Abstract
Early-life stress (ES) increases the risk for psychopathology and cognitive decline later in life. Because the neurobiological substrates affected by ES (i.e., cognition, neuroplasticity, and neuroinflammation) are also altered in aging, we set out to investigate if and how ES in the first week of life affects these domains at an advanced age, and how ES modulates the aging trajectory per se. We subjected C57BL/6j mice to an established ES mouse model from postnatal days 2–9. Mice underwent behavioral testing at 19 months of age and were sacrificed at 20 months to investigate their physiology, hippocampal neuroplasticity, neuroinflammation, and telomere length. ES mice, as a group, did not perform differently from controls in the open field or Morris water maze (MWM). Hippocampal neurogenesis and synaptic marker gene expression were not different in ES mice at this age. While we find aging-associated alterations to neuroinflammatory gene expression and telomere length, these were unaffected by ES. When integrating the current data with those from our previously reported 4- and 10-month-old cohorts, we conclude that ES leads to a ‘premature’ shift in the aging trajectory, consisting of early changes that do not further worsen at the advanced age of 20 months. This could be explained e.g. by a ‘floor’ effect in ES-induced impairments, and/or age-induced impairments in control mice. Future studies should help understand how exactly ES affects the overall aging trajectory.
Highlights
Individuals with a history of early-life stress (ES) are at increased risk to develop psychopathologies and negative mental health outcomes later in life (Bellis et al, 2019; Ferraro et al, 2016; Hughes et al, 2017; Schafer and Ferraro, 2012)
It has been postulated that ES might interact with the aging process (Miller et al, 2011), and, aging affects many of the systems that are targeted by ES
Relative telomere length was decreased in the hippocampi of 20month-old mice compared to younger age groups, but was not affected by ES at any of the ages studied (condition: F(1) = 1.869, p = 0.18483; age: F(2) = 9.346, p = 0.00107; interaction: F(2) = 0.747, p = 0.4851; post-hoc: 4vs10Mo p = 0.073, 4vs20Mo p = 0.001, 10vs20Mo p = 0.325; Fig. 4C)
Summary
Individuals with a history of early-life stress (ES) are at increased risk to develop psychopathologies and negative mental health outcomes later in life (Bellis et al, 2019; Ferraro et al, 2016; Hughes et al, 2017; Schafer and Ferraro, 2012). ES-exposed individuals exhibit a higher prevalence of mild cognitive impairment, which seems to be more se vere in nature (Kang et al, 2017; Wang et al, 2016), and is accompanied by reductions in their hippocampal volume (Ahmed-Leitao et al, 2016; Riem et al, 2015; Teicher et al, 2012). Aging rodents typically exhibit cognitive decline that varies between individuals (Drapeau et al, 2003), and is associated with a reduced hippocampal volume, altered neuroplasticity, neurogenesis and synaptic plasticity (Drapeau et al, 2003; Foster, 1999; Kempermann, 2015; Lynch et al, 2006; Montaron et al, 2020; Rose nzweig and Barnes, 2003).
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