{"doi":"10.1093/gerona/glac153","title":"Hippocampal DNA Methylation, Epigenetic Age, and Spatial Memory Performance in Young and Old Rats","abstract":"<jats:title>Abstract</jats:title><jats:p>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 hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6- and 26.6-month-old rats. Spatial memory performance was assessed with the Barnes maze test. To evaluate learning ability and spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNAm data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpG 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. These results suggest that age-related hypermethylation of transcription factors related to certain gene families, such as 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.</jats:p>","journal":"The Journals of Gerontology: Series A","year":2022,"id":612880,"datarank":0.44166584687496613,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.0,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":553017,"name":"Marianne Lehmann","orcid":null,"position":1,"is_corresponding":false},{"id":1578264,"name":"Martina Canatelli Mallat","orcid":null,"position":2,"is_corresponding":false},{"id":376705,"name":"Joseph A. Zoller","orcid":"0000-0001-6309-0291","position":3,"is_corresponding":false},{"id":1578265,"name":"Claudia B Herenu","orcid":null,"position":4,"is_corresponding":false},{"id":1578266,"name":"Gustavo R Morel","orcid":null,"position":5,"is_corresponding":false},{"id":38267,"name":"Steve Horvath","orcid":"0000-0002-4110-3589","position":6,"is_corresponding":false},{"id":1578267,"name":"Rodolfo G Goya","orcid":null,"position":7,"is_corresponding":false},{"id":551742,"name":"Priscila Chiavellini","orcid":"0000-0001-6983-5127","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Hippocampal DNA Methylation, Epigenetic Age, and Spatial Memory Performance in Young and Old Rats","abstract":"<jats:title>Abstract</jats:title><jats:p>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 hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6- and 26.6-month-old rats. Spatial memory performance was assessed with the Barnes maze test. To evaluate learning ability and spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNAm data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpG 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. These results suggest that age-related hypermethylation of transcription factors related to certain gene families, such as 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.</jats:p>","is_dataset_classified":null,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35917578","pmcid":null,"openalex_id":"https://openalex.org/W4289519790","authors":[],"funders":[{"funder_name":"National Agency for the Promotion of Science and Technology, Argentina","grant_id":"SEGR-9-23-21","title":null},{"funder_name":"Society for Experimental Gerontological Research","grant_id":"PICT 2018-2446","title":null},{"funder_name":"Society for Experimental Gerontological Research","grant_id":"PICT16-1070","title":null},{"funder_name":"Paul G. Allen Frontiers Group","grant_id":"","title":null}],"total_grants":4,"fwci":1.427,"citation_percentile":0.81251543,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":6},{"year":2024,"count":5},{"year":2025,"count":5},{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc-sa","oa_locations":[{"url":"http://hdl.handle.net/11336/204545","host_type":"repository"},{"url":"http://hdl.handle.net/11336/204545","host_type":"repository"},{"url":"https://academic.oup.com/biomedgerontology/advance-article-pdf/doi/10.1093/gerona/glac153/46129568/glac153.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/biomedgerontology/article-pdf/77/12/2387/48444367/glac153.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/gerona/glac153","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35917578","host_type":"repository"}],"fields_of_study":["Epigenetics and DNA Methylation","Neurogenesis and neuroplasticity mechanisms","Genetics and Neurodevelopmental Disorders","Animals","Rats","Aging","Cell Cycle Proteins","DNA Methylation","Epigenesis, Genetic","Hippocampus","Maze Learning","Spatial Memory","Transcription Factors"],"mesh_terms":["Aging","Animals","Hippocampus","Transcription Factors","Maze Learning","Cell Cycle Proteins","DNA Methylation","Epigenesis, Genetic","Rats","Spatial Memory"],"keywords":["dNaM","Hippocampal formation","DNA methylation","Morris water navigation task","Hippocampus","Epigenetics","Methylation","Biology","Neuroscience","Psychology","Genetics","Gene","Gene expression","Aging","Dnam Age","Methylation Landscape","Hippocampus–spatial Memory"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T05:22:50.039869Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}