There is the suspicion that the aging of the immune system into incapacity, inflammation, and malfunction includes a meaningful degree of low-grade autoimmunity, pathological and disruptive attacks by the immune system on the body’s own structures, but not evidently rising to the level of a well-defined autoimmune condition. This is perhaps less well researched that it might be, given the many other far more evident ways in which an aged immune system becomes harmful. That the immune system does fall apart in a very complex set of ways is a strong argument for blunt approaches that involve destruction and then replacement of existing immune populations. Where this can be accomplished in a limited way in animal models, cell type by cell type, such as for microglia or for B cells, it appears to be a beneficial strategy.
Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood.
Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance.
Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and bispecific T cell engagers (BiTEs), to tackle autoimmune-related conditions in aging and obesity.
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