Unraveling of Molecular Mechanisms of Cognitive Frailty in Chronic Kidney Disease: How Exercise Makes a Difference

Abstract

As our population ages, the medical challenges it faces become increasingly acute, with chronic kidney disease (CKD) becoming more prevalent among older adults. Frailty is alarmingly more common in CKD patients than in the general populace, putting the elderly at high risk of both physical and cognitive decline. CKD not only accelerates physical deterioration, but also heightens vascular dysfunction, calcification, arterial rigidity, systemic inflammation, oxidative stress, and cognitive impairment. Cognitive frailty, a distinct syndrome marked by cognitive deficits caused by physiological causes (excluding Alzheimer's and other dementias), is a critical concern. Although cognitive impairment has been well-studied, the molecular mechanisms driving cognitive frailty remain largely uncharted. Comprehensive interventions, including cutting-edge pharmaceuticals and lifestyle changes, are pivotal and effective, especially in the early stages of CKD. Recent research suggests that systematic exercise could counteract cognitive decline by improving brain blood flow, boosting neuroplasticity through the brain-derived neurotrophic factor (BDNF), and by triggering the release of neurotrophic factors such as insulin-like growth factor (IGF-1). This review delves into the molecular pathways of cognitive frailty in CKD, identifies key risk factors, and highlights therapeutic approaches, particularly the potent role of exercise in enhancing cognitive health.

Keywords: chronic kidney disease; cognitive impairment; exercise; frailty; mechanisms; physical activity.

Figure 1

Traditional and non-traditional risk factors for cognitive frailty in CKD patients. Red color = traditional risk factors. Blue color = non-traditional risk factors. ↑ = increase and ↓ = decrease. CPMD: calcium and phosphorus metabolism disorder; SHPT: secondary hyperparathyroidism.

Figure 2

Exercise-induced mechanisms contrasting cognitive decline in subjects with or without CKD. ↑ = increase and ↓ = decrease. Nrf2: nuclear factor erythroid 2-related factor 2; NF-κΒ: nuclear factor κappa B; TNF-α: tumor necrosis factor-alpha; IL-6: interleukin 6; ROS: reactive oxygen species; MDA: malondialdehyde; BDNF: brain-derived neurotrophic factor; IGF-1: insulin-like growth factor; ucOC: uncarboxylated osteocalcin; PGC-1a: peroxisome proliferator-activated receptor γ coactivator 1α; FNDC5: fibronectin type III domain-containing 5.