LONGEVITY EXTENSION MECHANISMS IN MICE OVEREXPRESSING CYB5R3, A NEW LONG-LIVED GENETIC MODEL (Q3136931): Difference between revisions
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(Created claim: summary (P836): AFTER YEARS OF INTENSE RESEARCH ACTIVITY, THE IDENTIFICATION OF ENZYMES WITH THE ABILITY TO PROMOTE HEALTHY AGING IS ONLY BEGINNING TO EMERGE. NADH-CYTOCHROME B5 REDUCTASE-3 (NADH:FERRICITOCROMO B5 OXYDORREDUCTASE, EC1.6.2.2, CYB5R3) IS A FLAVOPROTEIN THAT CATALYSES THE TRANSFER OF ELECTRONS FROM NADH TO CYTOCHROME B5 (CYB5) OR TO ALTERNATIVE ACCEPTORS SUCH AS PLASMA MEMBRANE COENZYME Q AND VARIOUS EXOGENOS COMPOUNDS. CYB5R3 INDUCEMENT IS REGULA...) |
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LONGEVITY EXTENSION MECHANISMS IN MICE OVEREXPRESSING CYB5R3, A NEW LONG-LIVED GENETIC MODEL | |||
Revision as of 13:41, 12 October 2021
Project Q3136931 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | LONGEVITY EXTENSION MECHANISMS IN MICE OVEREXPRESSING CYB5R3, A NEW LONG-LIVED GENETIC MODEL |
Project Q3136931 in Spain |
Statements
116,160.0 Euro
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145,200.0 Euro
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80.0 percent
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1 January 2016
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31 December 2019
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UNIVERSIDAD DE CORDOBA
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37°53'4.49"N, 4°46'33.64"W
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14021
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TRAS AÑOS DE INTENSA ACTIVIDAD INVESTIGADORA, LA IDENTIFICACION DE ENZIMAS CON LA CAPACIDAD DE PROMOVER UN ENVEJECIMIENTO SALUDABLE ESTA SOLO COMENZANDO A EMERGER. LA NADH-CITOCROMO B5 REDUCTASA-3 (NADH:FERRICITOCROMO B5 OXIDORREDUCTASA, EC1.6.2.2, CYB5R3) ES UNA FLAVOPROTEINA QUE CATALIZA LA TRANSFERENCIA DE ELECTRONES DESDE EL NADH HASTA EL CITOCROMO B5 (CYB5) O HASTA ACEPTORES ALTERNATIVOS COMO EL COENZIMA Q DE LA MEMBRANA PLASMATICA Y DISTINTOS COMPUESTOS EXOGENOS. LA INDUCCION DE CYB5R3 SE REGULA POR LA ACCION COORDINADA DE NRF2 Y FOXO3A EN RESPUESTA A FACTORES DE ESTRES AMBIENTAL Y NUTRICIONAL. CYB5R3 SE ENCUENTRA ALTAMENTE EXPRESADA EN CONDICIONES DE RESTRICCION CALORICA, Y SU SOBRE-EXPRESION EN RATONES TRANSGENICOS EXTIENDE LA LONGEVIDAD, AUMENTA LA SENSIBILIDAD A LA INSULINA Y MEJORA LA HOMEOSTASIS DE LA GLUCOSA, DISMINUYE LA INFLAMACION Y EL ESTRES OXIDATIVO, BAJA EL POTENCIAL DE MEMBRANA MITOCONDRIAL, Y PROTEGE A LOS RATONES FRENTE A LA INDUCCION DEL CANCER, SUGIRIENDO QUE LAS ESTRATEGIAS BASADAS EN CYB5R3 PUEDEN CONSTITUIR UNA INTERVENCION VIABLE PARA CONFERIR PROTECCION FRENTE A ENFERMEDADES METABOLICAS Y MEJORAR LA SALUD DE LOS INDIVIDUOS A LARGO PLAZO. LA EXPRESION DE GENES IMPLICADOS EN LA SINTESIS DE ACIDOS GRASOS TAMBIEN SE ENCUENTRA INCREMENTADA EN EL HIGADO DE LOS RATONES QUE SOBRE-EXPRESAN CYB5R3 QUE, A SU VEZ, TAMBIEN CONTIENEN UNA MAYOR PROPORCION DE ACIDOS GRASOS INSATURADOS DE CADENA LARGA. LOS ACIDOS GRASOS SON COMPONENTES QUE TAMBIEN PUEDEN INFLUENCIAR LA LONGEVIDAD DE LOS ANIMALES. HEMOS DEMOSTRADO PREVIAMENTE QUE LA COMPOSICION DE ACIDOS GRASOS DE LAS MEMBRANAS MODULA LAS FUNCIONES MITOCONDRIALES Y LA ACCION PRO-LONGEVIDAD DE LA RESTRICCION CALORICA. NUESTRA PROPUESTA VA DIRIGIDA A COMPROBAR LA HIPOTESIS DE QUE LOS EFECTOS SALUDABLES DE LA SOBRE-EXPRESION DE CYB5R3 RESULTAN DEL INCREMENTO DE ACIDOS GRASOS INSATURADOS DE CADENA LARGA Y DE UNA PRESERVACION OPTIMA DE LA FUNCION MITOCONDRIAL. NUESTRO OBJETIVO GENERAL SERA ELUCIDAR LOS MECANISMOS POR LOS CUALES LA SOBRE-EXPRESION DE CYB5R3 OPTIMIZA LAS FUNCIONES MITOCONDRIALES QUE MEJORAN DEL METABOLISMO Y LA LONGEVIDAD EN RATONES TRANSGENICOS CYB5R3. SE ABORDARAN LOS SIGUIENTES OBJETIVOS ESPECIFICOS: 1) DETERMINAR LA INFLUENCIA DE LA SOBRE-EXPRESION DE CYB5R3 SOBRE PROCESOS DE LA MEMBRANA MITOCONDRIAL QUE JUEGAN UN PAPEL RELEVANTE EN EL ENVEJECIMIENTO; 2) DETERMINAR UN PERFIL DE DIETA QUE MAXIMICE LA PRESERVACION MITOCONDRIAL POR SOBRE-EXPRESION DE CYB5R3; Y 3) INVESTIGAR EL PAPEL DE LAS ISOFORMAS DE CYB5 EN EL EFECTO SALUDABLE DE LA SOBRE-EXPRESION DE CYB5R3, Y DEFINIR NUEVOS FACTORES IMPLICADOS EN SU ACCION PRO-LONGEVIDAD EN UN MODELO CELULAR. NUESTRO PROYECTO ESTABLECERA UN PRIMER PASO PARA DEFINIR LAS DIANAS MITOCONDRIALES QUE MEDIAN EL EFECTO SALUDABLE DE UNA ACTIVIDAD CYB5R3 INCREMENTADA, Y AYUDARAN A ELUCIDAR LAS CONDICIONES EN QUE ESTE EFECTO SE PRODUCE DE MANERA OPTIMA. POR TANTO, NUESTRA INVESTIGACION PUEDE CONTRIBUIR A LA IDENTIFICACION DE ESTILOS DE VIDA SALUDABLES Y PATRONES NUTRICIONALES QUE ACTUEN SOBRE LOS SISTEMAS CELULARES Y MOLECULARES BASICOS QUE REGULAN EL ENVEJECIMIENTO PARA MANTENER UN ESTADO OPTIMO DE SALUD A MEDIDA QUE ENVEJECEMOS. NUESTRA PROPUESTA SE AJUSTA ADECUADAMENTE A LAS PRIORIDADES DEFINIDAS EN EL PLAN ESTATAL DE INVESTIGACION CIENTIFICA Y TECNICA, RETO 1.- SALUD, CAMBIO DEMOGRAFICO Y BIENESTAR, UNA PRIORIDAD TAMBIEN COMPARTIDA POR LA UNION EUROPEA (EUROPA 2020 ¿ POR UNA UNION EUROPEA MAS SALUDABLE). (Spanish)
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AFTER YEARS OF INTENSE RESEARCH ACTIVITY, THE IDENTIFICATION OF ENZYMES WITH THE ABILITY TO PROMOTE HEALTHY AGING IS ONLY BEGINNING TO EMERGE. NADH-CYTOCHROME B5 REDUCTASE-3 (NADH:FERRICITOCROMO B5 OXYDORREDUCTASE, EC1.6.2.2, CYB5R3) IS A FLAVOPROTEIN THAT CATALYSES THE TRANSFER OF ELECTRONS FROM NADH TO CYTOCHROME B5 (CYB5) OR TO ALTERNATIVE ACCEPTORS SUCH AS PLASMA MEMBRANE COENZYME Q AND VARIOUS EXOGENOS COMPOUNDS. CYB5R3 INDUCEMENT IS REGULATED BY THE COORDINATED ACTION OF NRF2 AND FOXO3A IN RESPONSE TO ENVIRONMENTAL AND NUTRITIONAL STRESS FACTORS. CYB5R3 IS HIGHLY EXPRESSED IN CONDITIONS OF CALORIC RESTRICTION, AND ITS OVER-EXPRESSION IN TRANSGENIC MICE EXTENDS LONGEVITY, INCREASES INSULIN SENSITIVITY AND IMPROVES GLUCOSE HOMEOSTASIS, DECREASES INFLAMMATION AND OXIDATIVE STRESS, LOWERS MITOCHONDRIAL MEMBRANE POTENTIAL, AND PROTECTS MICE AGAINST CANCER INDUCEMENT, SUGGESTING THAT CYB5R3-BASED STRATEGIES MAY CONSTITUTE A VIABLE INTERVENTION TO PROVIDE PROTECTION AGAINST METABOLIC DISEASES AND IMPROVE LONG-TERM HEALTH OF INDIVIDUALS. THE EXPRESSION OF GENES INVOLVED IN THE SYNTHESIS OF FATTY ACIDS IS ALSO INCREASED IN THE LIVER OF MICE OVEREXPRESSING CYB5R3 WHICH, IN TURN, ALSO CONTAIN A GREATER PROPORTION OF LONG-CHAIN UNSATURATED FATTY ACIDS. FATTY ACIDS ARE COMPONENTS THAT CAN ALSO INFLUENCE THE LONGEVITY OF ANIMALS. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMPOSITION OF FATTY ACIDS OF THE MEMBRANES MODULATES THE MITOCHONDRIAL FUNCTIONS AND THE PRO-LONGEVITY ACTION OF THE CALORIC RESTRICTION. OUR PROPOSAL AIMS TO TEST THE HYPOTHESIS THAT THE HEALTHY EFFECTS OF CYB5R3 OVER-EXPRESSION RESULT FROM THE INCREASE IN LONG-CHAIN UNSATURATED FATTY ACIDS AND AN OPTIMAL PRESERVATION OF MITOCHONDRIAL FUNCTION. OUR GENERAL OBJECTIVE WILL BE TO ELUCIDATE THE MECHANISMS BY WHICH CYB5R3 OVER-EXPRESSION OPTIMISES MITOCHONDRIAL FUNCTIONS THAT IMPROVE METABOLISM AND LONGEVITY IN CYB5R3 TRANSGENIC MICE. THE FOLLOWING SPECIFIC OBJECTIVES WILL BE ADDRESSED: 1) DETERMINE THE INFLUENCE OF CYB5R3 OVER-EXPRESSION ON MITOCHONDRIAL MEMBRANE PROCESSES THAT PLAY A RELEVANT ROLE IN AGING; 2) DETERMINE A DIET PROFILE THAT MAXIMISES MITOCHONDRIAL PRESERVATION BY OVER-EXPRESSION OF CYB5R3; AND 3) INVESTIGATE THE ROLE OF CYB5 ISOFORMS IN THE HEALTHY EFFECT OF CYB5R3 OVER-EXPRESSION, AND DEFINE NEW FACTORS INVOLVED IN ITS PRO-LONGEVITY ACTION IN A CELL MODEL. OUR PROJECT WILL ESTABLISH A FIRST STEP IN DEFINING THE MITOCHONDRIAL TARGETS THAT MEDIATE THE HEALTHY EFFECT OF AN INCREASED CYB5R3 ACTIVITY, AND HELP ELUCIDATE THE CONDITIONS UNDER WHICH THIS EFFECT OCCURS OPTIMALLY. THEREFORE, OUR RESEARCH CAN CONTRIBUTE TO THE IDENTIFICATION OF HEALTHY LIFESTYLES AND NUTRITIONAL PATTERNS THAT ACT ON THE BASIC CELLULAR AND MOLECULAR SYSTEMS THAT REGULATE AGING TO MAINTAIN AN OPTIMAL STATE OF HEALTH AS WE AGE. OUR PROPOSAL FITS APPROPRIATELY WITH THE PRIORITIES DEFINED IN THE STATE PLAN OF SCIENTIFIC AND TECHNICAL RESEARCH, CHALLENGE 1.- HEALTH, DEMOGRAPHIC CHANGE AND WELL-BEING, A PRIORITY ALSO SHARED BY THE EUROPEAN UNION (EUROPE 2020 FOR A HEALTHIER EUROPEAN UNION). (English)
12 October 2021
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Córdoba
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Identifiers
BFU2015-64630-R
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