOR (-17.5 kCal/mol), SIRT1 (-28.54 kCal/mol) and two active sites in AMPK (-41.8 kCal/mol; -36.0 kCal/mol) during molecular dynamics simulations. The computational study acts as a foundation for future laboratory and clinical research into the potential of repurposing therapeutic phytopeptides against cellular senescence and associated pathophysiology. Communicated by Ramaswamy H. Sarma.

Marine phycocompound screening reveals a potential source of novel senotherapeutics.

Cells undergo a controlled and systematic cycle of growth, replication and death. However, the integrity of this process gradually declines, leading to accumulation of senescent cells, a major hallmark of biological ageing. Dietary algae, particularly marine algae, have been long reported to exert anti-ageing benefits as cosmeceuticals and nutraceuticals with limited understanding of the molecular mechanisms underlying their activity. In this study, we have incorporated 1,202 previously reported bioactive small phycocompounds and subjected them to cheminformatic queries to assess these interactions. In-silico ADMET, 2-phase docking, metabolic pathway interaction and molecular dynamics simulations reveal multiple marine phycocompounds to have safe and effective senolytic potentials. We employed a novel deep convolutional neural network driven screening approach to identify (2R*, 3S*, 6R*, 7S*, 10R*, 13R*)-7,13-Dihydroxy-2,6-cyclo-1(9),14-xenicadiene-18,19-dial derived from Dilophus Fasciola, Laurendecumenyne A from Laurencia decumbens and 4-Bromo-3-ethyl-9-[(2E)-2-penten-4-yn-1-yl]-2,8-dioxabicyclo[5.2.1]decan-6-ol from Laurencia sp. to be potent inhibitors of multiple target senescent-cell anti-apoptotic pathway proteins. We simulated the best overall target inhibitors, specific protein inhibitors and molecular pathway regulators with each target protein and found stable interactions with minimum deviations (mean RMSD = 0.17 ± 0.01 nm) and gyrations (mean Rg = 1.64 ± 0.16 nm) of the simulated protein-compound complexes. Finally, molecular mechanics calculation suggests potent (mean ΔG = -69.56 ± 27.19 kCal/mol) and frequent hydrophobic interactions between the top performing marine phycocompounds and target proteins.

In silico insights into potential gut microbial modulation of NAD+ metabolism and longevity.

Recent evidence has prompted the notion of gut-microbial signatures as an indirect marker of aging and aging-associated decline in humans. However, the underlying host-symbiont molecular interactions contributing to these signatures remain poorly understood. In this study, we address this gap using cheminformatic analyses to elucidate potential gut microbial metabolites that may perturb the longevity-associated NAD+ metabolic network. In silico ADMET, KEGG interaction analysis, molecular docking, molecular dynamics simulation, and molecular mechanics calculation predict a large number of safe and bioavailable microbial metabolites to be direct and/or indirect activators of NAD+-dependent sirtuin proteins. Our simulation results suggest dihydropteroate, phenylpyruvic acid, indole-3-propionic acid, phenyllactic acid, all-trans-retinoic acid, and multiple deoxy-, methyl-, and cyclic nucleotides from intestinal microbiota as the best-performing regulators of NAD+ metabolism. Retracing these molecules to their source microorganisms also suggest commensal Escherichia, Bacteroides, Bifidobacteria, and Lactobacilli to be associated with the highest number of pro-longevity metabolites. These findings from our early-stage study, therefore, provide an informatics-based context for previous evidence in the area and grant novel insights for future clinical investigation intersecting anti-aging drug discovery, probiotics, and gut microbial signatures.

Energy Metabolism Focused Analysis of Sexual Dimorphism in Biological Aging and Hypothesized Sex-specificity in Sirtuin Dependency.

The process of biological aging or senescence refers to the gradual loss of homeostasis and subsequent loss of function - leading to higher chances of mortality. Many mechanisms and driving forces have been suggested to facilitate the evolution of a molecular circuit acting as a trade-off between survival and proliferation, resulting in senescence. A major observation on biological aging and longevity in humans and model organisms is the prevalence of significant sexual divergence in the onset, mechanisms and effects of aging associated processes. In the current account, we describe possible mechanisms by which aging, sex and reproduction are evolutionarily intertwined in order to maintain systemic energy homeostasis. We also interrogate existing literature on the sexual dimorphism of genetic, cellular, metabolic, endocrine and epigenetic processes driving cellular and systemic aging. Subsequently, based on available evidence, we propose a hypothetic model of sex-limited decoupling of female longevity from sirtuins, a major family of regulator proteins of the survival-proliferation trade-off. We also provide necessary considerations to be made in order to test the hypothesis and explore the physiological and therapeutic implications of this decoupling event in male and female longevity after reaching reproductive maturity. HYPOTHESIS STATEMENT: Sirtuins provide survival benefits in a sex-nonspecific manner but the dependency on sirtuins in driving metabolic networks after reaching reproductive maturity is evolutionarily decoupled from female longevity.