Polyphenols as Potential Geroprotectors.

Significance: Currently, a large amount of evidence of beneficial effects of diets enriched with polyphenols on various aspects of health has been accumulated. These phytochemicals have a geroprotective potential slowing down the pathological processes associated with aging and ensuring longevity. In this study, a comprehensive analysis was conducted to determine the adherence of individual polyphenols to geroprotector criteria. Data from experimental models, clinical trials, and epidemiological studies were analyzed. Recent Advances: Sixty-two polyphenols have been described to increase the life span and improve biomarkers of aging in animal models. They act via evolutionarily conserved molecular mechanisms, including hormesis and maintenance of redox homeostasis, epigenetic regulation, response to cellular damage, metabolic control, and anti-inflammatory and senolytic activity. Epidemiological and clinical studies suggest that certain polyphenols have a potential for prevention and treatment of various diseases, including cancer, metabolic disorders, and cardiovascular conditions in humans. Critical Issues: Among the reviewed phytochemicals, chlorogenic acid, quercetin, epicatechin, genistein, resveratrol, and curcumin were identified as compounds with the highest geroprotective potential. However, there is a lack of unambiguous information on the effectiveness and safety of polyphenols for increasing health span, preventing and treating aging-associated diseases in humans. Future Directions: Further research is needed to fully understand the effects of polyphenols considering their long-term consumption, metabolic modification and bioavailability, complex interactions between different groups of polyphenols and with other phytochemicals, as well as their effects on individuals with different health status. Antioxid. Redox Signal. 40, 564-593.

Berberis vulgaris L. extract supplementation exerts regulatory effects on the lifespan and healthspan of Drosophila through its antioxidant activity depending on the sex.

Worldwide the aging population continues to increase, so the concept of healthy longevity medicine has become increasingly significant in modern society. Berberis vulgaris L. fruits serve as a functional food supplement with a high concentration of bioactive compounds, which offer numerous health-promoting benefits. The goal of this study was to investigate the geroprotective effect of Berberis vulgaris L. extract. Here we show that extract of Berberis vulgaris L. can, depending on concentrate, increases lifespan up to 6%, promote healthspan (stress resistance up to 35%, locomotor activity up to 25%, integrity of the intestinal barrier up to 12%, metabolic rate up to 5%) of Drosophila melanogaster (in vitro) and exhibits antioxidant (using red blood cell tests) and antiglycation activity (using glycation of bovine serum albumin) (in vitro). In addition to this, the extract does not exhibit cytotoxic properties in vitro, unlike the well-known polyphenolic compound quercetin. qRT-PCR has revealed the involvement of metabolic, heat shock response and lipid metabolism genes in the observed effects.

Antioxidant Properties and Geroprotective Potential of Wheat Bran Extracts with Increased Content of Anthocyanins.

In recent years, there has been a focus on breeding wheat with high anthocyanin levels in order to improve food quality and human health. The objective of this study was to examine the antioxidant and geroprotective properties of wheat bran extracts using both in vitro and in vivo research methods. Two wheat lines were used: one with uncolored pericarp (anthocyanin-free) and another with colored pericarp (anthocyanin-containing). These lines differed in a specific region of chromosome 2A containing the Pp3/TaMyc1 gene, which regulates anthocyanin production. High-performance liquid chromatography-mass spectrometry revealed the presence of cyanidin glucoside and cyanidin arabinoside in the anthocyanin-containing wheat bran extract (+AWBE), while no anthocyanins were found in the anthocyanin-free wheat bran extract (-AWBE). The +AWBE showed higher radical scavenging activity (DPPH and ABTS assays) and membrane protective activity (AAPH oxidative hemolysis model) compared to the -AWBE. Both extracts extended the lifespan of female Drosophila, indicating geroprotective properties. This study demonstrates that wheat bran extracts with high anthocyanin levels have antioxidant and geroprotective effects. However, other secondary metabolites in wheat bran can also contribute to its antioxidant and geroprotective potential.

Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster.

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 µM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.

Studying the Geroprotective Properties of YAP/TAZ Signaling Inhibitors on Drosophila melanogaster Model.

The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process, depending on the cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz increase the lifespan of Drosophila melanogaster. Real-time qRT-PCR was performed to measure the changes in the expression of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan-increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression levels of the wg and E2f1 genes. However, further analysis is required to understand the link between the YAP/TAZ pathway and aging.

Simultaneous activation of the hydrogen sulfide biosynthesis genes (CBS and CSE) induces sex-specific geroprotective effects in Drosophila melanogaster.

Hydrogen sulfide (H2S) is one of the most important gasotransmitters that affect lifespan and provide resistance to adverse environmental conditions. Here we investigated geroprotective effects of the individual and simultaneous overexpression of genes encoding key enzymes of H2S biosynthesis - cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) on D. melanogaster model. Simultaneous overexpression of CBS and CSE resulted in additive (in males) and synergistic (in females) beneficial effects on median lifespan. Individual overexpression of CBS was associated with increased thermotolerance and decreased transcription level of genes encoding stress-responsive transcription factors HIF1 and Hsf, while individual overexpression of CSE was associated with increased resistance to paraquat. Simultaneous overexpression of both genes increased resistance to hyperthermia in old females or paraquat in old males. The obtained results suggest sex-specific epistatic interaction of CBS and CSE overexpression effects on longevity and stress resistance.

Molecular mechanisms of exceptional lifespan increase of Drosophila melanogaster with different genotypes after combinations of pro-longevity interventions.

Aging is one of the global challenges of our time. The search for new anti-aging interventions is also an issue of great actuality. We report on the success of Drosophila melanogaster lifespan extension under the combined influence of dietary restriction, co-administration of berberine, fucoxanthin, and rapamycin, photodeprivation, and low-temperature conditions up to 185 days in w1118 strain and up to 213 days in long-lived E(z)/w mutants. The trade-off was found between longevity and locomotion. The transcriptome analysis showed an impact of epigenetic alterations, lipid metabolism, cellular respiration, nutrient sensing, immune response, and autophagy in the registered effect.

Deletions of the cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) genes, involved in the control of hydrogen sulfide biosynthesis, significantly affect lifespan and fitness components of Drosophila melanogaster.

The gasotransmitter hydrogen sulfide (H2S) is an important biological mediator, playing an essential role in many physiological and pathological processes. It is produced by transsulfuration - an evolutionarily highly conserved pathway for the metabolism of sulfur-containing amino acids methionine and cysteine. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in cysteine metabolism and H2S production. Here we investigated the fitness components (longevity, stress resistance, viability of preimaginal stages, and reproductive function parameters) in D. melanogaster lines containing deletions of the CBS and CSE genes. Surprisingly, in most tests, CSE deletion improved, and CBS worsened the fitness. Lines with deletion of both CBS and CSE demonstrated better stress resistance and longevity than lines with single CBS deletion. At the same time, deletion of both CBS and CSE genes causes more serious disturbances of reproductive function parameters than single CBS deletion. Thus, a complex interaction of H2S-producing pathways and cellular stress response in determining the lifespan and fitness components of the whole organism was revealed.

Honeysuckle extract (Lonicera pallasii L.) exerts antioxidant properties and extends the lifespan and healthspan of Drosophila melanogaster.

Honeysuckle Lonicera pallasii (Lonicera caerulea L.) is an excellent source of anthocyanins which have a number of health-promoting properties mainly associated with antioxidant and anti-inflammatory activities. Cyanidin-3-O-glucoside (C3G) is one of the most common anthocyanins naturally found in honeysuckle. The goal of the present study was to investigate antioxidant and anti-aging properties of Lonicera pallasii (Lonicera caerulea L.) extract (LE) and C3G using red blood cells (RBC) and Drosophila melanogaster models. LE and C3G treatment at a concentration of 100 µM induced enhancement of median and maximum lifespan up to 8%. LE and C3G supplementation at a concentration of 100 µM increased stress resistance up to 10%. The locomotor activity decreased during LE and C3G treatment in 4 and 6 weeks up to 52% in females. The integrity of the intestinal barrier was increased by 4% after LE treatment. These effects were accompanied by increased expression of Hif1 (pro-longevity gene) in response to C3G treatment and decreased expression of Keap1 (anti-longevity gene) after C3G and LE supplementation. RNA interference-mediated knockdown of Sirt6 completely abolished the positive effect obtained of LE and C3G supplementation in males which indicates that lifespan-extending effect is associated with Sirt6 activation. The experiments on the various in-vitro models (including radical scavenging activity and oxidative hemolysis of RBC demonstrated antioxidant and membrane-protective activities of LE and C3G. The present study indicates that Lonicera extract can prolong the lifespan and improve the healthspan of Drosophila model through biological and antioxidant activities.

Erratum: Einstein-Cartan Portal to Dark Matter [Phys. Rev. Lett. 126, 161301 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.161301.

Uniting Low-Scale Leptogenesis Mechanisms.

In this Letter we demonstrate that what was previously considered as different mechanisms of baryon asymmetry generation involving two right-handed Majorana neutrinos with masses far below the Grand Unified Theory scale-leptogenesis via neutrino oscillations and resonant leptogenesis-are actually united. We show that the observed baryon asymmetry can be generated for all experimentally allowed values of the right-handed neutrino masses above M_{N}≳100 MeV. Leptogenesis is effective in a broad range of the parameters, including mass splitting between two right-handed neutrinos as big as ΔM_{N}/M_{N}∼0.1, as well as mixing angles between the heavy and light neutrinos large enough to be accessible to planned intensity experiments or future colliders.

Chronobiotics KL001 and KS15 Extend Lifespan and Modify Circadian Rhythms of Drosophila melanogaster.

Chronobiotics are a group of drugs, which are utilized to modify circadian rhythms targeting clock-associated molecular mechanisms. The circadian clock is known as a controller of numerous processes in connection with aging. Hypothesis: KL001 and KS15 targeting CRY, affect lifespan, locomotor activity and circadian rhythm of Drosophila melanogaster. We observed a slight (2%, p < 0.001) geroprotective effect on median lifespan (5 µM solution of KL001 in 0.1% DMSO) and a 14% increase in maximum lifespan in the same group. KS15 10 µM solution extended males' median lifespan by 8% (p < 0.05). The statistically significant positive effects of KL001 and KS15 on lifespan were not observed in female flies. KL001 5 µM solution improved locomotor activity in young male imagoes (p < 0.05), elevated morning activity peak in aged imagoes and modified robustness of their circadian rhythms, leaving the period intact. KS15 10 µM solution decreased the locomotor activity in constant darkness and minimized the number of rhythmic flies. KL001 5 µM solution improved by 9% the mean starvation resistance in male flies (p < 0.01), while median resistance was elevated by 50% (p < 0.0001). This phenomenon may suggest the presence of the mechanism associated with improvement of fat body glucose depos' utilization in starvation conditions which is activated by dCRY binding KL001.

Einstein-Cartan Portal to Dark Matter.

It is well known since the works of Utiyama and Kibble that the gravitational force can be obtained by gauging the Poincaré group, which puts gravity on the same footing as the standard model fields. The resulting theory-Einstein-Cartan gravity-inevitably contains four-fermion and scalar-fermion interactions that originate from torsion associated with spin degrees of freedom. We show that these interactions lead to a novel mechanism for producing singlet fermions in the early Universe. These fermions can play the role of dark matter particles. The mechanism is operative in a large range of dark matter particle masses: from a few keV up to ∼10^{8} GeV. We discuss potential observational consequences of keV-scale dark matter produced this way, in particular for right-handed neutrinos. We conclude that a determination of the primordial dark matter momentum distribution might be able to shed light on the gravity-induced fermionic interactions.

Tissue-Specific Knockdown of Genes of the Argonaute Family Modulates Lifespan and Radioresistance in Drosophila Melanogaster.

Small RNAs are essential to coordinate many cellular processes, including the regulation of gene expression patterns, the prevention of genomic instability, and the suppression of the mutagenic transposon activity. These processes determine the aging, longevity, and sensitivity of cells and an organism to stress factors (particularly, ionizing radiation). The biogenesis and activity of small RNAs are provided by proteins of the Argonaute family. These proteins participate in the processing of small RNA precursors and the formation of an RNA-induced silencing complex. However, the role of Argonaute proteins in regulating lifespan and radioresistance remains poorly explored. We studied the effect of knockdown of Argonaute genes (AGO1, AGO2, AGO3, piwi) in various tissues on the Drosophila melanogaster lifespan and survival after the γ-irradiation at a dose of 700 Gy. In most cases, these parameters are reduced or did not change significantly in flies with tissue-specific RNA interference. Surprisingly, piwi knockdown in both the fat body and the nervous system causes a lifespan increase. But changes in radioresistance depend on the tissue in which the gene was knocked out. In addition, analysis of changes in retrotransposon levels and expression of stress response genes allow us to determine associated molecular mechanisms.

Geroprotective potential of genetic and pharmacological interventions to endogenous hydrogen sulfide synthesis in Drosophila melanogaster.

Endogenous hydrogen sulfide (H2S) is a gasotransmitter with a wide range of physiological functions. Aging is accompanied by disruption of H2S homeostasis, therefore, interventions to the processes of H2S metabolism to maintain its balance may have geroprotective potential. Here we demonstrated the additive geroprotective effect of combined genetic and pharmacological interventions to the hydrogen sulfide biosynthesis system by overexpression of cystathionine-ß-synthase and cystathionine-γ-lyase genes and treatment with precursors of H2S synthesis cysteine (Cys) and N-acetyl-L-cysteine (NAC). The obtained results suggest that additive effects of genetic and pharmacological interventions to H2S metabolism may be associated with the complex interaction between beneficial action of H2S production and prevention of adverse effects of excess H2S production by Cys and NAC treatment.

Hydrogen sulfide in longevity and pathologies: Inconsistency is malodorous.

Hydrogen sulfide (H2S) is one of the biologically active gases (gasotransmitters), which plays an important role in various physiological processes and aging. Its production in the course of methionine and cysteine catabolism and its degradation are finely balanced, and impairment of H2S homeostasis is associated with various pathologies. Despite the strong geroprotective action of exogenous H2S in C. elegans, there are controversial effects of hydrogen sulfide and its donors on longevity in other models, as well as on stress resistance, age-related pathologies and aging processes, including regulation of senescence-associated secretory phenotype (SASP) and senescent cell anti-apoptotic pathways (SCAPs). Here we discuss that the translation potential of H2S as a geroprotective compound is influenced by a multiplicity of its molecular targets, pleiotropic biological effects, and the overlapping ranges of toxic and beneficial doses. We also consider the challenges of the targeted delivery of H2S at the required dose. Along with this, the complexity of determining the natural levels of H2S in animal and human organs and their ambiguous correlations with longevity are reviewed.

The Resistance of Drosophila melanogaster to Oxidative, Genotoxic, Proteotoxic, Osmotic Stress, Infection, and Starvation Depends on Age According to the Stress Factor.

We studied how aging affects the ability of Drosophila melanogaster to tolerate various types of stress factors. Data were obtained on the resistance of D. melanogaster to oxidative and genotoxic (separately paraquat, Fe3+, Cu2+, and Zn2+ ions), proteotoxic (hyperthermia, Cd2+ ions), and osmotic (NaCl) stresses, starvation, and infection with the pathological Beauveria bassiana fungus at different ages. In all cases, we observed a strong negative correlation between age and stress tolerance. The largest change in the age-dependent decline in survival occurred under oxidative and osmotic stress. In most experiments, we observed that young Drosophila females have higher stress resistance than males. We checked whether it is possible to accurately assess the biological age of D. melanogaster based on an assessment of stress tolerance. We have proposed a new approach for assessing a biological age of D. melanogaster using a two-parameter survival curve model. For the model, we used an algorithm that evaluated the quality of age prediction for different age and gender groups. The best predictions were obtained for females who were exposed to CdCl2 and ZnCl2 with an average error of 0.32 days and 0.36 days, respectively. For males, the best results were observed for paraquat and NaCl with an average error of 0.61 and 0.68 days, respectively. The average accuracy for all stresses in our model was 1.73 days.

Amyloid-ß peptides slightly affect lifespan or antimicrobial peptide gene expression in Drosophila melanogaster.

BACKGROUND: Beta-amyloid peptide (Aß) is the key protein in the pathogenesis of Alzheimer's disease, the most common age-related neurodegenerative disorder in humans. Aß peptide induced pathological phenotypes in different model organisms include neurodegeneration and lifespan decrease. However, recent experimental evidence suggests that Aß may utilize oligomerization and fibrillization to function as an antimicrobial peptide (AMP), and protect the host from infections. We used the power of Drosophila model to study mechanisms underlying a dual role for Aß peptides. RESULTS: We investigated the effects of Drosophila treatment with three Aß42 peptide isoforms, which differ in their ability to form oligomers and aggregates on the lifespan, locomotor activity and AMP genes expression. Aß42 slightly decreased female's median lifespan (by 4.5%), but the effect was not related to the toxicity of peptide isoform. The lifespan and relative levels of AMP gene expression in male flies as well as locomotor activity in both sexes were largely unaffected by Aß42 peptide treatment. Regardless of the effects on lifespan, Aß42 peptide treatment induced decrease in AMP genes expression in females, but the effects were not robust. CONCLUSIONS: The results demonstrate that chronic treatment with Aß42 peptides does not drastically affect fly aging or immunity.

Genome-Protecting Compounds as Potential Geroprotectors.

Throughout life, organisms are exposed to various exogenous and endogenous factors that cause DNA damages and somatic mutations provoking genomic instability. At a young age, compensatory mechanisms of genome protection are activated to prevent phenotypic and functional changes. However, the increasing stress and age-related deterioration in the functioning of these mechanisms result in damage accumulation, overcoming the functional threshold. This leads to aging and the development of age-related diseases. There are several ways to counteract these changes: 1) prevention of DNA damage through stimulation of antioxidant and detoxification systems, as well as transition metal chelation; 2) regulation of DNA methylation, chromatin structure, non-coding RNA activity and prevention of nuclear architecture alterations; 3) improving DNA damage response and repair; 4) selective removal of damaged non-functional and senescent cells. In the article, we have reviewed data about the effects of various trace elements, vitamins, polyphenols, terpenes, and other phytochemicals, as well as a number of synthetic pharmacological substances in these ways. Most of the compounds demonstrate the geroprotective potential and increase the lifespan in model organisms. However, their genome-protecting effects are non-selective and often are conditioned by hormesis. Consequently, the development of selective drugs targeting genome protection is an advanced direction.

Terpenoids as Potential Geroprotectors.

Terpenes and terpenoids are the largest groups of plant secondary metabolites. However, unlike polyphenols, they are rarely associated with geroprotective properties. Here we evaluated the conformity of the biological effects of terpenoids with the criteria of geroprotectors, including primary criteria (lifespan-extending effects in model organisms, improvement of aging biomarkers, low toxicity, minimal adverse effects, improvement of the quality of life) and secondary criteria (evolutionarily conserved mechanisms of action, reproducibility of the effects on different models, prevention of age-associated diseases, increasing of stress-resistance). The number of substances that demonstrate the greatest compliance with both primary and secondary criteria of geroprotectors were found among different classes of terpenoids. Thus, terpenoids are an underestimated source of potential geroprotectors that can effectively influence the mechanisms of aging and age-related diseases.