Taurine deficiency as a driver of aging.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Anti-Oxidative and Anti-Aging Effects of Probiotic Fermented Ginseng by Modulating Gut Microbiota and Metabolites in Caenorhabditis elegans.

Antioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis.

Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n = 1223 from 23 studies comprising 46 effect sizes involving DR (n = 17) and rapamycin treatment (n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR = - 0.72; CI = - 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

Supplementation with Queen Bee Larva Powder Extended the Longevity of Caenorhabditis elegans.

Queen bee larva (QBL) is one kind of important edible insect that is harvested during royal jelly production process. QBL has many physiological functions; however, limited information is available regarding its antiaging effects. In this study, the antiaging function of freeze-dried QBL powder (QBLP) was investigated by combining the Caenorhabditis elegans (C. elegans) model and transcriptomics. The administration of QBLP to C. elegans was shown to improve lifespan parameters. Additionally, QBLP improved the mobility of nematodes. Transcriptome analysis showed the differentially expressed genes (DEGs) were significantly enriched in Gene Ontology (GO) terms that were almost all related to the biological functions of cell metabolism and stress, which are associated with lifespan. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the lifespan of C. elegans was related to the longevity regulating pathway-worm. The expression levels of the key genes sod-3, gst-6, hsp-12.6, lips-7, ins-8, and lips-17 were upregulated. sod-3, hsp-12.6, lips-7, and lips-17 are downstream targets of DAF-16, which is an important transcription factor related to lifespan extension. CF1038 (daf-16(mu86)) supplemented with QBLP did not show a life-prolonging. This indicates that the antiaging function of QBLP is closely related to daf-16. Thus, QBLP is a component that could potentially be used as a functional material to ameliorate aging and aging-related symptoms.

Integrity of hypothalamic-pituitary-testicular axis in exceptional longevity.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic-pituitary-testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90-106 years. We found that 94% of men exhibited preserved hypothalamic-pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging-related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic-pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.

Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.

Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.

A Fat-Promoting Botanical Extract From Artemisia scoparia Exerts Geroprotective Effects on Caenorhabditis elegans Life Span and Stress Resistance.

Like other biological processes, aging is not random but subject to molecular control. Natural products that modify core metabolic parameters, including fat content, may provide entry points to extend animal life span and promote healthy aging. Here, we show that a botanical extract from Artemisia scoparia (SCO), which promotes fat storage and metabolic resiliency in mice, extends the life span of the nematode Caenorhabditis elegans by up to 40%. Notably, this life-span extension depends significantly on SCO's effects on fat; SCO-treated worms exhibit heightened levels of unsaturated fat, and inhibition of Δ9 desaturases, which oversee biosynthesis of monounsaturated fatty acids, prevents SCO-dependent fat accumulation and life-span extension. At an upstream signaling level, SCO prompts changes to C. elegans fat regulation by stimulating nuclear translocation of transcription factor DAF-16/FOXO, an event that requires AMP-activated protein kinase under this condition. Importantly, animals treated with SCO are not only long-lived but also show improved stress resistance in late adulthood, suggesting that this fat-promoting intervention may enhance some aspects of physiological health in older age. These findings identify SCO as a natural product that can modify fat regulation for longevity benefit and add to growing evidence indicating that elevated fat can be prolongevity in some circumstances.

Handelin extends lifespan and healthspan of Caenorhabditis elegans by reducing ROS generation and improving motor function.

Aging and aging-related disorders contribute to formidable socioeconomic and healthcare challenges. Several promising small molecules have been identified to target conserved genetic pathways delaying aging to extend lifespan and healthspan in many organisms. We previously found that extract from an edible and medicinal plant Chrysanthemum indicum L. (C. indicum L.) protect skin from UVB-induced photoaging, partially by reducing reactive oxygen species (ROS) generation. Thus, we hypothesized that C. indicum L. and its biological active compound may extend lifespan and health span in vivo. We find that both water and ethanol extracts from C. indicum L. extended lifespan of Caenorhabditis elegans, with better biological effect on life extending for ethanol extracts. As one of the major biological active compounds, handelin extended lifespan of C. elegans too. RNA-seq analysis revealed overall gene expression change of C. elegans post stimulation of handelin focus on several antioxidative proteins. Handelin significantly reduced ROS level and maintained the number and morphology of mitochondria. Moreover, handelin improveed many C. elegans behaviors related to healthspan, including increased pharyngeal pumping and body movement. Muscle fiber imaging analyses revealed that handelin maintains muscle architecture by stabilizing myofilaments. In conclusion, our present study finds a novel compound handelin, from C. indicum L., which bring about biologically beneficial effects by mild stress response, termed as hormetin, that can extend both lifespan and healthspan in vivo on C. elegans. Further study on mammal animal model of natural aging or sarcopenia will verify the potential clinical value of handelin.

The adult lifespan of the female honey bee (Apis mellifera): Metabolic rate, AGE pigment and the effect of dietary fatty acids.

Female honey bees can be queens or workers and although genetically identical, workers have an adult lifespan of weeks while queens can live for years. The mechanisms underlying this extraordinary difference remain unknown. This study examines three potential explanations of the queen-worker lifespan difference. Metabolic rates were similar in age-matched queens and workers and thus are not an explanation. The accumulation of fluorescent AGE pigment has been successfully used as a good measure of cellular senescence in many species. Unlike other animals, AGE pigment level reduced during adult life of queens and workers. This unusual finding suggests female honey bees can either modify, or remove from their body, AGE pigment. Another queen-worker difference is that, as adults, workers eat pollen but queens do not. Pollen is a source of polyunsaturated fatty acids. Its consumption explains the queen-worker difference in membrane fat composition of female adult honey bees which has previously been suggested as a cause of the lifespan difference. We were able to produce "queen-worker" membrane differences in workers by manipulation of diet that did not change worker lifespan and we can, thus, also rule out pollen consumption by workers as an explanation of the dramatic queen-worker lifespan difference.

Investigational drugs and nutrients for human longevity. Recent clinical trials registered in ClinicalTrials.gov and clinicaltrialsregister.eu.

Introduction:Several pharmacological drugs have shown proof of concept for longevity in animal models. I aimed to identify and review those longevity drug candidates that are undergoing clinical trials.Areas covered:Recent (post-2017) longevity clinical trials were found in US and EU clinical trial registries. Longevity drug candidates are the antidiabetic drugs metformin and acarbose, and the immunosuppressant rapamycin. These medicinal drugs are tested on biochemical and clinical markers of aging. In addition, vitamin D supplementation is being investigated in two mega-trials (sample size> 5000) for its efficacy in reducing all-cause mortality.Expert opinion:Anti-aging effects of longevity drug candidates suggest, but do not demonstrate that they prolong life. The two megatrials with vitamin D supplementation make it possible to detect differences in life expectancy between vitamin D and placebo. Therefore, a protocol similar to that for vitamin D could be used to demonstrate pro-longevity effects of metformin, acarbose, and rapamycin.

Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.

Antioxidant Blend of Curcumin and Broccoli Seed Extract Exhibits Protective Effect on Neurodegeneration and Promotes Drosophila Lifespan.

Antioxidants and related compounds are anti-inflammatory and exhibit great potential in promoting human health. They are also often considered to be important elements in the process of neurodegeneration. Here we describe a antioxidant blend of Curcumin and Broccoli Seed Extract (BSE). Flies treated with the blend exhibit extended lifespan. RNA-seq analysis of samples from adult fly brains reveals a wide array of new genes with differential expression upon treatment with the blend. Interestingly, abolishing expression of some of the identified genes in dopaminergic (DA) neurons does not affect DA neuron number. Taken together, our findings reveal an antioxidant blend that promotes fly longevity and exhibits protective effect over neurodegeneration, demonstrating the importance of antioxidants in health and pathology.

Increased Stress Resistance and Lifespan in Chaenorhabditis elegans Wildtype and Knockout Mutants-Implications for Depression Treatment by Medicinal Herbs.

Depression and anxiety disorders are widespread diseases, and they belong to the leading causes of disability and greatest burdens on healthcare systems worldwide. It is expected that the numbers will dramatically rise during the COVID-19 pandemic. Established medications are not sufficient to adequately treat depression and are not available for everyone. Plants from traditional medicine may be promising alternatives to treat depressive symptoms. The model organism Chaenorhabditis elegans was used to assess the stress reducing effects of methanol/dichlormethane extracts from plants used in traditional medicine. After initial screening for antioxidant activity, nine extracts were selected for in vivo testing in oxidative stress, heat stress, and osmotic stress assays. Additionally, anti-aging properties were evaluated in lifespan assay. The extracts from Acanthopanax senticosus, Campsis grandiflora, Centella asiatica, Corydalis yanhusuo, Dan Zhi, Houttuynia cordata, Psoralea corylifolia, Valeriana officinalis, and Withaniasomnifera showed antioxidant activity of more than 15 Trolox equivalents per mg extract. The extracts significantly lowered ROS in mutants, increased resistance to heat stress and osmotic stress, and the extended lifespan of the nematodes. The plant extracts tested showed promising results in increasing stress resistance in the nematode model. Further analyses are needed, in order to unravel underlying mechanisms and transfer results to humans.

Small Molecule Rescue of ATXN3 Toxicity in C. elegans via TFEB/HLH-30.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a polyglutamine expansion disease arising from a trinucleotide CAG repeat expansion in exon 10 of the gene ATXN3. There are no effective pharmacological treatments for MJD, thus the identification of new pathogenic mechanisms, and the development of novel therapeutics is urgently needed. In this study, we performed a comprehensive, blind drug screen of 3942 compounds (many FDA approved) and identified small molecules that rescued the motor-deficient phenotype in transgenic ATXN3 Caenorhabditis elegans strain. Out of this screen, five lead compounds restoring motility, protecting against neurodegeneration, and increasing the lifespan in ATXN3-CAG89 mutant worms were identified. These compounds were alfacalcidol, chenodiol, cyclophosphamide, fenbufen, and sulfaphenazole. We then investigated how these molecules might exert their neuroprotective properties. We found that three of these compounds, chenodiol, fenbufen, and sulfaphenazole, act as modulators for TFEB/HLH-30, a key transcriptional regulator of the autophagy process, and require this gene for their neuroprotective activities. These genetic-chemical approaches, using genetic C. elegans models for MJD and the screening, are promising tools to understand the mechanisms and pathways causing neurodegeneration, leading to MJD. Positively acting compounds may be promising candidates for investigation in mammalian models of MJD and preclinical applications in the treatment of this disease.

Of Mice and Men: Impacts of Calorie Restriction on Metabolomics of the Cerebellum.

The main purpose of research in mice is to explore metabolic changes in animal models and then predict or propose potential translational benefits in humans. Although some researchers in the brain research field have mentioned that the mouse experiments results still lack the complex neuroanatomy of humans, caution is required to interpret the findings. In mice, we observed in article seventeenth of the series of the effects of graded levels of calorie restriction, metabolomic changes in the cerebellum indicated activation of hypothalamocerebellar connections driven by hunger responses. Therefore, the purpose of the current perspective is to set this latest paper into a wider context of the physiological, behavioral, and molecular changes seen in these mice and to compare and contrast them with previous human studies.

Does the longevity of the Sardinian population date back to Roman times? A comprehensive review of the available evidence.

The discovery early in this century of the exceptional longevity of the Sardinian population has given new impetus to demographic studies of this phenomenon during the classical period. In the 1970s, it was hypothesised that the average mortality rate in Roman Sardinia was lower than in metropolitan Rome itself, postulating an ancient precedent for the remarkable longevity observable nowadays in the island's population. In the present study, the available evidence was examined in order to test this hypothesis. Literary, juridical, epigraphic, papyrological, anthropological and archaeological sources regarding the population of the Roman Empire, including Sardinia, were retrieved by accessing Science Direct, PubMed, Scopus and Google Scholar databases, as well as regional libraries, regardless of time limitation, and were independently reviewed by the authors. For Roman Sardinia, only funerary epitaphs were retrieved, in contrast with the numerous sources available for the whole Roman Empire. Inscriptions revealing the existence of three alleged nonagenarians, two centenarians, two ultracentenarians and one supercentenarian were found, corresponding to 2% in a total of 381 inscriptions. The majority were located in a highly Romanised rural area of central-western Sardinia. However, the ages reported in the epitaphs may be inaccurate because of the influence of confounders such as age rounding, approximations and/or amplifications, and are unrelated to the total number of inhabitants. In conclusion, the funerary evidence, the only available data from Roman Sardinia, is too weak to estimate the life expectancy of the local ancient population and cannot offer valuable arguments to support the hypothesis that exceptional longevity has been a Sardinian trait since Roman times.

Downregulation of the tyrosine degradation pathway extends Drosophila lifespan.

Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived Drosophila melanogaster. Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.

Can Serum Nitrosoproteome Predict Longevity of Aged Women?

Aging is characterized by increase in reactive oxygen (ROS) and nitrogen (RNS) species, key factors of cardiac failure and disuse-induced muscle atrophy. This study focused on serum nitroproteome as a trait of longevity by adopting two complementary gel-based techniques: two-dimensional differential in gel electrophoresis (2-D DIGE) and Nitro-DIGE coupled with mass spectrometry of albumin-depleted serum of aged (A, n = 15) and centenarian (C, n = 15) versus young females (Y, n = 15). Results indicate spots differently expressed in A and C compared to Y and spots changed in A vs. C. Nitro-DIGE revealed nitrosated protein spots in A and C compared to Y and spots changed in A vs. C only (p-value < 0.01). Nitro-proteoforms of alpha-1-antitripsin (SERPINA1), alpha-1-antichimotripsin (SERPINA3), ceruloplasmin (CP), 13 proteoforms of haptoglobin (HP), and inactive glycosyltransferase 25 family member 3 (CERCAM) increased in A vs. Y and C. Conversely, nitrosation levels decreased in C vs. Y and A, for immunoglobulin light chain 1 (IGLC1), serotransferrin (TF), transthyretin (TTR), and vitamin D-binding protein (VDBP). Immunoblottings of alcohol dehydrogenase 5/S-nitrosoglutathione reductase (ADH5/GSNOR) and thioredoxin reductase 1 (TRXR1) indicated lower levels of ADH5 in A vs. Y and C, whereas TRXR1 decreased in A and C in comparison to Y. In conclusion, the study identified putative markers in C of healthy aging and high levels of ADH5/GSNOR that can sustain the denitrosylase activity, promoting longevity.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17ß-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.