Sex differences in inflammation, mitochondrial function and energy sensing during early recovery from COVID 19 in older adults

Abstract SARS-CoV-2 infections induce mitochondrial dysfunction and exacerbate systemic inflammation. In the present study, sex differences were investigated among post-COVID-19 patients during the early recovery phase, as emerging evidence indicates that sex critically influences post-COVID-19 outcomes, particularly in older adults. Mitochondrial dysfunction, energy stress signaling through AMP-activated protein kinase (AMPK), and inflammatory dysregulation represent pathogenic mechanisms implicated in prolonged recovery. In this study, we analyzed peripheral blood mononuclear cells (PBMCs) and plasma from aged male and female patients during early post-COVID-19 recovery (1–4 weeks after obtaining a negative SARS-CoV-2 PCR test), comparing them to an inflammatory control group. Female post-COVID-19 patients exhibited elevated circulating TNF-α levels and a trend toward increased mRNA levels of proinflammatory interleukins IL-1β and IL-18 in PBMCs, accompanied by enhanced acetylation and decreased activity of mitochondrial superoxide dismutase 2 (SOD2). Both sexes displayed increased phosphorylation of AMPK, suggesting altered energy-sensing pathways. Mitochondrial gene expression was upregulated in female post-COVID-19 patients, potentially indicating compensatory responses to energy deficits. These findings reveal sex-dependent inflammatory and mitochondrial alterations during early recovery, suggesting a mechanistic link to the higher prevalence of long COVID-19 in women. These findings emphasize the need for sex-specific therapeutic approaches targeting mitochondrial and immunometabolic dysfunction in post-COVID-19 patients.