A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Raúl F. Pérez, Patricia Tezanos, Alfonso Peñarroya, Alejandro González-Ramón, Rocío G. Urdinguio, Javier Gancedo-Verdejo, Juan Ramón Tejedor, Pablo Santamarina-Ojeda, Juan José Alba-Linares, Lidia Sainz-Ledo, Annalisa Roberti, Virginia López, Cristina Mangas, María Moro, Elisa Cintado Reyes, Pablo Muela Martínez, Mar Rodríguez-Santamaría, Ignacio Ortea, Ramón Iglesias-Rey, Juan Castilla-Silgado, Cristina Tomás-Zapico, Eduardo Iglesias-Gutiérrez, Benjamín Fernández-García, Jose Vicente Sanchez-Mut, José Luis Trejo, Agustín F. Fernández () and Mario F. Fraga ()
Additional contact information
Raúl F. Pérez: Universidad de Oviedo
Patricia Tezanos: Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Alfonso Peñarroya: Universidad de Oviedo
Alejandro González-Ramón: Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC)
Rocío G. Urdinguio: Universidad de Oviedo
Javier Gancedo-Verdejo: Universidad de Oviedo
Juan Ramón Tejedor: Universidad de Oviedo
Pablo Santamarina-Ojeda: Universidad de Oviedo
Juan José Alba-Linares: Universidad de Oviedo
Lidia Sainz-Ledo: Universidad de Oviedo
Annalisa Roberti: Universidad de Oviedo
Virginia López: Universidad de Oviedo
Cristina Mangas: Universidad de Oviedo
María Moro: Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Elisa Cintado Reyes: Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Pablo Muela Martínez: Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Mar Rodríguez-Santamaría: Universidad de Oviedo
Ignacio Ortea: Universidad de Oviedo
Ramón Iglesias-Rey: Health Research Institute of Santiago de Compostela (IDIS)
Juan Castilla-Silgado: Universidad de Oviedo
Cristina Tomás-Zapico: Universidad de Oviedo
Eduardo Iglesias-Gutiérrez: Universidad de Oviedo
Benjamín Fernández-García: Universidad de Oviedo
Jose Vicente Sanchez-Mut: Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC)
José Luis Trejo: Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Agustín F. Fernández: Universidad de Oviedo
Mario F. Fraga: Universidad de Oviedo

Nature Communications, 2024, vol. 15, issue 1, 1-26

Abstract: Abstract Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

Date: 2024
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DOI: 10.1038/s41467-024-49608-z

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