PMC

Representative scheme of epigenetic and molecular mechanisms modified in the hippocampus of Senescence-Accelerated Prone Mice (SAMP8) across generations. Significant modifications are shown in bold and potential modifications with the symbol *.

Endoplasmic Reticulum (ER) stress markers sensors in the hippocampus of females and males at 6 months of age for all mice groups. Representative Western blot for BiP), ratio p-PERK/PERK Total, ratio p-EIF2α/EIF2α, ATF-6 and their respective quantification (A–D). Values in bar graphs are adjusted to 100% for protein levels of the CT group). Values are the mean ± SEM; n = 18 (CT n = 6, F1 n = 6, F2 n = 6 for each group, females n = 3, males n = 3). Statistics: * p < 0.05.

AMPK/mTOR signaling cascade in the hippocampus of females and males at 6 months of age for all mice groups. Representative Western blot for ratio p-AMPK/AMPK, ratio p-mTOR/mTOR, Total and Beclin-1 protein levels, and their respective quantification (A,C,D). Values in bar graphs are adjusted to 100% for protein levels of the CT group. Representative gene expression for Pgc-1α (B). Gene expression levels were measured by real-time PCR from hippocampal mRNA. Values are mean ± SEM; n = 18 (CT n = 6, F1 n = 6, F2 n = 6 for each group, females n = 3, males n = 3). Statistics: *** p < 0.001; **** p < 0.0001.

Global 5-methylated and 5-hydroxymethylated cytosine levels in the hippocampus of females and males at 6 months of age for all mice groups (A). Relative gene expression of Dnmt1, Dnmt3a, Dnmt3b, Tet1, and Tet2 (B). Gene expression levels were measured by real-time polymerase chain reaction (PCR) from hippocampal mRNA. Mean ± SEM in bar graphs are adjusted to 100% for each gene of CT group; n = 18 to 21 (CT n = 6 to 7, F1 n = 6 to 7, F2 n = 6 to 7; for each group, females 3 to 4, males n = 3). Statistics: * p < 0.05; ** p < 0.01; *** p < 0.001.

Experimental design and offspring generation of F1 (intergenerational inheritance) and F2 (transgenerational inheritance), and control (CT) mice group. At 6 months of age, mice were tested by memory tests followed by euthanasia, brain extraction, and molecular analysis (A). Results of body weight each week in both females and males (B). Results of total body weight increase in both females and males (C). Values represented are mean ± standard error of the mean (SEM); n = 60 (CT n = 20, F1 = 20, F2 n = 20; for each group, females n = 10, males n = 10). Statistics: vs. female CT group: **** p < 0.0001 vs. female F2 group: ^$$$$ p < 0.0001 vs. female F2 group: ^&&&& p < 0.0001.

Results of DI of Novel Object Recognition Test (NORT) in females and males at 6 months of age in both females and males for all mice groups. Summary from short-term memory (A), and a summary from long-term memory (B). Results of Morris Water Maze (MWM) in females and males at 6 months of age for all mice groups. Learning curves of MWM during the spatial acquisition phase (C). Latency to the target of MWM on the memory test (D). Representative swim paths on the memory test (E). Values represented are mean ± SEM; n = 60 (CT n = 20, F1 = 20, F2 n = 20; for each group, females n = 10, males n = 10). Statistics: vs. female CT group: * p < 0.05; ** p < 0.01; **** p < 0.0001 vs. male CT group: ^$ p < 0.05; ^$$ p < 0.01; ^$$$$ p < 0.0001.

DNA methylation analysis of the Nrf2 (A) and NF-kβ (E) gene promoter in the hippocampus of females and males at 6 months of age for all mice groups. Percentage of gene methylation was determined by real-time PCR. Mean ± values in bar graphs are adjusted to 100% for each gene of the CT mice group. Representative Oxidative stress measured as hydrogen peroxide concentration in homogenates of hippocampus tissue (D). Representative gene expression for Hmox1 (B), Aox1 (C), Il-6 (F), Cxcl10 (G). Gene expression levels were measured by real-time PCR from hippocampal mRNA. Mean ± SEM in bar graphs are adjusted to 100% for each gene of the CT; n = 18 (CT n = 6, F1 n = 6, F2 n = 6; for each group, females n = 3, males n = 3). Statistics: * p < 0.05; *** p < 0.001.