Renal Gluconeogenesis Failure as a Metabolic Driver of Sarcopenia and Frailty in Aging and CKD

Metabolic imbalance is a key driver of senescence. Renal proximal tubular cells possess intrinsic gluconeogenic capacity, and its loss has been reported in chronic kidney disease (CKD), although systemic effects remain unclear. CKD promotes multisystem aging and frailty and is considered a model of premature aging. We hypothesized that renal metabolic decline disrupts systemic glucose homeostasis and accelerates senescence. Sarcopenia, an aging-related disorder, is strongly associated with CKD, yet young CKD mice rarely show muscle atrophy. As most CKD patients harbor multiple metabolic and age-related risks, we assumed that aging or metabolic stress forms a vulnerable background on which renal dysfunction synergistically accelerates systemic senescence. We confirmed rapid sarcopenia in aged CKD mice and reproduced similar premature aging in young mice treated with a high-fat diet and nitric oxide synthase inhibitor (L-NAME). Both aged and metabolically stressed CKD mice showed reduced hepatic and renal gluconeogenesis. Using these models and human kidney biopsy specimens with clinical data, this study clarifies how aging- or CKD-related loss of renal glucose production leads to systemic energy depletion and sarcopenia.

Three models were used: (1) Aged + CKD—young, aged, and aged mice with sub nephrectomy; (2) Aging-mimic—young mice fed a high-fat diet (HFD) and given L-NAME, with or without sub nephrectomy; and (3) Nutritional intervention—sucrose replaced with cornstarch for sustained glucose supply. Muscle mass, strength, and endurance were assessed with metabolomic analysis, lactate–pyruvate tests, and liver and muscle RNA-seq. Renal biopsies from nephrosclerosis patients (GFR > 30 mL/min/1.73 m², 2017–2023) were examined for tubular PCK1 in younger (n = 15) and older (n = 20) groups.

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.

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.