THERAPEUTICAL MODULATION OF THE MICROGLIA-NEURONAL INTERACTION BY CHRONOKINES TO TREAT CHRONIC BRAIN INFLAMMATION ASSOCIATED WITH AGING

AGING IS A MULTIFACTORIAL PROCESS RESULTING IN THE PROGRESSIVE AND IRREVERSIBLE TIME-DEPENDENT FRAGILITY AND DETERIORATION OF BIOLOGICAL FUNCTIONAL DRIVERS THAT TYPICALLY KEEP ORGANS AND TISSUES HEALTHY. IN THE BRAIN, AGING IS ASSOCIATED WITH A GREATER FRAGILITY OF NEURONAL PHYSIOLOGY. THIS GREATER FRAGILITY LEADS NOT ONLY TO THE DEVELOPMENT OF COGNITIVE DEFICITS AND MILD COGNITIVE IMPAIRMENT, BUT TO A GREATER PREDISPOSITION TO NEURODEGENERATIVE DISEASES, LIKE ALZHEIMER'S DISEASE (AD). CURRENT TREATMENTS FOR SOME OF THE MOST SERIOUS DISEASES OF AGING HAVE BEEN LARGELY UNSUCCESSFUL AND USUALLY ONLY PROVIDE SYMPTOMATIC RELIEF. IN THIS CONTEXT, FASCINATING FUNDAMENTAL STUDIES USING YOUNG PLASMA INJECTIONS INTO OLD ANIMALS HAVE DEMONSTRATED THAT AGING IS MALLEABLE AND THAT DIFFERENT SOLUBLE FACTORS, CALLED CHRONOKINES, WHICH LEVELS IN PLASMA CHANGE WITH AGING, ACT AS BIOLOGICAL DRIVERS OF FUNCTION AND HAVE THE ABILITY TO RESTORE MUSCULAR, HEPATIC AND VASCULAR FUNCTIONS IN OLD ANIMALS. THE RESULTS GENERATED BY OUR RESEARCH GROUP DEMONSTRATE THE THERAPEUTIC BENEFITS OF KLOTHO AND HEBE CHRONOKINES ON NEURONS TO IMPROVE COGNITIVE DECLINE ASSOCIATED WITH BOTH AGING AND NEURODEGENERATION. TAKING INTO ACCOUNT THIS, TOGETHER WITH THE KEY ROLE PLAYED BY MICROGLIA IN GOVERNING NEUROINFLAMMATION, OUR STARTING HYPOTHESIS IS THAT BESIDES NEURONS CHRONOKINES WILL ALSO IMPACT MICROGLIAL CELLS BY: (I) IMPROVING THEIR FUNCTIONING AND (II) REDUCING CHRONIC BRAIN INFLAMMATION, WHICH WILL FINALLY RESULT IN A HEALTHIER BRAIN AGING. TO DEMONSTRATE THIS HYPOTHESIS OUR MAIN OBJECTIVES ARE: (AIM 1), MORPHOLOGICAL AND FUNCTIONAL IN VITRO STUDY OF MODIFICATIONS IN MICROGLIA INDUCED BY CHRONOKINES; (AIM 2), IN VIVO ANALYSIS OF LONG-TERM (PREVENTIVE AND THERAPEUTIC) CHRONOKINE’S EXPOSURE TO RESCUE MICROGLIAL FUNCTIONING DURING CHRONIC BRAIN INFLAMMATION ASSOCIATED WITH AGING. (AIM 3), INTEGRATIVE FUNCTIONAL MODEL OF CHRONOKINES IN THE MICROGLIA-NEURONAL INTERACTION. TO ADDRESS IT SUCCESSFULLY: (I) WE HAVE A TEAM CONSISTING OF 7 MEMBERS (RESEARCHERS, TECHNICIANS AND PHD STUDENTS) WITH A LONG AND PROVEN EXPERIENCE IN MOLECULAR BIOLOGY AND BIOCHEMICAL ANALYSIS, ANIMAL EXPERIMENTATION, ADVANCED THERAPIES, AND RESEARCH IN CNS; (II) WE WILL USE STATE-OF-THE-ART EQUIPMENT AND FACILITIES; AND (III) WE WILL USE A TRANSVERSAL INNOVATIVE APPROACHES FROM FIELDS AS DIVERSE AS BIOCHEMISTRY AND MOLECULAR BIOLOGY, HEALTH SCIENCES, AND ARTIFICIAL INTELLIGENCE. IT IS THEREFORE EXPECTED THAT RELEVANT RESULTS BE OBTAINED WITH OBVIOUS TECHNICAL APPLICATIONS. IN SUMMARY, µ-4-WELL-AGING IS A PROJECT WITH OBVIOUS SOCIAL AND HEALTH CONNOTATIONS BECAUSE IT IS FOCUSED ON VERY PREVALENT PATHOLOGIES SUCH AS THOSE ASSOCIATED WITH AGING AS CHRONIC BRAIN INFLAMMATION, AND NEURODEGENERATIVE DISEASES INCLUDING AD. IT IS, THEREFORE, AN AMBITIOUS PROJECT, THOUGH WE BELIEVE THE TRAJECTORY OF THE RESEARCH TEAM MAKES IT VIABLE.