nephrosclerosis patients (GFR > 30 mL/min/1.73m 2 , 2017-2023) were examined for tubular PCK1 in younger (n = 15) and older (n = 20) groups.Results: Young CKD mice showed no muscle loss, whereas aged CKD mice displayed marked declines in mass, strength, and endurance.HFD + L-NAME alone did not cause sarcopenia, but its combination with CKD did, indicating that aging or metabolic stress interacts with renal dysfunction.Gluconeogenesis was preserved in young CKD mice but markedly reduced in aged CKD and HFD + L-NAME + CKD groups.Although the liver did not exhibit steatosis, hepatic G6PC and PCK1 were decreased with substrate accumulation, and compensatory renal gluconeogenesis was lost, causing global glucose reduction.Liver RNA-seq showed suppressed PPAR signaling and activated inflammatory pathways resembling aged liver.In muscle, reduced glycolytic genes (Mlxipl, HK2) and metabolites indicated impaired glucose use and fasting-induced energy deficit.Cornstarch feeding improved fasting glucose, muscle parameters, and frailty-like appearance.Even aged mice without CKD showed reduced renal gluconeogenesis and glucose output.In human kidneys, tubular PCK1 was lower in older subjects despite preserved GFR, accompanied by hypoalbuminemia and weight loss-features of frailty.Conclusion: Aging and metabolic stress impair hepatic and renal gluconeogenesis, leading to systemic glucose shortage and muscle energy loss.Renal gluconeogenic failure thus links CKD, aging, and frailty and represents a potential target to preserve energy balance and prevent sarcopenia.I have no potential conflict of interest to disclose.I used generative AI and AI-assisted technologies in the writing process.During the preparation of this work the author(s) used ChatGPts in order to improve readability and language.After using this tool/service,
Abdallah et al. (Wed,) studied this question.