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An acute systemic immune challenge rapidly decreases tau phosphorylation in htau mice expressing murine tau
Abstracts
and flies (Schosserer et al., 2015). Interestingly, reduced expression of other ribosomal RNA methyltransferases in addition to nsun-5, such as nol-1 and T07A9.8, were implicated in regulating the lifespan of Caenorhabditis elegans as well (Curran and Ruvkun, 2007). Thus, methylation of ribosomal RNA might represent an important regulator of organismal aging, but the precise molecular mechanisms underlying this lifespan modulation have not been investigated so far. We will here present a characterization of the aforementioned RNA methlytransferases in C. elegans regarding RNA substrate and effects on translation and show that their depletion influences lifeand healthspan.
doi:10.1016/j.exger.2017.02.030
Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity Evie van der Spoela, Steffy W. Jansena, Abimbola A. Akintolaa, Bart E. Ballieuxb, Christa Cobbaertb, P. Eline Slagboomc, Gerard Jan Blauwa, Rudi G.J. Westendorpa,e, Hanno Pijld, Ferdinand Roelfsemad, Diana van Heemsta,⁎ aSection Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands bDepartment of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands cSection Molecular Epidemiology, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands dSection Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands eDepartment of Public Health and Center of Healthy Aging, University of Copenhagen, Copenhagen, Denmark ⁎Corresponding author. Reduced growth hormone (GH) signaling has been consistently associated with increased health and life span in various mouse models, while pathological GH excess reduces life expectancy in both mice and men. It is unknown whether healthy human longevity is associated with differences in GH secretion. In this study, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as age-matched controls. Circulating GH concentrations were measured every 10 min and concentrations of insulin-like growth factor 1 (IGF-1) and insulinlike growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-hour total GH secretion was 28% lower (p = 0.04) in offspring (172 (128–216) mU/L) compared to controls (238 (193–284) mU/L). We used approximate entropy (ApEn) to quantify the regularity of 24-hour GH concentration profiles, with lower values being indicative of greater regularity due to tighter (feedback and/or feedforward) control. ApEn was lower (p = 0.001) in offspring (0.45 (0.39–0.53)) compared to controls (0.66 (0.56–0.77)). No significant differences were observed in circulating concentrations of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control, without differences in circulating levels of IGF-1 and IGFBP3. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.
doi:10.1016/j.exger.2017.02.031
115
An acute systemic immune challenge rapidly decreases tau phosphorylation in htau mice expressing murine tau Matthew Barrona, Jane Gartlonb, Lee Dawsonc, Peter Atkinsonb, Marie-Christine Pardona,⁎ aSchool of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, NG7 2UH bEisai Ltd., European Knowledge Centre, Mosquito way, Hatfield, AL10 9SN cAstex Pharmaceuticals, 436 Cambridge Science Park Rd, Cambridge CB4 0QA ⁎Corresponding author. Introduction: Human tau (hTau) mice, devoid of murine tau (mTau), express all 6 human tau isoforms. hTau mice exhibiting tau pathology akin to Alzheimer’s disease (AD), show an isoform ratio imbalance. To restore the isoform imbalance to further resemble AD, mice were bred on mTau +/- background. hTau (mTau +/-) mice demonstrate aggravated tau phosphorylation compared to hTau (mTau -/-). Consequently, the impact of isoform ratio on lipopolysaccharide (LPS)-induced tau phosphorylation was assessed. Methods: Daily-activity was evaluated with the food burrowing task in 3-month male wild-type, mTau +/-, mTau -/-, hTau (mTau +/-) and hTau (mTau -/-) mice prior to LPS administration: 0, 100, 250 or 330μg/kg (i.v., n=6-8). The susceptibility to LPS-induced “sickness” behaviour and spatial working memory was assessed in the spontaneous alternation task 4 hours following. Hippocampal tau was quantified through immunoblotting (n=4-6). Results: Both hTau genotypes demonstrated comparable, impaired, food burrowing behaviour (p b0.01). Spatial working memory was similar among genotypes (p N0.05). LPS only failed to inhibited locomotor activity hTau (mTau +/-), indicative of reduced “sickness” syndrome (pN0.05). LPS failed to impair spatial working memory in all genotypes (pN0.05). hTau (mTau +/-) mice exhibited an improved isoform ratio (pb0.05) and increased phosphorylated tau at ps202 and ps396/ps404 epitopes (pb0.05) compared to hTau (mTau -/-). Unexpectedly, LPS decreased the level of ps202 in hTau (mTau +/-) mice at 250 and 330μg/kg (pb0.05). Conclusion: hTau (mTau +/-) mice, behaviourally similar to hTau (mTau -/-) mice in the current tasks, exhibit a greater ADrelevant isoform ratio with increased tau phosphorylation. The novel immediate effect of LPS decreasing tau phosphorylation again provides a dichotomic role of inflammation in AD, which mechanistic studies will elucidate.
doi:10.1016/j.exger.2017.02.032
NSUN5 methylates ribosomal RNA and modulates ribosome function in human cells Clemens Heissenbergera, Nemanja Dimitrijevica, Yulia Gonskikhb, Angela Lindera, Regina Grillari-Voglauera, Martin Košc, Norbert Polacekb, Johannes Grillaria, Markus Schosserera,⁎ aUniversity of Natural Resources and Life Sciences, Vienna, Department of Biotechnology, Austria bUniversity of Bern, Department of Chemistry & Biochemistry, Switzerland cUniversity of Heidelberg, Biochemistry Center (BZH), Germany ⁎Corresponding author. One of the very few evolutionarily conserved mechanisms involved in the regulation of aging is the reduction of overall protein translation converging on the ribosome. Deletion of ribosomal proteins or factors involved in the regulation of ribosomal activity have been shown previously to extend the lifespan of several model organisms, but the underlying molecular mechanisms remain elusive. One proposed mode of action is the generation of “specialized ribosomes” upon aging and stress, which are able to modulate gene expression patterns during
and flies (Schosserer et al., 2015). Interestingly, reduced expression of other ribosomal RNA methyltransferases in addition to nsun-5, such as nol-1 and T07A9.8, were implicated in regulating the lifespan of Caenorhabditis elegans as well (Curran and Ruvkun, 2007). Thus, methylation of ribosomal RNA might represent an important regulator of organismal aging, but the precise molecular mechanisms underlying this lifespan modulation have not been investigated so far. We will here present a characterization of the aforementioned RNA methlytransferases in C. elegans regarding RNA substrate and effects on translation and show that their depletion influences lifeand healthspan.
doi:10.1016/j.exger.2017.02.030
Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity Evie van der Spoela, Steffy W. Jansena, Abimbola A. Akintolaa, Bart E. Ballieuxb, Christa Cobbaertb, P. Eline Slagboomc, Gerard Jan Blauwa, Rudi G.J. Westendorpa,e, Hanno Pijld, Ferdinand Roelfsemad, Diana van Heemsta,⁎ aSection Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands bDepartment of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands cSection Molecular Epidemiology, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands dSection Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands eDepartment of Public Health and Center of Healthy Aging, University of Copenhagen, Copenhagen, Denmark ⁎Corresponding author. Reduced growth hormone (GH) signaling has been consistently associated with increased health and life span in various mouse models, while pathological GH excess reduces life expectancy in both mice and men. It is unknown whether healthy human longevity is associated with differences in GH secretion. In this study, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as age-matched controls. Circulating GH concentrations were measured every 10 min and concentrations of insulin-like growth factor 1 (IGF-1) and insulinlike growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-hour total GH secretion was 28% lower (p = 0.04) in offspring (172 (128–216) mU/L) compared to controls (238 (193–284) mU/L). We used approximate entropy (ApEn) to quantify the regularity of 24-hour GH concentration profiles, with lower values being indicative of greater regularity due to tighter (feedback and/or feedforward) control. ApEn was lower (p = 0.001) in offspring (0.45 (0.39–0.53)) compared to controls (0.66 (0.56–0.77)). No significant differences were observed in circulating concentrations of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control, without differences in circulating levels of IGF-1 and IGFBP3. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.
doi:10.1016/j.exger.2017.02.031
115
An acute systemic immune challenge rapidly decreases tau phosphorylation in htau mice expressing murine tau Matthew Barrona, Jane Gartlonb, Lee Dawsonc, Peter Atkinsonb, Marie-Christine Pardona,⁎ aSchool of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, NG7 2UH bEisai Ltd., European Knowledge Centre, Mosquito way, Hatfield, AL10 9SN cAstex Pharmaceuticals, 436 Cambridge Science Park Rd, Cambridge CB4 0QA ⁎Corresponding author. Introduction: Human tau (hTau) mice, devoid of murine tau (mTau), express all 6 human tau isoforms. hTau mice exhibiting tau pathology akin to Alzheimer’s disease (AD), show an isoform ratio imbalance. To restore the isoform imbalance to further resemble AD, mice were bred on mTau +/- background. hTau (mTau +/-) mice demonstrate aggravated tau phosphorylation compared to hTau (mTau -/-). Consequently, the impact of isoform ratio on lipopolysaccharide (LPS)-induced tau phosphorylation was assessed. Methods: Daily-activity was evaluated with the food burrowing task in 3-month male wild-type, mTau +/-, mTau -/-, hTau (mTau +/-) and hTau (mTau -/-) mice prior to LPS administration: 0, 100, 250 or 330μg/kg (i.v., n=6-8). The susceptibility to LPS-induced “sickness” behaviour and spatial working memory was assessed in the spontaneous alternation task 4 hours following. Hippocampal tau was quantified through immunoblotting (n=4-6). Results: Both hTau genotypes demonstrated comparable, impaired, food burrowing behaviour (p b0.01). Spatial working memory was similar among genotypes (p N0.05). LPS only failed to inhibited locomotor activity hTau (mTau +/-), indicative of reduced “sickness” syndrome (pN0.05). LPS failed to impair spatial working memory in all genotypes (pN0.05). hTau (mTau +/-) mice exhibited an improved isoform ratio (pb0.05) and increased phosphorylated tau at ps202 and ps396/ps404 epitopes (pb0.05) compared to hTau (mTau -/-). Unexpectedly, LPS decreased the level of ps202 in hTau (mTau +/-) mice at 250 and 330μg/kg (pb0.05). Conclusion: hTau (mTau +/-) mice, behaviourally similar to hTau (mTau -/-) mice in the current tasks, exhibit a greater ADrelevant isoform ratio with increased tau phosphorylation. The novel immediate effect of LPS decreasing tau phosphorylation again provides a dichotomic role of inflammation in AD, which mechanistic studies will elucidate.
doi:10.1016/j.exger.2017.02.032
NSUN5 methylates ribosomal RNA and modulates ribosome function in human cells Clemens Heissenbergera, Nemanja Dimitrijevica, Yulia Gonskikhb, Angela Lindera, Regina Grillari-Voglauera, Martin Košc, Norbert Polacekb, Johannes Grillaria, Markus Schosserera,⁎ aUniversity of Natural Resources and Life Sciences, Vienna, Department of Biotechnology, Austria bUniversity of Bern, Department of Chemistry & Biochemistry, Switzerland cUniversity of Heidelberg, Biochemistry Center (BZH), Germany ⁎Corresponding author. One of the very few evolutionarily conserved mechanisms involved in the regulation of aging is the reduction of overall protein translation converging on the ribosome. Deletion of ribosomal proteins or factors involved in the regulation of ribosomal activity have been shown previously to extend the lifespan of several model organisms, but the underlying molecular mechanisms remain elusive. One proposed mode of action is the generation of “specialized ribosomes” upon aging and stress, which are able to modulate gene expression patterns during