Project Grant R01AG088223

TISSUE MECHANISMS OF AGING IN THE GENETIC MODEL C. ELEGANS - PROJECT SUMMARY/ABSTRACT THE NEMATODE C. ELEGANS IS A LEADING EXPERIMENTAL AND GENETIC MODEL FOR AGING, AND BOTH PUBLIC AND PRIVATE INSTITUTIONS HAVE MADE ENORMOUS INVESTMENTS IN AGING RESEARCH IN THIS SYSTEM. SEVERAL LINES OF EVIDENCE SHOW THAT THE INTESTINE IS THE MAJOR TISSUE AFFECTING HEALTHY LIFESPAN IN C. ELEGANS. THE INTESTINE IS LIKELY TO BE A SENSITIVE AND EARLY INDICATOR OF AGE-DEPENDENT CELLULAR STRESS, AS THE INTESTINE LACKS AN APOPTOSIS PATHWAY OR STEM CELL POPULATION TO REMOVE OR REPLACE DAMAGED CELLS. INTESTINAL NUCLEI HAVE BEEN SHOWN TO UNDERGO PROGRESSIVE DETERIORATION DURING AGING, INCLUDING THE LOSS OF ENTIRE NUCLEI. OLD, ABNORMAL INTESTINAL NUCLEI SHOW A LOSS OF PERIPHERAL HETEROCHROMATIN, A DISRUPTION OF CHROMOSOMAL ORGANIZATION, AND THE ACCUMULATION OF INTRANUCLEAR BODIES THAT CONTAIN THE PROTEIN LAMIN. RECENT STUDIES SHOWED THAT SOME INTESTINAL NUCLEI SHOW ABNORMALITIES AS EARLY AS THE FIRST TWO DAYS OF ADULTHOOD, AND THAT THESE EARLY ABNORMALITIES INCLUDE THE FORMATION OF LAMIN-CONTAINING NUCLEAR BODIES AND THE LOSS OF PERIPHERAL HETEROCHROMATIN. BECAUSE THESE DEFECTS OCCUR EARLY IN DEVELOPMENT, THEY ARE LIKELY TO REPRESENT CRITICAL EVENTS THAT DRIVE NUCLEAR DETERIORATION DURING AGING, RATHER THAN INDIRECT CONSEQUENCES OF AGE-COMPROMISED CELLS. SOME OF THE INTRANUCLEAR LAMIN AND LOSS OF PERIPHERAL HETEROCHROMATIN IS ASSOCIATED WITH FAT ACCUMULATION IN THE NUCLEUS, CALLED NUCLEAR LIPID DROPLETS OR NLDS. RECENT STUDIES HAVE SHOWN THAT DIVERSE LIVER DISEASES IN HUMANS ARE ASSOCIATED WITH INCREASED NUMBERS OF NLDS, AND NLDS IN C. ELEGANS HAVE BEEN SHOWN TO INCREASE DURING AGING. NLDS IN OTHER SYSTEMS SHOW A COMPLEX RELATIONSHIP WITH FAT, AND NLDS IN THE C. ELEGANS INTESTINE APPEAR TO BE CORRELATED WITH CHANGES IN LIPID STORAGE THAT OCCUR DURING REPRODUCTIVE DEVELOPMENT. THIS PROPOSAL INVESTIGATES THE ORIGIN OF INTRANUCLEAR LAMIN IN INTESTINAL CELLS, ITS RELATIONSHIP TO NLDS, AND THE ROLE OF LIPID STORAGE. THE RESEARCH USES C. ELEGANS TOOLS FOR FORWARD AND REVERSE GENETICS TO IDENTIFY PATHWAYS THAT CAUSE, OR ACT TO REMOVE, THE INTRANUCLEAR LAMIN. THE PROJECT ANALYZES SPECIFIC ROLES FOR TWO GENES WHICH ARE INVOLVED IN NLD FORMATION AND THAT ARE CONSERVED IN HUMANS. THE LONG-TERM GOAL OF THE PROJECT IS TO DEVELOP STRATEGIES THAT MODULATE THESE PATHWAYS TO INTERVENE IN AGE-ASSOCIATED TISSUE DETERIORATION.