👤 Patrizia Genini

Stressful life events (SLE) are associated with an increased likelihood of developing depression. However, the underlying mechanisms and the long-lasting consequences of SLE exposure during adolescence, a critical period for physical, sexual, and behavioural maturation, are largely unknown. Recent studies suggest that they might be mediated by aberrant epigenetic mechanisms, such as alterations in DNA methylation, histone modifications and the expression of microRNAs. This systematic review aims at investigating the epigenetic markers affected by SLE during adolescence and their (causal) contribution to the onset of depression later in life. In line with the PRISMA 2020 guidelines and following a pre-registered protocol (CRD42023441784), PubMed, Web of Science and Embase were screened and 30 studies, including both rodents (n = 19) and humans (n = 11), met the pre-defined inclusion criteria. The preclinical findings converge on SLE-related changes in DNA methylation of Bdnf gene and alterations in microRNAs implicated in the regulation of Bdnf- and glucocorticoid-related pathways. The clinical studies focused primarily on DNA methylation and microRNAs alterations. Whilst a consensus on specific SLE-related epigenetic modifications did not emerge, novel pathways, including extracellular vesicle (EV) miRNAs, should be further investigated to be employed as biomarkers for preventive screening. Overall, our systematic review provides early suggestive evidence on the role of epigenetic mechanisms in mediating the effects of SLE in adolescence and the consequent onset of depression-relevant symptoms in later life. However, the paucity and the heterogeneity of the findings highlight the need for additional studies to address this fundamental research question and provide solid evidence for causality. Show less

Depression is a leading cause of global disability and is increasingly recognized as a multifactorial disorder characterized by fundamental disruptions in neuroplasticity, including diminished hippocampal neurogenesis, impaired synaptic plasticity, and dysregulated stress-response systems. Given the limited efficacy of conventional pharmacological treatments, lifestyle-based interventions-most notably physical exercise-have gained considerable attention for their antidepressant effects, partly mediated by secreted exerkines. Among these, adiponectin has emerged as a particularly compelling candidate linking metabolic regulation to neuroplasticity and mood. Recent evidence suggests that adiponectin contributes to the antidepressant effects of exercise by modulating hippocampal neurogenesis, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. Despite these advances, the mechanisms by which adiponectin influences depression remain incompletely understood. This review synthesizes current knowledge on adiponectin's role in depression pathophysiology, with emphasis on its capacity to enhance neuroplasticity and hippocampal neurogenesis, and its potential to mediate exercise-induced antidepressant effects via defined molecular pathways. Building on these insights, we discuss adiponectin's translational promise as both a predictive biomarker of treatment response and a novel therapeutic target. By integrating preclinical and clinical evidence, this review offers a comprehensive perspective on adiponectin's involvement in depression while identifying critical gaps to guide future mechanistic research. Show less