Project Grant R01AG071995

THE ROLE OF DIET AND AGING IN PHOTORECEPTOR HOMEOSTASIS AND VISUAL FUNCTION DECLINE - PROJECT SUMMARY/ABSTRACT MORE THAN HALF OF THE ELDERLY POPULATION SUFFER FROM AGE-RELATED EYE DISORDERS THAT COMPROMISE THEIR ABILITY TO PERFORM DAILY ACTIVITIES. AGING IS A SIGNIFICANT RISK FACTOR FOR SUCH DISORDERS, AND DIETARY RESTRICTION (DR) IS A ROBUST INTERVENTION THAT CAN SLOW AGING AND EXTEND HEALTHSPAN. NUTRIENT RESTRICTION INCREASES CIRCADIAN CLOCK AMPLITUDE, WHILE OVERNUTRITION AND OBESITY DAMPEN CIRCADIAN RHYTHMS, INCREASING THE RISK OF EYE DISEASES. HOWEVER, THE ROLE OF DR AND CIRCADIAN CLOCKS IN SLOWING AGE-RELATED DECLINE IN VISUAL FUNCTION IS NOT WELL UNDERSTOOD. THEREFORE, IT IS IMPERATIVE TO ADDRESS THIS GAP IN THE FIELD. THE GOAL OF THIS PROPOSAL IS TO DETERMINE THE MOLECULAR MECHANISMS THAT SLOW AGE-RELATED LOSS OF THE VISUAL SYSTEM, DEPENDING ON AGING AND DIET. WE HYPOTHESIZE THAT DR ENHANCES CIRCADIAN CLOCK GENE EXPRESSION, PROMOTING PHOTORECEPTOR HOMEOSTASIS, AND MODULATING LIFESPAN. OUR RECENT CIRCADIAN TRANSCRIPTOME PROFILING UPON DR SHOWED ENHANCEMENT OF GENES INVOLVED IN PHOTORECEPTOR HOMEOSTASIS AND DELAYED VISUAL SENESCENCE. PRIOR RESULTS SUGGEST THAT AGING LEADS TO A GRADUAL DECLINE IN CIRCADIAN RHYTHMS; HOWEVER, DR CAN SLOW THIS DECLINE. INHIBITION OF THE CIRCADIAN TRANSCRIPTION FACTOR, CLOCK (CLK), ACCELERATES THE AGE-RELATED DECLINE IN VISUAL FUNCTION, AND PHOTORECEPTOR DEGENERATION RESULTS IN SYSTEMIC INFLAMMATION AND SHORTENED LIFESPAN, WHICH DR PROTECTS AGAINST. WE HYPOTHESIZE THAT CLK PREVENTS LIGHT-INDUCED DAMAGE TO THE PHOTORECEPTORS, THUS SUPPORTING THE 'ESCAPE THE LIGHT HYPOTHESIS' FOR THE EVOLUTION OF CIRCADIAN CLOCKS. IN THIS STUDY, WE AIM TO DETERMINE THE CELLULAR PROCESSES IN PHOTORECEPTORS THAT PROTECT THEM FROM DAMAGE DUE TO AGE AND DIET, REVEALING NOVEL TARGETS FOR AGE-RELATED EYE DISEASES AND ASSOCIATED MORBIDITIES. WE PROPOSE THREE SPECIFIC AIMS TO ACHIEVE THIS GOAL. FIRST, WE WILL DETERMINE DOWNSTREAM EFFECTORS OF THE CORE CIRCADIAN CLOCK GENE, CLK, ALTERING THE AGE-RELATED DECLINE IN VISUAL SYSTEM FUNCTION UPON MODULATION OF DIET AND LIGHT. SECOND, WE WILL DETERMINE DIET-DEPENDENT TRANSCRIPTIONAL NETWORKS OF RHYTHMIC PHOTOTRANSDUCTION GENES AND THEIR IMPACT ON AGE-RELATED CHANGES IN VISUAL SYSTEM FUNCTION. THIRD, WE WILL STUDY FLY ORTHOLOGS OF GENES FROM OUR HUMAN GWAS STUDY THAT INFLUENCE RETINAL EYE AGING FOR THEIR INTERACTIONS WITH DIET, AGING, AND CIRCADIAN CLOCKS USING THE FLY. EXPECTED OUTCOMES OF THIS STUDY INCLUDE DELINEATING THE DIET AND AGING-DEPENDENT GENES INCLUDING CIRCADIAN TRANSCRIPTIONAL NETWORKS AND THEIR OUTPUTS INVOLVED IN PHOTOTRANSDUCTION HOMEOSTASIS TO MEDIATE CHANGES IN VISUAL SENESCENCE IN FLIES AND HUMANS. BY DETERMINING CELLULAR PROCESSES UNDER CIRCADIAN CONTROL IN THE PHOTORECEPTOR THAT PROTECT IT FROM DAMAGE DUE TO AGE, DIET, AND LIGHT, THIS STUDY WILL REVEAL NOVEL GENETIC TARGETS AND LIFESTYLE INTERVENTIONS MODULATING THE EFFECT OF DIET AND AGE ON EYE FUNCTION, PROVIDING POTENTIAL TREATMENT OPTIONS FOR AGE-RELATED EYE DISEASES AND ASSOCIATED MORBIDITIES.