LAUSR

Inflammaging is defined as a chronic low-grade and systemic inflammation that accelerates the process of biological aging and is associated with many age-related diseases including cardiovascular disease (CVD), rheumatoid arthritis (RA), myeloproliferative disease, inflammatory bowel disease, Alzheimer's disease, and frailty.1 There are many contributors to this inflammatory status including adiposity, senescent cells, and aged monocytes, which secrete a low level of pro-inflammatory cytokines in the absence of antigenic challenge.2 Senescent cells are metabolically active, non-proliferative, but highly pro-inflammatory cells that accumulate in tissue and organs throughout the body in association with age-related decline in the innate immune system's clearance capability (eg, natural killer cells).3 Aging is of course strongly associated with increased risk of CVD, the leading cause of worldwide mortality.4 Platelets play a vital role in normal hemostasis and are key players in the pathogenesis of atherothrombosis. These abundant anuclear cells not only directly mediate thrombosis but are now recognized as true inflammatory cells that can both propagate inflammatory responses and directly respond to inflammation.5 Antiplatelet drugs are therefore important for the prevention of thrombotic events in high-risk patients with established CVD. Intrinsic platelet reactivity varies between individuals and increases with age.6,7 In older individuals, platelet hyperreactivity therefore occurs more commonly and is associated with chronic age-related CVD, comorbidities, and mortality. Furthermore, underlying platelet reactivity can significantly affect responsiveness to antiplatelet drugs used to prevent thrombosis.8-10 Although the mechanisms that govern platelet reactivity in age are multifactorial (eg, genetics, poor glucose control, dyslipidemia, and oxidative stress), the precise pathways linking inflammaging to platelet function are not yet fully defined. Despite this, inflammatory cytokines such as TNF-α, IL-1β, IL-8, and IL-6 are elevated with age and associated with a suite of inflammatory conditions and CVD. Inflammatory mediators can also modify platelet function. For example, IL-6 has been implicated in altering the megakaryocytic/platelet axis, potentially leading to polyploidization and consequent thrombopoiesis with a shift toward a more prothrombotic phenotype and a higher mean platelet volume (MPV).11 Furthermore, platelets express GP130, which can bind to complexes of IL-6 and soluble IL-6 receptor α (sIL-6Rα) to further prime platelets via transcellular signalling and further increase their reactivity during inflammation.12 The incidence of CVD as a comorbidity in age-related diseases is also high suggesting a common pathophysiology mediated by inflammatory cytokines. Acquired platelet hyperreactivity is thus an important modifiable phenotype that forms an attractive therapeutic target for an aging population at risk of chronic diseases mediated by inflammaging. A recent paper by Davizon-Castillo et al13 in Blood now further establishes how platelet hyperreactivity is driven by chronic inflammation. An excellent commentary on this article by Podrez14 was also in the same issue. This research builds upon a series of studies from some of the authors studying altered platelet function in aging. The authors now demonstrate that the pro-inflammatory cytokine TNF-α drives metabolic reprogramming of megakaryocytes (MK), platelet mitochondrial dysfunction, and platelet hyperreactivity as part of normal aging in humans and mice. Furthermore, exogenous administration of TNF-α to young mice also recapitulated the aging platelet phenotype. Older mice had increased plasma levels of TNF-α and increased platelet counts but with no change in leukocyte count, in agreement with previous studies.15,16 Upon stimulation, washed murine platelets from older mice exhibited heightened αIIbβ3 integrin expression, increased phosphatidylserine exposure, and formed larger thrombi more rapidly on collagen-coated slides. Interestingly it has been shown previously that TNF-α levels are much higher in the bone marrow compartment when compared to plasma in aged mice suggesting that local bone marrow MKs will be more susceptible to inflammaging.17 There is good evidence implicating monocytes as a source of both bone marrow and systemic increases in pro-inflammatory Manuscript handled by: Ton Lisman