The effect of late-life environmental enrichment on stress and anxiety: The role of sex and age-related differences in coping with aversive stimuli

Anxiety significantly diminishes the quality of life in older adults, and the drugs used for its treatment often come with risky side effects. Non-pharmacological protocols could be valuable, but more research is needed in this area. Environmental enrichment induces positive effects on anxiety-like behavior in young and adult animals; whether the same happens in aged animals is still elusive. The aged brain undergoes changes that contribute to make it “fragile” and consequently even mild, potentially positive stimuli can trigger dyshomeostasis, worsening rather than ameliorating functioning. Here, by combining behavioral analysis and measurement of serum and brain corticosterone levels, we show that late-life environmental enrichment can induce eustress or distress, depending on sex and hypothalamic-pituitary-adrenal axis function. These findings pave the way for optimizing outcomes and minimizing undesired effects in the clinical setting, underscoring the need to overcome the limits of gender medicine and emphasizing the crucial role of individually tailored therapies. •We applied environmental enrichment (EE) to aged rats.•By behavior and corticosterone assays, we proved that EE induced eustress or distress.•Only animals who positively coped with EE (eustress) reduced anxiety.•Aged stress response depends on sex and hypothalamic-pituitary-adrenal axis function.•Serum corticosterone mirrored the brain hormone, proving to be a reliable biomarker.