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Principal Investigator: Russell T Hepple
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $499,863
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
Physical frailty (hereafter simplified to “frailty”) refers to a clinical state associated with an
individual’s increased risk of dependence or mortality when exposed to a stressor and has
emerged as a major predictor of poor health outcomes in the elderly. Unfortunately, the
mechanisms contributing to the exacerbation of normal aging that precipitates frailty are largely
unknown. In this regard, recent epidemiological studies find that elevated circulating levels of
kynurenine, a product of tryptophan metabolism that accumulates in blood with aging, strongly
associate with poor physical function and elevated risk of frailty. However, a causal relationship
between elevated kynurenine and poor physical function/frailty has not been tested. Our
preliminary data show that kynurenine causes atrophy and impaired mitochondrial function in
skeletal muscle cells that can be rescued by increasing the capacity for kynurenine
biotransformation into the neuroprotective metabolite, kynurenic acid. Since kynurenine is also an
agonist of the ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR),
it is noteworthy that we find that transcripts regulated by the AHR are upregulated in aging muscle,
and that AHR knockdown blunts kynurenine-induced mitochondrial dysfunction. Finally, we also
show that chronic AHR activity alone is sufficient to induce atrophy, mitochondrial dysfunction and
neuromuscular junction degeneration in young mice, which are hallmarks of aging that are
exacerbated in frailty. On this basis, the first goal of this project is to determine if elevated
kynurenine levels accelerate the physical function decline and frailty with aging in mice. Secondly,
we will determine if enhancing kynurenine metabolism attenuates the decline of physical function
and frailty with aging in mice, with or without elevated kynurenine. Thirdly, we will test if knockout
of the AHR attenuates the decline of physical function and frailty with aging in mice, with or without
elevated kynurenine. Finally, we will test if chronic AHR activity in muscle alone is sufficient to
accelerate physical function decline and frailty with aging in mice. By doing so, our studies will lay
the foundation for future testing of therapies that augment kynurenine metabolism and/or inhibit
the AHR as a means of attenuating frailty with aging.
Terms: <2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors><3-hydroxykynurenine transaminase><AH Receptors><Acceleration><Active Oxygen><Aging><Agonist><Aryl Hydrocarbon Receptor><Atrophic><Atrophy><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Binding><Biotransformation><Blood><Blood Reticuloendothelial System><Body Tissues><Body Weight><Catabolism><Cell Body><Cells><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Research><Clinical Study><Coupled><Cytochrome P-450><Cytochrome P-450 Enzyme System><Cytochrome P450><Cytochrome P450 Family Gene><Cytosol><Data><Denervation><Dependence><Deterioration><Diet><Dimensions><Dioxin Receptors><Disease><Disorder><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Dysfunction><Elderly><Enzyme Gene><Enzymes><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Exposure to><FDA approved><Foundations><Frail Elderly><Frail Elders><Frail Older Adults><Frail Seniors><Functional disorder><Future><GOT2><GOT2 gene><General Transcription Factor Gene><General Transcription Factors><Genetic Models><Goals><Grip strength><Hand Strength><Health><Human><Impairment><In Situ><Individual><Intermediary Metabolism><Isoforms><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Kynurenic Acid><Kynurenine><Kynurenine-oxoglutarate aminotransferase><L-Tryptophan><Learning><Levotryptophan><Life Expectancy><Ligands><Link><Metabolic><Metabolic Biotransformation><Metabolic Drug Detoxications><Metabolic Processes><Metabolism><Metabolism of Toxic Agents><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Modernization><Molecular Interaction><Morbidity><Morbidity - disease rate><Motor><Motor Cell><Motor Neurons><Murine><Mus><Muscle><Muscle Atrophy><Muscle Fibers><Muscle Tissue><Muscular Atrophy><Myoneural Junction><Myotubes><Neuromuscular Junction><Nuclear Translocator><Null Mouse><Outcome><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><P450><Pathway interactions><Phenotype><Physical Function><Physiologic><Physiological><Physiopathology><Polyaromatic Hydrocarbon Receptors><Predisposition><Pro-Oxidants><Protein Cleavage><Protein Isoforms><Proteolysis><QOL><Quality of life><Reactive Oxygen Species><Receptor Activation><Reporting><Research><Resveratrol><Rhabdomyocyte><Risk><Rodent><Rodentia><Rodents Mammals><Role><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Susceptibility><TCDD Receptors><Testing><Tissues><Transcript><Transcription Factor Proto-Oncogene><Transcription factor genes><Tryptophan><Tryptophan Metabolism><Tryptophan Metabolism Pathway><Voluntary Muscle><Work><accelerated aging><accelerated biological age><accelerated biological aging><advanced age><age acceleration><age associated decline><age dependent decline><age related decline><aged muscle><aging of muscle><ahr ligand><antagonism><antagonist><aryl hydrocarbon receptor ligand><attenuate><attenuates><chronic disorder><decline with age><detoxification><diets><drug detection><drug testing><epidemiologic investigation><epidemiology study><exercise training><frail older adult><frailty><geriatric><hallmarks of aging><health-span><healthspan><healthy aging><healthy human aging><healthy life span><indexing><inhibitor><knock-down><knockdown><kynurenine aminotransferase><kynurenine-oxoglutarate transaminase><loss of function><mitochondrial><mitochondrial dysfunction><mortality><motoneuron><muscle aging><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle wasting><muscular><natural aging><nerve cell death><nerve cell loss><neuromuscular><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuroprotection><neuroprotective><normal aging><normative aging><older adult><older adulthood><pathophysiology><pathway><pillars of aging><poor health outcome><reduced health outcome><sarcopenia><sarcopenic><senior citizen><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><social role><stressor><therapeutic target><transcription factor><walking pace><walking speed><worse health outcome>