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  • 1
    Online Resource
    Online Resource
    Elsevier BV ; 2016
    In:  Archives of Biochemistry and Biophysics Vol. 589 ( 2016-01), p. 168-176
    In: Archives of Biochemistry and Biophysics, Elsevier BV, Vol. 589 ( 2016-01), p. 168-176
    Type of Medium: Online Resource
    ISSN: 0003-9861
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
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  • 2
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6649 ( 2023-06-09)
    Abstract: Aging is an inevitable multifactorial process. Aging-related changes manifest as the “hallmarks of aging,” cause organ functions to decline, and increase the risk of disease and death. Aging is associated with systemic changes in the concentrations of molecules such as metabolites. However, whether such changes are merely the consequence of aging or whether these molecules are drivers of aging remains largely unexplored. If these were blood-based drivers of aging, then restoring their concentration or functions to “youthful” levels could serve as an antiaging intervention. RATIONALE Taurine, a semiessential micronutrient, is one of the most abundant amino acids in humans and other eukaryotes. Earlier studies have shown that the concentration of taurine in blood correlates with health, but it is unknown whether blood taurine concentrations affect aging. To address this gap in knowledge, we measured the blood concentration of taurine during aging and investigated the effect of taurine supplementation on health span and life span in several species. RESULTS Blood concentration of taurine declines with age in mice, monkeys, and humans. To investigate whether this decline contributes to aging, we orally fed taurine or a control solution once daily to middle-aged wild-type female and male C57Bl/6J mice until the end of life. Taurine-fed mice of both sexes survived longer than the control mice. The median life span of taurine-treated mice increased by 10 to 12%, and life expectancy at 28 months increased by about 18 to 25%. A meaningful antiaging therapy should not only improve life span but also health span, the period of healthy living. We, therefore, investigated the health of taurine-fed middle-aged mice and found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in health span. We observed similar effects in monkeys. To check whether the observed effects of taurine transcended the species boundary, we investigated whether taurine supplementation increased life span in worms and yeast. Although taurine did not affect the replicative life span of unicellular yeast, it increased life span in multicellular worms. Investigations into the mechanism or mechanisms through which taurine supplementation improved the health span and life span revealed that taurine positively affected several hallmarks of aging. Taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammation. An association analysis of metabolite clinical risk factors in humans showed that lower taurine, hypotaurine, and N -acetyltaurine concentrations were associated with adverse health, such as increased abdominal obesity, hypertension, inflammation, and prevalence of type 2 diabetes. Moreover, we found that a bout of exercise increased the concentrations of taurine metabolites in blood, which might partially underlie the antiaging effects of exercise. CONCLUSION Taurine abundance decreases during aging. A reversal of this decline through taurine supplementation increases health span and life span in mice and worms and health span in monkeys. This identifies taurine deficiency as a driver of aging in these species. To test whether taurine deficiency is a driver of aging in humans as well, long-term, well-controlled taurine supplementation trials that measure health span and life span as outcomes are required. Taurine deficiency as a driver of aging. Taurine concentration in blood declines with aging (top left). A reversal of this drop through taurine supplementation increased healthy life span in mice and worms but not in yeast (bottom left and top middle). Taurine supplementation affected several hallmarks of aging (middle). In humans, lower taurine concentrations were associated with multiple diseases (top right). A randomized controlled clinical trial in humans is warranted to assess the antiaging effects of taurine (bottom right). BMI, body mass index.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 3
    In: Nature, Springer Science and Business Media LLC
    Abstract: The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics 1 .
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 4
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 118, No. 7 ( 2022-06-22), p. 1742-1757
    Abstract: Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and results We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
    Type of Medium: Online Resource
    ISSN: 0008-6363 , 1755-3245
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 5
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 374, No. 6569 ( 2021-11-12)
    Abstract: Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
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  • 6
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2014
    In:  Nucleic Acids Research Vol. 42, No. D1 ( 2014-01), p. D671-D676
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 42, No. D1 ( 2014-01), p. D671-D676
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 1472175-2
    SSG: 12
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  • 7
    In: Nature, Springer Science and Business Media LLC, Vol. 477, No. 7362 ( 2011-9), p. 54-60
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
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