Interplay of STAT1 signaling, mitochondrial and NAD homeostasis in myeloid cells in chronic inflammation and ageing – STATmiNADage

The number of old people is rising worldwide and cardiovascular diseases are the largest contributor to morbidity and mortality in this population. Changes in diet and lifestyle contribute to the high cardiovascular morbidity and mortality in old individuals, but many biological processes that are altered with aging also contribute to this increased cardiovascular risk. As a result, therapies for cardiovascular disease that are effective in young and middle-aged people might be less effective in older people. Deciphering the mechanisms by which aging promotes atherosclerotic cardiovascular disease will be fundamental for the development of novel therapies to reduce the burden of atherosclerosis with aging. Aging is associated with a decline in mitochondrial function characterized by altered respiratory capacity, reduced NAD levels, defective nutrient-sensing, mitochondrial stress response (impaired mitophagy and impaired mitochondrial UPR response (UPRmt)). The roots of these broad metabolic alterations are complex but NAD appears to play a central role in these processes. Thanks to the discoveries of Partner 2 (Auwerx Lab, EPFL, Lausanne, Switzerland), NAD evolved from being seen as a simple metabolic cofactor to a pivotal co-substrate for proteins regulating metabolism and longevity. Partner 2 contributed to demonstrate that restoring NAD levels promotes mitochondrial OXPHOS, mitophagy and UPRmt and is associated with increase lifespan and improvement of many age-related disorders. Low-grade inflammation is another hallmark of aging. The underlying mechanisms are poorly understood but are likely related to altered metabolic functions in immune cells. It was recently shown that kynurenine pathway, which contributes to the maintenance of intracellular NAD stores, is impaired in macrophages from aged mice and humans. Increasing de novo NAD regeneration in these cells restored oxidative phosphorylation and reduced inflammatory markers. Monocytes and macrophages play a pivotal role in the initiation and progression of atherosclerotic lesions as well as in the worsening of advanced lesions, ultimately leading to plaque rupture. Plaque macrophages subsets display various intermediate phenotypes from pro-inflammatory macrophages to anti-inflammatory macrophages. The functions of these polarized macrophages relies on metabolic reprogramming. Increasing lines of evidence showed that targeting the metabolism of myeloid cells allow to mitigate their functions and their inflammatory status. Targeting NAD metabolism recently emerged as a strategy to tackle inflammation and immune cell functions. Partner 1 (Lipness Team, UMR INSERM 1231, Dijon, France) recently demonstrated that targeting mitophagy is also an approach to modulate myeloid cell activation and inflammation. Partner 1 also demonstrated that the activation STAT1 signaling leads to the inhibition of mitophagy which triggers activation of macrophages and contributes to enhanced bacterial defense and survival upon sepsis. The existence of a similar mechanism in the context of sterile inflammation is yet unknown as well as its eventual consequences on NAD metabolism and UPRmt. STATmiNADage project will to take benefit of the complementary expertise of partner 1 and partner 2 to unravel the interplay between STAT1 signaling, mitochondrial and NAD homeostasis in myeloid cells in chronic inflammation atherosclerosis and aging. This will provide new scientific insights in the physiopathology of atherosclerosis in the course of aging with a focus NAD metabolism and mitochondrial function in myeloid cells. In addition to basic research approaches combining in vitro and in vivo approaches to state-of-the art multi-layered genetic and omics strategies, novel therapeutic strategies will be assessed in in vitro and in vivo in human and mouse models. Moreover, the translational value of this work will be assessed in atherosclerotic patients.