TY - JOUR
T1 - Transcriptomic Insights into Late-Life Depression and the Role of Environmental Drinking Water Composition
T2 - A Study on 18-Month-Old Mice
AU - Costa-Nunes, João Pedro
AU - Sitdikova, Kseniia
AU - Svirin, Evgeniy
AU - de Munter, Johannes
AU - Somlyai, Gabor
AU - Gorlova, Anna
AU - Litavrin, Alexandr
AU - Arajyan, Gohar M.
AU - Nefedova, Zlata
AU - Lyundup, Alexei
AU - Morozov, Sergey
AU - Umriukhin, Aleksei
AU - Iliynskaya, Sofia
AU - Chernopiatko, Anton
AU - Strekalova, Tatyana
N1 - Funding Information:
We thank Dolores Bonapartes, the Portuguese Foundation for Science (FCT), New Lisbon University, and Sanda Bakayewa for their important support of the study. We thank Giacomo Dell\u2019Omo and Technosmart EUROPE (Rome, Italy) for a support provided. No conflicts are declared by the authors.
Funding Information:
This research was funded by AquaSynapse EU framework (2021\u20132026, to TS and GS), European Union\u2019s HORIZON 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement 101086453; and NIIOPP state task Ministry of Education and Research RF FGFU-2025-0012 (to K.S. and S.M.). The Aqua-Synapse project has received funding from the European Union\u2019s HORIZON 2020 research and innovation program under the Marie Sklodowska-Curie grant EU agreement. This publication reflects only the authors\u2019 views, and the European Commission is not liable for any use that may be made of the information contained therein.
Publisher Copyright:
© 2025 by the authors.
PY - 2025/11/1
Y1 - 2025/11/1
N2 - The study of molecular mechanisms underlying late-life depression (LLD) is increasingly important in light of population aging. To date, LLD-related molecular brain changes remain poorly understood. Furthermore, environmental factors such as climate change and geography contribute to LDD risks. One overlooked factor might be deuterium—a stable hydrogen isotope—whose concentration in drinking water can vary geographically (~90–155 ppm) and alter the incidence of mood disorders. Conversely, potential effects of natural variations in deuterium content in drinking water on LLD symptoms and brain gene expression remain unknown. We conducted Illumina gene expression profiling in the hippocampi and prefrontal cortexes of 18-month-old C57BL/6J mice, a model of LLD-like behaviors, compared to 3-month-old controls. Separately, aged mice were allowed to consume deuterium-depleted (DDW, ~90 ppm) or control (~140 ppm) water for 21 days and were studied for LLD-like behaviors and Illumina gene expression of the brain. Naïve old mice displayed =2-fold significant changes of 35 genes. Housing on DDW increased their hedonic sensitivity and novelty exploration, reduced helplessness, improved memory, and significantly altered brain expression of Egr1, Per2, Homer1, Gadd45a, and Prdx4, among others. These genes revealed significant alterations in several GO-BP and KEGG pathways implicated in inflammation, cellular stress, synaptic plasticity, emotionality, and regeneration. Additionally, we found that incubation of primary neuronal cultures in DDW-containing buffer ameliorated Ca2+ influx and mitochondrial potential in a toxicity model, suggesting the involvement of mitochondrial mechanisms in the effects of decreased deuterium levels. Thus, aging induced profound brain molecular changes that may at least in part contribute to LLD pathophysiology. Reduced deuterium intake exerted modest but significant effects on LLD-related behaviors in aged mice, which can be attributed to, but not limited by ameliorated mitochondrial function and changes in brain gene expression.
AB - The study of molecular mechanisms underlying late-life depression (LLD) is increasingly important in light of population aging. To date, LLD-related molecular brain changes remain poorly understood. Furthermore, environmental factors such as climate change and geography contribute to LDD risks. One overlooked factor might be deuterium—a stable hydrogen isotope—whose concentration in drinking water can vary geographically (~90–155 ppm) and alter the incidence of mood disorders. Conversely, potential effects of natural variations in deuterium content in drinking water on LLD symptoms and brain gene expression remain unknown. We conducted Illumina gene expression profiling in the hippocampi and prefrontal cortexes of 18-month-old C57BL/6J mice, a model of LLD-like behaviors, compared to 3-month-old controls. Separately, aged mice were allowed to consume deuterium-depleted (DDW, ~90 ppm) or control (~140 ppm) water for 21 days and were studied for LLD-like behaviors and Illumina gene expression of the brain. Naïve old mice displayed =2-fold significant changes of 35 genes. Housing on DDW increased their hedonic sensitivity and novelty exploration, reduced helplessness, improved memory, and significantly altered brain expression of Egr1, Per2, Homer1, Gadd45a, and Prdx4, among others. These genes revealed significant alterations in several GO-BP and KEGG pathways implicated in inflammation, cellular stress, synaptic plasticity, emotionality, and regeneration. Additionally, we found that incubation of primary neuronal cultures in DDW-containing buffer ameliorated Ca2+ influx and mitochondrial potential in a toxicity model, suggesting the involvement of mitochondrial mechanisms in the effects of decreased deuterium levels. Thus, aging induced profound brain molecular changes that may at least in part contribute to LLD pathophysiology. Reduced deuterium intake exerted modest but significant effects on LLD-related behaviors in aged mice, which can be attributed to, but not limited by ameliorated mitochondrial function and changes in brain gene expression.
KW - aging
KW - anhedonia
KW - animal models
KW - depression
KW - deuterium
KW - environment
KW - Illumina gene profiling
KW - late-life depression
KW - mice
U2 - 10.3390/ijms262110626
DO - 10.3390/ijms262110626
M3 - Article
SN - 1661-6596
VL - 26
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 21
M1 - 10626
ER -