Fight Aging!

The authors of today's open access paper present an interesting and novel way in which visceral fat tissue provokes chronic inflammation. It has been noted that dysfunctional B cells accumulate with age. Here, dysfunctional B cells of a specific subtype are shown to accumulate in aged visceral fat tissue, acting to provoke other immune cells in visceral fat tissue, such as macrophages, into a more pro-inflammatory state. The researchers demonstrate that removing the B cell population helps to reduce the age-related inflammation generated by visceral fat by removing the contribution to inflammatory macrophage behavior.

Of note, B cells regenerate quite rapidly following clearance, and it seems that using pharmacological means or gene therapies to clear out B cells in aged individuals would improve a number of issues. Targeted clearance of specific immune cells (such as microglia in the brain), or indeed the immune system as a whole, is an underdeveloped area of medical research, and one that could in principle produce therapies capable of reversing a number of aspects of immune aging.

Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis

Aging is accompanied by an increase in visceral adiposity, immune cell activation, and decreased ability of visceral white adipose tissue (vWAT) to maintain homeostatic functions such as lipolysis that is required for the generation of free fatty acids. Lipolysis is activated via canonical (catecholamine) or non-canonical pathways (bacteria or inflammatory cytokines). The chronic inflammatory activation of macrophages and B cells seen during aging suppresses catecholamine-stimulated lipolysis by limiting the bioavailability of catecholamines, but it is unclear whether these vWAT immune cells from older organisms would enhance or suppress the stimulated lipolysis in the context of sepsis and inflammation.

Canonical lipolysis induced by catecholamines declines during aging due to factors including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation; however, the extent to which the non-canonical pathway of lipolysis is active and impacted by immune cells during aging remains unclear.

Therefore, we aimed to define the extent to which immune cells from old mice influence non-canonical lipolysis during sepsis. We identified age-associated impairments of non-canonical lipolysis and an accumulation of dysfunctional B1 B cells in the visceral white adipose tissue (vWAT) of old mice. B cells can be classified as innate-like B1 B cells that acutely produce non-specific natural antibodies during bacterial infections or adaptive B2 B cells that become memory B cells and produce high-affinity antibodies. These subsets expand equally with age and can be distinguished by the expression of CD11b on the B1 subset but not the B2 subset.

Lifelong deficiency of B cells in mice results in restored non-canonical lipolysis and reductions in pro-inflammatory macrophage populations. This data indicates that age-related accumulation of B cells promotes a pro-inflammatory macrophage phenotype including the upregulation of NLRP3 inflammasome activation, supporting a model in which B cells indirectly suppress non-canonical lipolysis by promoting macrophage inflammation.