A prospective randomized comparative placebo-controlled double-blind study in two groups to assess the effect of the use of biologically active additives with Siberian fir terpenes for the biological age of a person.

A prospective randomized comparative placebo-controlled double-blind study was carried out based on Arterial Indices model of biological age. The study involved 60 men and women aged 40-65 years that were randomly divided into two equal groups of 30 people: the main group and the control one. The study participants from the main group received a dietary supplement containing Siberian fir terpenes, limonene, alpha-linolenic acid, and vitamin E-1 capsule 3 times a day for 90 days. Patients in the comparison group received a placebo according to a similar scheme. Anthropometric and biochemical characteristics of patients from both groups have not undergone any significant changes. According to ultrasound examination of the carotid arteries, we observed a statistically significant decrease in the minimum thickness of the intima-media complex (by 45%). The maximum carotid artery stenosis on the right or left and the expansion index in patients of both groups did not change significantly during treatment. According to the results of applanation tonometry, it was revealed that when taking the studied dietary supplement, the pulse wave velocity significantly decreased compared to the initial one (by 10%). Accordingly, the Arterial Indices biological age decreased by 2.5 years compared to the baseline level in patients of the main group and did not change in patients from the comparison group. Supplementation of fir terpenes in middle-aged patients of both sexes reduces the biological age reflecting the condition of the arteries.

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.

Antiaging Effects of Vicatia thibetica de Boiss Root Extract on Caenorhabditis elegans and Doxorubicin-Induced Premature Aging in Adult Mice.

The roots of Vicatia thibetica de Boiss are a kind of Chinese herb with homology of medicine and food. This is the first report showing the property of the extract of Vicatia thibetica de Boiss roots (HLB01) to extend the lifespan as well as promote the healthy parameters in Caenorhabditis elegans (C. elegans). For doxorubicin- (Doxo-) induced premature aging in adult mice, HLB01 counteracted the senescence-associated biomarkers, including P21 and γH2AX. Interestingly, HLB01 promoted the expression of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert the antiaging effects. In addition, HLB01 was also found as a scavenger of free radicals, thereby performing the antioxidant ability. Lifespan extension by HLB01 was also dependent on DAF-16 and HSF-1 via oxidative stress resistance and heat stress resistance. Taken together, overall data suggested that HLB01 could extend the lifespan and healthspan of C. elegans and resist Doxo-induced senescence in mice via promoting the expression of collagen, antioxidant potential, and stress resistance.

Effects of Siberian fir terpenes extract Abisil on antioxidant activity, autophagy, transcriptome and proteome of human fibroblasts.

BACKGROUND: Abisil is an extract of Siberian fir terpenes with antimicrobial and wound healing activities. Previous studies revealed that Abisil has geroprotective, anti-tumorigenic, and anti-angiogenic effects. Abisil decreased the expression of cyclin D1, E1, A2, and increased the phosphorylation rate of AMPK. OBJECTIVE: In the present study, we analyzed the effect of Abisil on autophagy, the mitochondrial potential of embryonic human lung fibroblasts. We evaluated its antioxidant activity and analyzed the transcriptomic and proteomic effects of Abisil treatment. RESULTS: Abisil treatment resulted in activation of autophagy, reversal of rotenone-induced elevation of reactive oxygen species (ROS) levels and several-fold decrease of mitochondrial potential. Lower doses of Abisil (25 µg/ml) showed a better oxidative effect than high doses (50 or 125 µg/ml). Estimation of metabolic changes after treatment with 50 µg/ml has not shown any changes in oxygen consumption rate, but extracellular acidification rate decreased significantly. Abisil treatment (5 and 50 µg/ml) of MRC5-SV40 cells induced a strong transcriptomic shift spanning several thousand genes (predominantly, expression decrease). Among down-regulated genes, we noticed an over-representation of genes involved in cell cycle progression, oxidative phosphorylation, and fatty acid biosynthesis. Additionally, we observed predominant downregulation of genes encoding for kinases. Proteome profiling also revealed that the content of hundreds of proteins is altered after Abisil treatment (mainly, decreased). These proteins were involved in cell cycle regulation, intracellular transport, RNA processing, translation, mitochondrial organization. CONCLUSIONS: Abisil demonstrated antioxidant and autophagy stimulating activity. Treatment with Abisil results in the predominant downregulation of genes involved in the cell cycle and oxidative phosphorylation.

Evaluation of the geroprotective effects of withaferin A in Drosophila melanogaster.

Withanolides are a class of compounds usually found in plant extracts which are an attractive geroprotective drug design starting point. We evaluated the geroprotective properties of Withaferin A (WA) in vivo using the Drosophila model. Flies were supplemented by nutrient medium with WA (at a concentration of 1, 10, or 100 µM dissolved in ethanol) for the experiment group and 30 µM of ethanol for the control group. WA treatment at 10 and 100 µM concentrations prolong the median life span of D. melanogaster's male by 7.7, 9.6% (respectively) and the maximum life span (the age of death 90% of individuals) by 11.1% both. Also WA treatment at 1, 10 and 100 µM improved the intestinal barrier permeability in older flies and affected an expression of genes involved in antioxidant defense (PrxV), recognition of DNA damage (Gadd45), heat shock proteins (Hsp68, Hsp83), and repair of double-strand breaks (Ku80). WA was also shown to have a multidirectional effect on the resistance of flies to the prooxidant paraquat (oxidative stress) and 33° C hyperthermia (heat shock). WA treatment increased the resistance to oxidative stress in males at 4 and 7 week old and decreased it at 6 weeks old. It increased the male's resistance to hyperthermia at 2, 4 and 7 weeks old and decreased it at 3, 5 and 8 weeks old. WA treatment decreased the resistance to hyperthermia in females at 1, 2 and 3 weeks old and not affected on their resistance to oxidative stress.

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.

Multi-omics approaches to human biological age estimation.

Multi-omics approach nowadays increasingly applied to molecular research in many fields of life sciences. Biogerontology is not an exception; multi-omics gives possibility to evaluate complex biomarkers (or panels) which consist of quantitative as well as phenotypic ones. It is especially important because of weak understanding of the nature of aging. The difficulty now is distinguishing between causes and effects of aging. The application of the whole set of metabolome, methylome, transcriptome, proteome or metagenome data in aging biomarker design becomes the only way to create a holistic view of aging landscape without missing undiscovered mechanisms and levels of organization. We found patents, up-to-date multi-omics datasets and studies, which include bioinformatics innovations to predict biological age in humans. We hope that the review will be also useful for clinicians, because it follows majorly translational purposes.

Artificial intelligence for aging and longevity research: Recent advances and perspectives.

The applications of modern artificial intelligence (AI) algorithms within the field of aging research offer tremendous opportunities. Aging is an almost universal unifying feature possessed by all living organisms, tissues, and cells. Modern deep learning techniques used to develop age predictors offer new possibilities for formerly incompatible dynamic and static data types. AI biomarkers of aging enable a holistic view of biological processes and allow for novel methods for building causal models-extracting the most important features and identifying biological targets and mechanisms. Recent developments in generative adversarial networks (GANs) and reinforcement learning (RL) permit the generation of diverse synthetic molecular and patient data, identification of novel biological targets, and generation of novel molecular compounds with desired properties and geroprotectors. These novel techniques can be combined into a unified, seamless end-to-end biomarker development, target identification, drug discovery and real world evidence pipeline that may help accelerate and improve pharmaceutical research and development practices. Modern AI is therefore expected to contribute to the credibility and prominence of longevity biotechnology in the healthcare and pharmaceutical industry, and to the convergence of countless areas of research.

Towards natural mimetics of metformin and rapamycin.

Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

Effects of Abies sibirica terpenes on cancer- and aging-associated pathways in human cells.

A large number of terpenoids exhibit potential geroprotector and anti-cancer properties. Here, we studied whole transcriptomic effects of Abisil, the extract of fir (Abies sibirica) terpenes, on normal and cancer cell lines. We used early passaged and senescent none-immortalized fibroblasts as cellular aging models. It was revealed that in normal fibroblasts, terpenes induced genes of stress response, apoptosis regulation and tissue regeneration. The restoration of the expression level of some prolongevity genes after fir extract treatment was shown in old cells. In Caco-2 and AsPC-1 cancer cell lines, Abisil induced expression of both onco-suppressors (members of GADD45, DUSP, and DDIT gene families), and proto-oncogenes (c-Myc, c-Jun, EGR and others). Thus, the study demonstrates the potential anti-aging and anti-cancer effects of Abisil on senescent and cancer cell lines.

Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import.

The common non-steroidal anti-inflammatory drug ibuprofen has been associated with a reduced risk of some age-related pathologies. However, a general pro-longevity role for ibuprofen and its mechanistic basis remains unclear. Here we show that ibuprofen increased the lifespan of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, indicative of conserved eukaryotic longevity effects. Studies in yeast indicate that ibuprofen destabilizes the Tat2p permease and inhibits tryptophan uptake. Loss of Tat2p increased replicative lifespan (RLS), but ibuprofen did not increase RLS when Tat2p was stabilized or in an already long-lived strain background impaired for aromatic amino acid uptake. Concomitant with lifespan extension, ibuprofen moderately reduced cell size at birth, leading to a delay in the G1 phase of the cell cycle. Similar changes in cell cycle progression were evident in a large dataset of replicatively long-lived yeast deletion strains. These results point to fundamental cell cycle signatures linked with longevity, implicate aromatic amino acid import in aging and identify a largely safe drug that extends lifespan across different kingdoms of life.

The effects of pectins on life span and stress resistance in Drosophila melanogaster.

The composition of diet is one of the major determining factors for lifespan. The dietary pectins are known to have anti-inflammatory properties and may influence aging and longevity. Here we demonstrate the lifespan-extending effect of the low methyl esterified (LM) commercial pectins CU701 and AU701 in wild-type strain of Drosophila melanogaster. The high methyl esterified (HM) pectin CU201 did not affect lifespan. LM pectin did not increase lifespan of males with a mutation in the Toll adaptor Myd88 gene and in both males and females with a mutation in the NF-κB ortholog Relish. LM pectin CU701 increased imagoes survival in stress conditions (oxidation, hyperthermia and starvation). However, the fertility of LM and HM pectins treated flies decreased. The treatment of the imagoes with LH and HM pectins induced the activation of whole-body expression of genes involved in DNA repair (D-GADD45, mei-9, spn-B), apoptosis (wrinkled/hid) and heat shock response (hsp70Aa). In contrast, the expression of proinflammatory PARP-1 gene decreased. In the intestines LH and HM pectins induced the mRNA expression of the NF-κB-dependent antimicrobial genes Defensin, Drosomycin and Metchnikowin. These results indicate that the observed lifespan-extending effect of the LM pectins may be mediated by intracellular pathways that involve NF-κB signalling and activation of stress resistance genes.