Lactate Secretion by Monocytes as a Determinant of Innate Immune Cell Fitness in Healthy Elderly

Immune cell metabolism is increasingly recognized as an important regulator of immune function, but its role in age-related immune dysfunction, chronic inflammation, and cardiometabolic complications in humans remains incompletely understood. This study investigated the impact of aging on monocyte metabolic and functional signatures in a healthy elderly population. We aimed to leverage these immunometabolic signatures to identify healthy elderly individuals with reduced immune cell fitness and, therefore, potentially at a higher risk for age-related complications. We characterized lactate and cytokine secretion, phagocytic capacity, and glycolytic and oxidative metabolic responses in monocytes from 103 elderly individuals and included 52 young adults as a reference group with healthy immune responses. We observed strong similarities in monocyte functional and metabolic signatures between young adults and elderly individuals. However, monocytes from the elderly secreted significantly more cytokines and displayed more ATP-linked respiration and a reduced proton leak compared to young adults. These significant differences were driven by a subgroup within the elderly population characterized by higher monocyte lactate secretion compared to the remainder of the elderly and young adults and were therefore classified as "immune-unfit". The immune-unfit elderly exhibited "hyperactive" monocytes, evidenced by significantly higher metabolic and functional signatures. Interestingly, compared to immune-fit individuals, immune-unfit elderly individuals had significantly elevated levels of circulating vascular endothelial growth factor and low-density lipoprotein cholesterol. Hence, we propose lactate secretion from monocytes as a parameter to classify "immune-unfit" elderly individuals with divergent immunometabolic properties of monocytes that could reflect increased susceptibility to age-related cardiometabolic complications. Trial Registration: NCT05940337.