A brake on inflammaging

Metformin reverses an aging-associated inflammatory immune profile. Age is a major risk factor for many life-threatening diseases including cardiometabolic disease, cancer, and neurodegeneration. Although age is non-adjustable, the aging-associated inflammation that underlies these prevalent diseases is potentially targetable. Yet the pathways that control this so-called inflammaging and their probable contribution to adverse disease progression remain poorly understood. Bharath et al. set out to define the immune profile during aging to better understand which treatments may be beneficial to promote healthy aging by comparing immune cells isolated from the blood of healthy 30-year-old and 60-year-old people. After activation outside the body, T cells from the older group produced more cytokines associated with Th17, a subset of T lymphocytes that promotes inflammation in many diseases. Because the glycemic control drug metformin is known to suppress inflammation and may dampen inflammaging, the authors tested whether this type 2 diabetes medication could reduce age-related T cell inflammation. Although metformin effectively ameliorated the Th17 inflammaging profile toward a young profile in cultured T cells, it remains to be demonstrated whether such switch also occurs in vivo. Next, the authors demonstrated that the Th17 profile coincided with increased oxidative phosphorylation and mitochondrial mass in aged T cells. This is rather surprising because oxidative phosphorylation is generally believed to be anti-inflammatory, and boosting mitochondrial fitness is considered to improve healthy aging. One could speculate that the increased mitochondrial abundance compensates for the accumulation of defective mitochondria. Metformin not only restored mitochondrial bioenergetics and the associated production of reactive oxygen species, it also improved the blunted autophagy in T cells of 60-year-old subjects. Autophagy is a major protein recycling pathway, and blocking this homeostatic process was enough to induce an inflammaging Th17 profile in T cells of young people. Is there enough evidence to take metformin to rejuvenate our immune system and promote healthy aging? Not yet, because its effects on chronic low-grade inflammation in vivo and also the contribution of monocytes and macrophages as major drivers of inflammaging were not studied. Nevertheless, this article justifies the establishment of clinical trials that test the effects of metformin on health span.