Fig 2: AAV‐NDRG2 weakens Tuina's effect in promoting glutamate uptake and synaptic plasticity in CCI rats. (A) Protein expression levels of ATP1A1 and ATP1B1 in SDH. GAPDH was used as the internal control. (B, C) Relative protein expression levels of ATP1A1 (B) and ATP1B1 (C) in each group. n = 4. (D) Pearson's correlation of glutamate and γ‐aminobutyric acid levels with ATP1A1 and ATP1B1 protein expression. (E, F) Concentrations of glutamate and γ‐aminobutyric acid in each group. n = 4. (G) Quantification analysis of the number of VGLUT1/PSD95 in SDH. n = 4. (H) Representative images of IF analysis of VGLUT1 (blue), PSD95 (pink) and Merge (white) in SDH among groups. Scale bar, 20 μm (top), 10 μm (bottom). Data are presented as mean ± SD *p < 0.05, **p < 0.01 versus CCI + Vector group. # p < 0.05, ## p < 0.01 versus CCI + Vector+Tuina group.

Fig 3: Co-cultured cells from each group: (A) Blot images of proteins related to glutamate release and lactate shuttle (n = 3); (B) vGLUT1 protein expression (Ordinary one-way ANOVA, n = 3); (C) MCT1 protein expression (Ordinary one-way ANOVA, n = 3); (D) MCT2 protein expression (Ordinary one-way ANOVA, n = 3); (E) MCT4 protein expression (Ordinary one-way ANOVA, n = 3). In comparison to the control group, ## p < 0.01, ### p < 0.001; In comparison to the OGD group, * p < 0.05, ** p < 0.01. Data are presented as mean ± SD. Drug: PAL treatment group. The original Western blot images can be found in the Supplementary Materials.

Fig 4: Brain tissue of rats in each group: (A) Blot images of proteins related to glutamate release and lactate shuttle (n = 3); (B) vGLUT1 protein expression (Ordinary one-way ANOVA, n = 3); (C) MCT1 protein expression (Ordinary one-way ANOVA, n = 3); (D) MCT2 protein expression (Ordinary one-way ANOVA, n = 3); (E) MCT4 protein expression (Ordinary one-way ANOVA, n = 3). In comparison to the sham group, ### p < 0.001. In comparison to the model group, ** p < 0.01, * p < 0.05. Data are presented as mean ± SD. High: PAL high-dose group. The original Western blot images can be found in the Supplementary Materials.

Fig 5: Mettl3 knockdown rescue the age-related olfactory dysfunction. (A) The flowchart of intervention experiment. (B) GFP (red) immunostaining in old mouse injected with lentivirus after 10 days. (C) Representative immunohistochemistry of shMettl3-injected mice and control mice using antibodies against the METTL3. (D) Quantification of METTL3 IOD/Area of positive cells, as determined by Student’s t-test. (E) Box plot showing the latency time of shMettl3 and control group in buried food seek buried test, as determined by Student’s t-test. (n = 5 per group) (F) Box plot showing the avoid index of shMettl3 and control group in olfactory avoidance test, as determined by Student’s t-test. (n = 5 per group) (G) The investigation time of shMettl3 and control group in olfactory habituation-dishabituation test, as determined by Student’s t-test. (n = 5 per group) (H) Box plot showing the weight of shMettl3 and control group, as determined by Student’s t-test. (I) RT-qPCR assay indicating the mRNA expression level of Wnt4, Ror2 and Nkd1 in shMettl3 and control group, as determined by Student’s t-test.(n = 3 per group) (J) Representative immunohistochemistry of shMettl3-injected mice and control mice using antibodies against the VGLUT1. (n = 5 per group) K) Quantification of VGLUT1 IOD/Area of positive cells, as determined by Student’s t-test