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; Pablo Muela; 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; Mario F Fraga

doi:10.1038/s41467-024-49608-z

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
, Pablo Muela
, 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, Mario F Fraga

Cancer Epigenetics and Nanomedicine Laboratory
Departamento de Neurociencia Translacional
Laboratory of Functional Epi-Genomics of Aging and Alzheimer's disease
Instituto Cajal-Consejo Superior de Investigaciones Científicas (IC-CSIC)
Madrid, Spain
Programa de Doctorado en Neurociencia
Universidad Autónoma de Madrid-Instituto Cajal
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA-FINBA)
Health Research Institute of Santiago de Compostela (IDIS)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	5829
Pages (from-to)	5829
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49608-z
Publication status	Published - 16 Jul 2024
Externally published	Yes

Keywords

Aging/genetics
Animals
Environment
Epigenesis, Genetic
Heterochromatin/metabolism
Hippocampus/metabolism
Male
Mice
Mice, Inbred C57BL
RNA, Messenger/metabolism
Single-Cell Analysis

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10.1038/s41467-024-49608-z

Cite this

Pérez, R. F., Tezanos, P., Peñarroya, A., González-Ramón, A., Urdinguio, R. G., Gancedo-Verdejo, J., Tejedor, J. R., Santamarina-Ojeda, P., Alba-Linares, J. J., Sainz-Ledo, L., Roberti, A., López, V., Mangas, C., Moro, M., Cintado, E., Muela, P., Rodríguez-Santamaría, M., Ortea, I., Iglesias-Rey, R., ... Fraga, M. F. (2024). A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment. Nature Communications, 15(1), 5829. Article 5829. https://doi.org/10.1038/s41467-024-49608-z

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title = "A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment",

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.",

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author = "P{\'e}rez, \{Ra{\'u}l F\} and Patricia Tezanos and Alfonso Pe{\~n}arroya and Alejandro Gonz{\'a}lez-Ram{\'o}n and Urdinguio, \{Roc{\'i}o G\} and Javier Gancedo-Verdejo and Tejedor, \{Juan Ram{\'o}n\} and Pablo Santamarina-Ojeda and Alba-Linares, \{Juan Jos{\'e}\} and Lidia Sainz-Ledo and Annalisa Roberti and Virginia L{\'o}pez and Cristina Mangas and Mar{\'i}a Moro and Elisa Cintado and Pablo Muela and Mar Rodr{\'i}guez-Santamar{\'i}a and Ignacio Ortea and Ram{\'o}n Iglesias-Rey and Juan Castilla-Silgado and Cristina Tom{\'a}s-Zapico and Eduardo Iglesias-Guti{\'e}rrez and Benjam{\'i}n Fern{\'a}ndez-Garc{\'i}a and Sanchez-Mut, \{Jose Vicente\} and Trejo, \{Jos{\'e} Luis\} and Fern{\'a}ndez, \{Agust{\'i}n F\} and Fraga, \{Mario F\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jul,

day = "16",

doi = "10.1038/s41467-024-49608-z",

language = "English",

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pages = "5829",

journal = "Nature Communications",

issn = "2041-1723",

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Pérez, RF, Tezanos, P, Peñarroya, A, González-Ramón, A, Urdinguio, RG, Gancedo-Verdejo, J, Tejedor, JR, Santamarina-Ojeda, P, Alba-Linares, JJ, Sainz-Ledo, L, Roberti, A, López, V, Mangas, C, Moro, M, Cintado, E, Muela, P, Rodríguez-Santamaría, M, Ortea, I, Iglesias-Rey, R, Castilla-Silgado, J, Tomás-Zapico, C, Iglesias-Gutiérrez, E, Fernández-García, B, Sanchez-Mut, JV, Trejo, JL, Fernández, AF & Fraga, MF 2024, 'A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment', Nature Communications, vol. 15, no. 1, 5829, pp. 5829. https://doi.org/10.1038/s41467-024-49608-z

TY - JOUR

T1 - A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

AU - Pérez, Raúl F

AU - Tezanos, Patricia

AU - Peñarroya, Alfonso

AU - González-Ramón, Alejandro

AU - Urdinguio, Rocío G

AU - Gancedo-Verdejo, Javier

AU - Tejedor, Juan Ramón

AU - Santamarina-Ojeda, Pablo

AU - Alba-Linares, Juan José

AU - Sainz-Ledo, Lidia

AU - Roberti, Annalisa

AU - López, Virginia

AU - Mangas, Cristina

AU - Moro, María

AU - Cintado, Elisa

AU - Muela, Pablo

AU - Rodríguez-Santamaría, Mar

AU - Ortea, Ignacio

AU - Iglesias-Rey, Ramón

AU - Castilla-Silgado, Juan

AU - Tomás-Zapico, Cristina

AU - Iglesias-Gutiérrez, Eduardo

AU - Fernández-García, Benjamín

AU - Sanchez-Mut, Jose Vicente

AU - Trejo, José Luis

AU - Fernández, Agustín F

AU - Fraga, Mario F

PY - 2024/7/16

Y1 - 2024/7/16

N2 - 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.

AB - 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.

KW - Aging/genetics

KW - Animals

KW - Environment

KW - Epigenesis, Genetic

KW - Heterochromatin/metabolism

KW - Hippocampus/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - RNA, Messenger/metabolism

KW - Single-Cell Analysis

UR - https://www.scopus.com/pages/publications/85198654904

U2 - 10.1038/s41467-024-49608-z

DO - 10.1038/s41467-024-49608-z

M3 - Article

C2 - 39013876

SN - 2041-1723

VL - 15

SP - 5829

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5829

ER -

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

Abstract

Keywords

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