Volume 5, Issue 6

Lucanic M, Graham J, Scott G, Bhaumik D, Benz CC, Hubbard A, Lithgow GJ, Melov S, . Age-related micro-RNA abundance in individual C. elegans. . 5:394-411. https://doi.org/10.18632/aging.100564

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                TY  - JOUR
                AU  - Lucanic, Mark 
                AU  - Graham, Jill 
                AU  - Scott, Gary 
                AU  - Bhaumik, Dipa 
                AU  - Benz, Christopher C. 
                AU  - Hubbard, Alan 
                AU  - Lithgow, Gordon J. 
                AU  - Melov, Simon 
                TI  - Age-related micro-RNA abundance in individual <i>C. elegans</i>
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100564
                DO  - 10.18632/aging.100564
                SP  - 394
                EP  - 411
                PY  - 
                AB  - Non-coding small RNAs of the micro-RNA class (miRNA) are conserved regulators of gene function with a broad impact on biological processes. We screened miRNA levels for age-related changes in individual worms and investigated their influence on the lifespan of the nematode C. elegans. We measured the abundance of 69 miRNAs expressed in individual animals at different ages with over thirty five thousand discrete quantitative nano-fluidic polymerase chain reactions. We found that miRNA abundance was highly variable between individual worms raised under identical conditions and that expression variability generally increased with age. To identify expression differences associated with either reproductive or somatic tissues, we analyzed wild type and mutants that lacked germlines. miRNAs from the mir-35-41 cluster increased in abundance with age in wild type animals, but were nearly absent from mutants lacking a germline, suggesting their age-related increase originates from the germline. Most miRNAs with age-dependent levels did not have a major effect on lifespan, as corresponding deletion mutants exhibited wild-type lifespans. The major exception to this was mir-71, which increased in abundance with age and was required for normal longevity. Our genetic characterization indicates that mir-71 acts at least partly in parallel to insulin/IGF like signals to influence lifespan.
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A decline in PABPN1 induces progressive muscle weakness in Oculopharyngeal muscle dystrophy and in muscle aging

Seyed Yahya Anvar, Yotam Raz, Nisha Verwey, Barbara van der Sluijs, Andrea Venema, Jelle J Goeman, John Vissing, Silvère M van der Maarel, Peter A.C. ‘t Hoen, Baziel G.M. van Engelen, Vered Raz,

https://doi.org/10.18632/aging.100567 pp 412—426

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Anvar SY, Raz Y, Verwey N, van der Sluijs B, Venema A, Goeman JJ, Vissing J, van der Maarel SM, ‘t Hoen PA, van Engelen BG, Raz V, . A decline in PABPN1 induces progressive muscle weakness in Oculopharyngeal muscle dystrophy and in muscle aging. . 5:412-426. https://doi.org/10.18632/aging.100567

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                TY  - JOUR
                AU  - Anvar, Seyed Yahya 
                AU  - Raz, Yotam 
                AU  - Verwey, Nisha 
                AU  - van der Sluijs, Barbara 
                AU  - Venema, Andrea 
                AU  - Goeman, Jelle J 
                AU  - Vissing, John 
                AU  - van der Maarel, Silvère M 
                AU  - ‘t Hoen, Peter A.C. 
                AU  - van Engelen, Baziel G.M. 
                AU  - Raz, Vered 
                TI  - A decline in PABPN1 induces progressive muscle weakness in Oculopharyngeal muscle dystrophy and in muscle aging
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100567
                DO  - 10.18632/aging.100567
                SP  - 412
                EP  - 426
                PY  - 
                AB  - Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P&lt;0.05). Using k-means clustering we identified age-dependent trends in both OPMD and controls, but trends were often accelerated in OPMD. We report an age-regulated decline in PABPN1 levels in Vastus lateralis muscles from the fifth decade. In concurrence with severe muscle degeneration in OPMD, the decline in PABPN1 accelerated in OPMD and was specific to skeletal muscles. Reduced PABPN1 levels (30% to 60%) in muscle cells induced myogenic defects and morphological signatures of cellular aging in proportion to PABPN1 expression levels. We suggest that PABPN1 levels regulate muscle cell aging and OPMD represents an accelerated muscle aging disorder.
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Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions

Sandra Favret, Francois Binet, Eric Lapalme, Dominique Leboeuf, Jose Carbadillo, Tina Rubic, Emilie Picard, Gaelle Mawambo, Nicolas Tetreault, Jean-Sebastien Joyal, Sylvain Chemtob, Florian Sennlaub, John Paul SanGiovanni, Martin Guimond, Przemyslaw Sapieha,

https://doi.org/10.18632/aging.100563 pp 427—444

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Favret S, Binet F, Lapalme E, Leboeuf D, Carbadillo J, Rubic T, Picard E, Mawambo G, Tetreault N, Joyal J, Chemtob S, Sennlaub F, SanGiovanni JP, et al, . Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions. . 5:427-444. https://doi.org/10.18632/aging.100563

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                TY  - JOUR
                AU  - Favret, Sandra 
                AU  - Binet, Francois 
                AU  - Lapalme, Eric 
                AU  - Leboeuf, Dominique 
                AU  - Carbadillo, Jose 
                AU  - Rubic, Tina 
                AU  - Picard, Emilie 
                AU  - Mawambo, Gaelle 
                AU  - Tetreault, Nicolas 
                AU  - Joyal, Jean-Sebastien 
                AU  - Chemtob, Sylvain 
                AU  - Sennlaub, Florian 
                AU  - SanGiovanni, John Paul 
                AU  - Guimond, Martin 
                AU  - Sapieha, Przemyslaw 
                TI  - Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100563
                DO  - 10.18632/aging.100563
                SP  - 427
                EP  - 444
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Favret, Sandra 
                AU  - Binet, Francois 
                AU  - Lapalme, Eric 
                AU  - Leboeuf, Dominique 
                AU  - Carbadillo, Jose 
                AU  - Rubic, Tina 
                AU  - Picard, Emilie 
                AU  - Mawambo, Gaelle 
                AU  - Tetreault, Nicolas 
                AU  - Joyal, Jean-Sebastien 
                AU  - Chemtob, Sylvain 
                AU  - Sennlaub, Florian 
                AU  - SanGiovanni, John Paul 
                AU  - Guimond, Martin 
                AU  - Sapieha, Przemyslaw 
                TI  - Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100563
                DO  - 10.18632/aging.100563
                SP  - 427
                EP  - 444
                PY  - 
                AB  - Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovasculature in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form may accompany it. Here we provide the first evidence for the protective role of the Retinal Pigment Epithelium (RPE)-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the outer retina. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in the SUCNR1 gene. In mice, outer retinal expression of SUCNR1 is observed in the RPE as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1−/− mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch's membrane and a buildup of subretinal microglia. The accumulation of microglia in Sucnr1-deficient mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wild-type microglia into Sucnr1−/− mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD and thus broaden our understanding of this clinically unmet need.
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Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C

Sven Starke, Peter Meinke, Daria Camozzi, Elisabetta Mattioli, Roland Pfaeffle, Manuela Siekmeyer, Wolfgang Hirsch, Lars Christian Horn, Uwe Paasch, Diana Mitter, Giovanna Lattanzi, Manfred Wehnert, Wieland Kiess,

https://doi.org/10.18632/aging.100566 pp 445—459

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Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, Kiess W, . Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C. . 5:445-459. https://doi.org/10.18632/aging.100566

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                TY  - JOUR
                AU  - Starke, Sven 
                AU  - Meinke, Peter 
                AU  - Camozzi, Daria 
                AU  - Mattioli, Elisabetta 
                AU  - Pfaeffle, Roland 
                AU  - Siekmeyer, Manuela 
                AU  - Hirsch, Wolfgang 
                AU  - Horn, Lars Christian 
                AU  - Paasch, Uwe 
                AU  - Mitter, Diana 
                AU  - Lattanzi, Giovanna 
                AU  - Wehnert, Manfred 
                AU  - Kiess, Wieland 
                TI  - Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100566
                DO  - 10.18632/aging.100566
                SP  - 445
                EP  - 459
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Starke, Sven 
                AU  - Meinke, Peter 
                AU  - Camozzi, Daria 
                AU  - Mattioli, Elisabetta 
                AU  - Pfaeffle, Roland 
                AU  - Siekmeyer, Manuela 
                AU  - Hirsch, Wolfgang 
                AU  - Horn, Lars Christian 
                AU  - Paasch, Uwe 
                AU  - Mitter, Diana 
                AU  - Lattanzi, Giovanna 
                AU  - Wehnert, Manfred 
                AU  - Kiess, Wieland 
                TI  - Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100566
                DO  - 10.18632/aging.100566
                SP  - 445
                EP  - 459
                PY  - 
                AB  - The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygous LMNA mutation c.1303C&gt;T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.
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Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress

Lolita S. Nidadavolu, Laura J. Niedernhofer, Saleem A. Khan,

https://doi.org/10.18632/aging.100571 pp 460—473

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Nidadavolu LS, Niedernhofer LJ, Khan SA, . Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress. . 5:460-473. https://doi.org/10.18632/aging.100571

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                TY  - JOUR
                AU  - Nidadavolu, Lolita S. 
                AU  - Niedernhofer, Laura J. 
                AU  - Khan, Saleem A. 
                TI  - Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100571
                DO  - 10.18632/aging.100571
                SP  - 460
                EP  - 473
                PY  - 
                AB  - XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely, offering a unique opportunity to identify factors that regulate senescence and aging. We compared microRNA (miRNA) expression in Ercc1−/− primary mouse embryonic fibroblasts (MEFs) and wild-type (WT) MEFs in different growth conditions to identify miRNAs that drive cellular senescence. Microarray analysis showed three differentially expressed miRNAs in passage 7 (P7) Ercc1−/− MEFs grown at 20% O2 compared to Ercc1−/− MEFs grown at 3% O2. Thirty-six differentially expressed miRNAs were identified in Ercc1−/− MEFs at P7 compared to early passage (P3) in 3% O2. Eight of these miRNAs (miR-449a, miR-455*, miR-128, miR-497, miR-543, miR-450b-3p, miR-872 and miR-10b) were similarly downregulated in the liver of progeroid Ercc1−/Δ and old WT mice compared to adult WT mice, a tissue that senesces with aging. Three miRNAs (miR-449a, miR-455* and miR-128) were also downregulated in Ercc1−/Δ and WT old mice kidneys compared to young WT mice. We also discovered that the miRNA expression regulator Dicer is significantly downregulated in tissues of old mice and late passage cells compared to young controls. Collectively these results support the conclusion that the miRNAs identified may play an important role in staving off cellular senescence and their altered expression could be indicative of aging.
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Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Nataliya G. Kolosova, Anton O. Vitovtov, Natalia A Muraleva, Andrey E. Akulov, Natalia A. Stefanova, Mikhail V. Blagosklonny,

https://doi.org/10.18632/aging.100573 pp 474—484

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Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV, . Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. . 5:474-484. https://doi.org/10.18632/aging.100573

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                TY  - JOUR
                AU  - Kolosova, Nataliya G. 
                AU  - Vitovtov, Anton O. 
                AU  - Muraleva, Natalia A 
                AU  - Akulov, Andrey E. 
                AU  - Stefanova, Natalia A. 
                AU  - Blagosklonny, Mikhail V. 
                TI  - Rapamycin suppresses brain aging in senescence-accelerated OXYS rats
                JO  - 
                JA  - 
                VL  - 5
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100573
                DO  - 10.18632/aging.100573
                SP  - 474
                EP  - 484
                PY  - 
                AB  - Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.
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Volume 5, Issue 6

Editorials

FGF21 drives a shift in adipokine tone to restore metabolic health

Andrew Charles Adams, Alexei Kharitonenkov,

Focusing the spotlight on GSK-3 in aging

Jibin Zhou, Thomas Force,

Emerging role of lymphatic vessels in reverse cholesterol transport

Angeli Veronique, Lim Hwee Ying,

Unveiling the last missing link of the cardiolipin synthetic pathway in mitochondria

Yasushi Tamura, Toshiya Endo,

Research Papers

Age-related micro-RNA abundance in individual C. elegans

Mark Lucanic, Jill Graham, Gary Scott, Dipa Bhaumik, Christopher C. Benz, Alan Hubbard, Gordon J. Lithgow, Simon Melov,

A decline in PABPN1 induces progressive muscle weakness in Oculopharyngeal muscle dystrophy and in muscle aging

Seyed Yahya Anvar, Yotam Raz, Nisha Verwey, Barbara van der Sluijs, Andrea Venema, Jelle J Goeman, John Vissing, Silvère M van der Maarel, Peter A.C. ‘t Hoen, Baziel G.M. van Engelen, Vered Raz,

Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions

Sandra Favret, Francois Binet, Eric Lapalme, Dominique Leboeuf, Jose Carbadillo, Tina Rubic, Emilie Picard, Gaelle Mawambo, Nicolas Tetreault, Jean-Sebastien Joyal, Sylvain Chemtob, Florian Sennlaub, John Paul SanGiovanni, Martin Guimond, Przemyslaw Sapieha,

Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C

Sven Starke, Peter Meinke, Daria Camozzi, Elisabetta Mattioli, Roland Pfaeffle, Manuela Siekmeyer, Wolfgang Hirsch, Lars Christian Horn, Uwe Paasch, Diana Mitter, Giovanna Lattanzi, Manfred Wehnert, Wieland Kiess,

Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress

Lolita S. Nidadavolu, Laura J. Niedernhofer, Saleem A. Khan,

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

Nataliya G. Kolosova, Anton O. Vitovtov, Natalia A Muraleva, Andrey E. Akulov, Natalia A. Stefanova, Mikhail V. Blagosklonny,

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