Minguang Yang

Cognitive frailty (CF), characterized by concurrent cognitive and motor decline, is a major challenge to healthy aging, yet effective interventions remain limited. Klotho, an anti-aging protein that declines with age, has been implicated in both hippocampal function and skeletal muscle homeostasis. In this study, we investigated whether aerobic exercise combined with multisensory stimulation training (CT) ameliorates age-related CF through systemic Klotho signaling. A 16-month-old mouse model of age-related CF was assigned to aerobic training, multisensory stimulation, or combined training, and behavioral, electrophysiological, histological, and molecular assessments were performed. To examine the mechanistic role of Klotho, dual-route shRNA delivery was used to inhibit systemic Klotho expression. CT significantly improved cognitive and motor performance compared with either intervention alone. CT also increased hippocampal dendritic spine density and long-term potentiation, reduced collagen deposition in gastrocnemius muscle, and upregulated Klotho, FGF19, and FGFR1 expression in both hippocampus and muscle, accompanied by elevated serum Klotho levels. Klotho knockdown attenuated these beneficial effects, reduced PSD95 and GluN2B expression, and increased MuRF3 and TNF-α levels. These findings suggest that CT alleviates cognitive frailty and that systemic Klotho is a key mediator linking hippocampal synaptic function and skeletal muscle homeostasis.

Electroacupuncture (EA) combined with neural stem cell transplantation (NSCT) represents a promising therapeutic strategy for neurological recovery after ischemic stroke. This study investigated the enhanced effects of EA at 'Quchi' (LI11) and 'Zusanli' (ST36) acupoints combined with NSCT on motor function and neurogenesis in a rat middle cerebral artery occlusion (MCAO) model, and explored the underlying tsRNA-associated molecular changes. Neural stem cells (NSCs) were isolated from neonatal rats and characterized. MCAO rats were randomized into five groups: sham, MCAO, EA, NSCT, and EA+NSCT groups. Infarct volume was assessed via T2-weighted MRI, and neurological deficits were evaluated using modified Neurological Severity Scores (mNSS). Motor function was tested via open field and rotarod assays. Neurogenesis was analyzed by immunofluorescence co-staining for Brdu/DCX, Brdu/NeuN, and Brdu/GFAP. TsRNA expression profiles were examined by high-throughput sequencing, followed by bioinformatics analysis. The mRNA and protein levels of predicted target genes BDNF and Wnt1 were quantified by quantitative real-time polymerase chain reaction (qPCR) and Western blot. The EA+NSCT group showed a significantly reduced infarct volume compared with monotherapy groups (P < 0.01), along with lower mNSS scores (P < 0.05) and improved motor performance (P < 0.001). Besides, EA+NSCT further promotes Brdu/GFAP and Brdu/NeuN expression in the peri-infarct cortex, surpassing either treatment alone. Preliminary TsRNA sequencing identified candidate tsRNAs, tRF-1:31-Gly-GCC-2-M2 and tRF-1:31-Gly-CCC-1-M2. The predicted target genes BDNF and Wnt1 were markedly upregulated at the protein level in all treatment groups, with the highest expression in the EA+NSCT group (P < 0.01). Combined EA and NSCT significantly enhances neurogenesis and functional recovery after ischemic stroke, outperforming either intervention alone. These findings suggest that combined EA and NSCT may be associated with altered tsRNA expression and increased BDNF and Wnt1 levels, which may contribute to NSC differentiation and neural repair.

Age-associated cognitive decline, characterized by progressive memory and executive function impairment without dementia, poses challenges to elderly health. While aerobic exercise and environmental enrichment training may improve cognitive function, the underlying neural mechanisms remain unclear. In this study, we developed a novel intervention combines aerobic exercise (AE) with multisensory stimulation environment training (MSET). This combined training (CT) was more effective in mitigating cognitive decline in aged mice than either individual component or controls, aligning with increased neuronal activity and synaptic plasticity in the hippocampus (HPC) and prefrontal cortex (PFC). Using neural circuit tracing and chemogenetics, we explored the importance of the HPC-PFC circuit. Inhibiting the HPC-PFC circuit reduced the improvement effect of combined training (CT) on cognitive function, whereas activating this circuit enhanced cognitive function. We found candidate molecules responsive to CT in the HPC and PFC using single-cell sequencing. We identified that AE component modulated the expression levels of proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) and lymphocyte antigen 6 family member H (LY6H) in neurons in the HPC and PFC. At the same time, MSET component influenced the expression levels of dipeptidyl peptidase like 6 (DPP6) and glutamate ionotropic receptor NMDA type subunit associated protein 1 (GRINA) in neurons of the HPC and PFC. CT was linked to the upregulation of these molecular targets, which correlated with its beneficial effects. These findings provide insight into the mechanism underlying cognitive improvement associated with CT, suggesting a potential basis for exploring strategies aimed at mitigating cognitive decline through interventions like CT.