Young extracellular vesicles restore burn-induced adipose tissue immunometabolic and mitochondrial function in older mice

The idea of blood as an elixir of youth led to the classical experiment of heterochronic parabiosis, which demonstrated that young blood could rejuvenate aged tissues in mice. Later, it was discovered that this rejuvenating capacity is due to the presence of circulating extracellular vesicles (EVs), which override deleterious signals from the aged environment via intercellular cues that promote tissue renewal. Aging is associated with alterations in the structure and cargo of EVs with diminished nucleic acid content. We know that aging is a chronological process of progressive cellular and tissue dysfunction that impairs the capacity of older trauma patients to adequately respond to stress, particularly burn trauma, with the adipose tissue serving as the central mediator. Our results demonstrated that, in addition to increasing senescence with chronological aging, burn injury further intensifies the senescence burden in adipose tissue. Notably, EVs from young mouse serum samples significantly reduced burn-induced senescence in aged adipose tissue. We further demonstrated that EVs mitigate lipolysis and are crucial in hepatocellular signaling for the regulation of hepatic inflammation, fat accumulation and dysfunction. Finally, we provide evidence that EV therapy reestablishes immuno-metabolic function, mitochondrial bioenergetics, immune cell infiltration and adipose tissue function.