Metabolic Adaptations to Aerobic Exercise in Aged Mice

Abstract Aerobic exercise training is a potent intervention for the treatment and prevention of age-related disease, such as heart disease, obesity, and Type 2 Diabetes. Insulin resistance, a hallmark of Type 2 Diabetes, is reversed in response to aerobic exercise training. However, the effect of aerobic exercise training on glucagon sensitivity is unclear. Glucagon signaling at the liver promotes fatty acid oxidation, inhibits De novo lipogenesis, and activates AMP Kinase, a key mediator of healthy aging. Like humans, aging in mice age leads to a decline in physical and metabolic function. To understand the role of glucagon signaling in exercise-induced improvements in physical and metabolic function in the mouse, we implemented a 16-week aerobic exercise training protocol in young and aged mice. 16 weeks of exercise training initiated at 6 months of age increased markers of physical function (P<0.01) and attenuated age-related weight gain (P<0.05) and fat mass (P<0.0001). Additionally, exercise training improved glucose clearance (P<0.01), enhanced glucose-stimulated insulin secretion (P<0.01) and decreased hepatic lipid accumulation (P<0.05). Importantly, exercise training decreased hypoglycemia stimulated glucagon secretion (P<0.01), with no effect on hepatic glucagon receptor mRNA expression or serum glucagon. Thus, we propose that aerobic exercise training enhances glucagon sensitivity at the liver, implicating glucagon as a potential mediator of exercise-induced improvements in aging. Studies initiating the same aerobic exercise training intervention at 18 months of age in the mouse are currently underway to establish the role of glucagon receptor signaling in exercise-induced improvements in aging.

We found significant decreases in CD20+ B cells and CD3+/ CD4+ T cell proportions with age, suggesting diminished antibody production and adaptive immune responses in older individuals.Age-associated increases in CD3+/CD8+, CD3+/CD4+/CD25+ T regulatory cells and CD14-/CD16+/ HLA-DR+ non-classical monocytes indicated heightened baseline inflammation in older animals.Social adversity recapitulated the effects of aging in CD14+/CD16-/HLA-DR+ classical monocytes, indicating immune deficits in phagocytosis and pathogen clearance in older and lower status individuals.Using RNA-seq, our stimulations (n=1,320) will allow us to identify molecular immune pathways that are disrupted by age and social adversity, similarities in response between age and adversity, and how the effect of adversity varies across the lifespan.

LOSS OF AWARENESS OR URINARY DYSFUNCTION? INVESTIGATING AMYLOIDOSIS AND URINARY PHYSIOLOGY IN A TRANSGENIC MOUSE
Cara Hardy, 1 Ramalakshmi Ramasamy, 1 Dawn Rosenberg, 1 Philip Scarpa, 1 Xiangyou Hu, 1 George Kuchel, 2 and Phillip Smith, 1 1.UConn Health,Farmington,Connecticut,United States,2. University of Connecticut Health,Farmington,Connecticut,United States Alzheimer's disease (AD) is a devastating disorder primarily affecting older adults and is the most common neurodegenerative disease in the US.More than one in three AD patients experience AD-associated urinary dysfunction (ADUD), which directly contributes to their institutionalization.While ADUD has been clinically regarded as a result of poor cognitive control over urinary function, the physiology underlying loss of urinary control remains unknown.We hypothesize that amyloidosis in the CNS results in pathologic changes in urinary structure and function.Tg-APP/PS1DE9 mice were used before plaque deposition (4-6 months) and after plaque accumulation (8-10 months) and compared to WT littermates.Behavioral assays (open field testing and voiding spot assays) were performed to assess cortical function.Pressure-flow cystometry was conducted under urethane anesthesia to assess autonomic control of urinary function without cortical influence.Pharmacomyography of bladder strips was used to determine tissue-level changes in the absence of CNS input.In Tg-APP/PS1DE9 mice, plaque accumulation resulted in significant cystometric changes to voiding phase parameters, but not storage phase parameters.Pharmacologic studies showed decreased sensitivity to adrenergic stimulation without change in muscarinic sensitivity.Behavioral assays demonstrated significant differences between transgenic animals and WT in locomotion and voiding spot sizes.We interpret our data to support AD-related pathology of Aβ accumulation results in a distinct urinary phenotype in our model, analogous to the ADUD observed in AD patients.Establishing and verifying models of ADUD may improve the efficacy of treating ADUD and increase quality of life for patients and their caregivers.Recognizing frailty in primary care is important to implement personalized care pathways and for prognostication.The aim of this study was to build and validate a frailty index based on routinely collected primary care data in Italy.We used clinical data from 308,280 Italian primary care patients 60+ with at least 5 years of follow-up, part of the Health Search Database.A heuristic algorithm was used to select the deficits to be included in a highly performant frailty index.The fitness of the index was assessed through the c-statistics derived by survival models.Results were externally validated using the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K).After testing 3.4 million of deficits combinations, 25 deficits were selected to be included in the Health Search Frailty Index (HS-FI).After adjusting by sex, age and geographical area, the HS-FI was associated with 5-year mortality (HR per 0.1 increase 1.99; 95%CI 1.95-2.02)and hospitalization rate (HR per 0.1 increase 1.25; 95%CI 1.23-1.27).In the external validation cohort, HS-FI independently predicted mortality, hospitalization, incident disability, incident dementia, and incident falls.This is the first frailty index built following a data-driven approach, using national representative primary care data.The implementation of such tool -derived by routinely collected datain primary care software will ease the prompt, comparable and reliable recognition of frailty at the population level.

METABOLOMICS-BASED BIOMARKERS FOR FRAILTY IN CHINESE OLDER ADULTS
Yiming Pan, 1 Pan Liu, 2 Yun Li, 2 and Lina Ma, 2 1.Capital Medical University Xuanwu Hospital, Beijing,Beijing,China (People's Republic),2. Xuanwu Hospital,Capital Medical University,National Research Center for Geriatric Medicine,Beijing,Beijing,China (People's Republic) Background: Frailty is a clinical state characterized by decline in physiological function, and increased vulnerability to adverse outcomes.The biological mechanisms underlying frailty have been extensively studied in recent years.Advances in the multi-omics platforms have provided new information on the molecular mechanisms of frailty.Thus, identifying omics-based biomarkers is helpful for both exploring the physiological mechanisms of frailty and evaluating the risk of frailty development and progression.Objective: To identify metabolomics biomarkers and possible pathogenic mechanisms for frailty with untargetedmetabolomics profiling.Methods: LC-MS-based untargeted metabolomics analysis was performed on serum samples of 25 frail older inpatients and 49 non-frail older controls.The metabolomics profiling was compared between the two groups.Results: We identified 349 metabolites belonging to 46 classes, in which 2 were increased and 3 were decreased in frail older adults.Citrate cycle (with up-regulated cis-Aconitic acid, Fumaric acid, L-Malic acid, and Isocitric acid), fatty acid metabolism (with up-regulated Palmitic acid and L-Palmitoylcarnitine) and tryptophan metabolism (with up-regulated 5-Hydroxy-L-tryptophan, L-Kynurenine, Kynurenic acid, and 5-Hydroxyindoleacetic acid) were significantly associated with frailty phenotype.Conclusions: Our results revealed characteristics of metabolites of frailty in Chinese older adults.The citrate cycle related metabolites (Isocitrate, (s)-Malate, Fumarate and cis-Aconitate), saturated fat (Palmitic acid), unsaturated fatty acid (Arachidonate and Linoleic acid), and some essential amino acid (Tryptophan) might be candidate biomarkers for early diagnosis of frailty.Disorders of energy metabolism, lipotoxicity of saturated fatty acids, disturbances of unsaturated fatty acid metabolism, and increased degradation of tryptophan were potential mechanisms and therapeutic targets of frailty.

THE ASSOCIATION BETWEEN METABOLIC SYNDROME AND FRAILTY IN HEALTHY COMMUNITY-DWELLING OLDER ADULTS
A R M Saifuddin Ekram, 1 Sara Espinoza, 2 Michael Ernst, 3 Lawrence Beilin, 4 Nigel P. Stocks, 5 Joanne Ryan, 6 and

4395 (Paper) Frailty Measurement CONSTRUCTION AND VALIDATION OF A FRAILTY INDEX IN PRIMARY CARE IN ITALY: THE HEALTH- SEARCH FRAILTY INDEX
Tyler Marx, Anastasiia Vasileva, Stephen Hutchison, and Jennifer Stern, University of Arizona, Tucson, Arizona, United States Aerobic exercise training is a potent intervention for the treatment and prevention of age-related disease, such as heart disease, obesity, and Type 2 Diabetes.Insulin resistance, a hallmark of Type 2 Diabetes, is reversed in response to aerobic exercise training.However, the effect of aerobic exercise training on glucagon sensitivity is unclear.Glucagon signaling at the liver promotes fatty acid oxidation, inhibits De novo lipogenesis, and activates AMP Kinase, a key mediator of healthy aging.Like humans, aging in mice age leads to a decline in physical and metabolic function.To understand the role of glucagon signaling in exercise-induced improvements in physical and metabolic function in the mouse, we implemented a 16-week aerobic exercise training protocol in young and aged mice.16 weeks of exercise training initiated at 6 months of age increased markers of physical function (P<0.01) and attenuated age-related weight gain (P<0.05) and fat mass (P<0.0001).Additionally, exercise training improved glucose clearance (P<0.01),enhanced glucose-stimulated insulin secretion (P<0.01) and decreased hepatic lipid accumulation (P<0.05).Importantly, exercise training decreased hypoglycemia stimulated glucagon secretion (P<0.01), with no effect on hepatic glucagon receptor mRNA expression or serum glucagon.Thus, we propose that aerobic exercise training enhances glucagon sensitivity at the liver, implicating glucagon as a potential mediator of exercise-induced improvements in aging.Studies initiating the same aerobic exercise training intervention at 18 months of age in the mouse are currently underway to establish the role of glucagon receptor signaling in exercise-induced improvements in aging.