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Principal Investigator: Pankaj Kapahi
Organization: BUCK INSTITUTE FOR RESEARCH ON AGING
Fiscal Year: 2024
Award: $745,418
Funding agency: National Institute on Aging
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.
Terms: <Acceleration><Address><Affect><Age><Aging><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Blindness><Body Tissues><Calories><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><ChIP assay><Circadian Rhythms><Cues><Cyclicity><Darkness><Data Set><Diabetic Retinopathy><Diet><Disease><Disorder><Dysfunction><Elderly><Evolution><Eye><Eye diseases><Eyeball><Flies><Functional disorder><GWA study><GWAS><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Polymorphism><Genetic Transcription><Goals><Health><Homeostasis><Housing><Human><Increase lifespan><Intervention><Intervention Strategies><Light><Light Signal Transduction><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Morphology><Murine><Mus><Nutrient><Nyctohemeral Rhythm><Obesity><Ortholog><Orthologous Gene><Outcome><Outcome Study><Output><Overnutrition><Pathway interactions><Periodicity><Peripheral><Photoradiation><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Phototransduction><Physiological Homeostasis><Physiopathology><Pigments><Population><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Retina><Rhodopsin><Rhythmicity><Risk><Risk Factors><Role><Sight><Subcellular Process><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Twenty-Four Hour Rhythm><Vision><Visual><Visual Purple><Visual Receptor><Visual System><Visual Transduction><accelerated aging><accelerated biological age><accelerated biological aging><adiposity><advanced age><age acceleration><age associated><age associated alterations><age associated changes><age associated decline><age associated effects><age clock><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age dependent decline><age effect><age linked><age related><age related alterations><age related changes><age related decline><age related effects><age specific><age specific alterations><age specific changes><ages><aging clocks><aging effect><alterations with age><base><bases><changes with age><chromatin immunoprecipitation><circadian><circadian clock><circadian pacemaker><circadian process><circadian transcriptome><clock measuring biological age><clock measuring biological aging><clock of biological aging><corpulence><daily biorhythm><death risk><decline with age><deep sequencing><diet restriction><dietary restriction><diets><elongating the lifespan><extend life span><extend lifespan><eye disorder><fly><fundus imaging><gene conservation><gene network><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><geriatric><health-span><healthspan><healthy life span><impact of age><influence of age><insight><interventional strategy><life span><life style intervention><lifespan><lifespan extension><lifestyle intervention><molecular clock><mortality risk><novel><ocular disease><ocular disorder><older adult><older adulthood><ophthalmopathy><pathophysiology><pathway><photoreceptor degeneration><pigment><polymorphism><prevent><preventing><protective effect><response><restricted diet><senescence><senescent><senior citizen><social role><systemic inflammation><systemic inflammatory response><therapeutic target><transcription factor><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><vision loss><visual function><visual loss><visual photoreceptor><whole genome association analysis><whole genome association studies><whole genome association study>