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CRUE-CSIC agreement; Springer Nature; Health Institute Carlos III (Plan Nacional de I + D +I); FEDER [PI18/01527, PI21/01067, COV00624]; Spanish Association Against Cancer [PROYE18061FERN]; Asturias Government (PCTI) [IDI/2018/146, IDI/2021/000077]; Junta de Andalucia [PY20_00051, 2021-048-INTRAMURAL NOV-TEVAR]; European Commission NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global); Spanish Ministry of Science and Innovation [SGL2021-03-39, SGL2021-03-040, IJC2018-036825-I, RYC2021-031799-I]; ISCIII [FI19/00085]; Spanish Ministry of Universities [PRDAS21642ALBA]; Severo Ochoa program [BP17-114, BP17-165]; Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER); AECC fellowship; CSIC [SOLAUT_00038505 SGL2103040]; [FPU20/04659]

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. Lifestyle interventions are promising tools for achieving healthy aging. Here, authors show how environmental enrichment can reverse multi-omic alterations associated with the aging process in the murine dorsal hippocampus.

Aging is a multifactorial biological process resulting in physiological and cellular decline. However, our understanding of age-related changes in 3D genome organization and the effect of external interventions on this process, remains limited. Here we describe alterations in the landscape of the 3D chromatin interactome upon aging, utilizing the low input Promoter Capture Hi-C (liCHi-C) technique with hippocampal neurons. We integrated liCHi-C data with RNA-seq data to identify functional implications. Furthermore, we assessed the effect of exposure to environmental enrichment (EE). Remarkably, our results demonstrated an age- dependent modulation of promoter interactions and expression with EE, with aging-like changes induced in young mice upon EE, likely associated with early brain maturation; while age-related alterations were reverted in old mice, leading to a partial rejuvenation of aged mouse hippocampi. These findings revealed a dynamic behaviour of the neuronal 3D chromatin structure over time, which can be modulated by external interventions.