Canatelli-Mallat, M. | Search bioRxiv

bioRxiv2021

HIPPOCAMPAL DNA METHYLATION, DNAm AGE AND SPATIAL MEMORY PERFORMANCE IN YOUNG AND OLD RATS

In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed the age-related changes in the DNA methylation (DNAm) landscape in the rat hippocampus and assessed the correlation of spatial memory performance with hippocampal DNAm age in young (2.6 mo.) and old (26.6 mo.) rats. Spatial memory performance was assessed with a modified version of the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent (permanence) by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNA methylation profiles of hippocampal tissue. The bisulfite converted genomic DNA was analyzed by Illumina Infinium HorvathMammalMethylChip40. The Horvath Mammal Methyl Chip40 assay provides quantitative measurements of DNA methylation for 22528 CpG dinucleotides that map to the Rattus norvegicus UCSC 6.0 genome. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in positively methylated CpGs. In the old rat hippocampi, the methylation levels of CpGs proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant when data from young and old rats were taken together. The above results suggest that age-related hypermethylation of certain gene families, like Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats.

neuroscience↗

bioRxiv2020

Reversing age: dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

developmental biology↗