Fight Aging!

Visceral fat tissue generates inflammation through a range of mechanisms, and this only becomes worse with advancing age. The more visceral fat tissue, the worse the long-term consequences for metabolism, driven by inflammatory signaling. One of these mechanisms is that fat tissue provokes a greater burden of cellular senescence, cells that shut down replication and focus their energies on generating disruptive pro-inflammatory signals. This tendency increases with age.

Today's open access paper focuses on the regulation of macrophage senescence in fat tissue, and identifies rising levels of osteopontin with age as an important contributing factor. Macrophages are innate immune cells found throughout the body, responsible for a broad portfolio of tasks that go beyond chasing down pathogens and destroying errant cells to include assisting in tissue maintenance and regeneration. Their activities are important to the state of chronic inflammation.

Increased osteopontin levels are implicated in a range of degenerative processes observed in aged tissues. Researchers have considered using osteopontin as a biomarker of aging. Much of this may be due to effects on stem cell function, as in muscle tissue and the hematopoietic system in bone marrow. That in turn may be mediated by inflammatory signaling, given effects on macrophage function noted here.

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction

In obesity, adipose tissue (AT) undergoes cellular senescence involving activation of adipose tissue macrophages (ATMs), which enhances AT remodeling through proinflammatory and profibrotic signaling. Macrophages play a pivotal role in both the induction and resolution of inflammation that results in cellular dysfunction and AT damage. Notably, increased infiltration of proinflammatory macrophages in AT impairs the secreted adipokine profile and contributes to insulin resistance through a senescence-associated secretory phenotype (SASP). Indeed, ATMs are an important source of chemokines, matrix metalloproteinases, and other profibrotic and inflammatory mediators that collectively constitute the SASP.

Macrophages are also critically involved in AT remodeling because they are key to the clearance of obesity-associated senescent or damaged AT cells. Recent observations suggest that senescence initiates tissue remodeling by recruiting immune cells through SASP to allow clearance and regeneration of the damaged tissue. With persistent damage, as occurs in obesity and aging, however, clearance and regeneration may be compromised by senescence-associated macrophage dysfunction.

Interestingly, we have recently established visceral AT (VAT) as the major source of osteopontin (OPN) during aging. OPN is a matricellular protein involved in intracellular and extracellular signaling mediating cell-to-cell interactions, immune cell function, inflammation, and tissue remodeling. Beyond the reported role of OPN in AT proinflammatory status, we identified OPN as an important SASP component among a variety of growth factors, proinflammatory cytokines/chemokines, and adipokines, with a major role in inducing remote cardiac tissue remodeling by modulating fibroblast function. However, the link among age-related OPN production, VAT senescence, and impairment of ATM function is elusive.

Here we show that during chronological aging ATMs acquire several features of senescent cells, which impair ATM function, and contribute to age-related VAT remodeling and dysfunction, a process mediated by OPN. Our findings highlight OPN inhibition as a potential therapeutic intervention to rejuvenate VAT, thus promoting healthy aging.