Source of Chronic Inflammation in Aging

Aging is a complex process that results from a combination of environmental, genetic, and epigenetic factors. A chronic pro-inflammatory status is a pervasive feature of aging. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as “inflammaging” and represents a significant risk factor for morbidity and mortality in the elderly. The low-grade inflammation persists even after reversing pro-inflammatory stimuli such as LDL cholesterol and the renin–angiotensin system (RAS). Recently, several possible sources of chronic low-grade inflammation observed during aging and age-related diseases have been proposed. Cell senescence and dysregulation of innate immunity is one such mechanism by which persistent prolonged inflammation occurs even after the initial stimulus has been removed. Additionally, the coagulation factor that activates inflammatory signaling beyond its role in the coagulation system has been identified. This signal could be a new source of chronic inflammation and cell senescence. Here, we summarized the factors and cellular pathways/processes that are known to regulate low-grade persistent inflammation in aging and age-related disease

IGF Binding Protein-5 Induces Cell Senescence

Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5) with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs), and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I) and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding

Gene-Therapeutic Strategies Targeting Angiogenesis in Peripheral Artery Disease

The World Health Organization announced that cardiovascular disease is the number one cause of death globally, representing 31% of all global deaths. Coronary artery disease (CAD) affects approximately 5% of the US population aged 40 years and older. With an age-adjusted prevalence of approximately 12%, peripheral artery disease (PAD) affects at least 8 to 12 million Americans. Both CAD and PAD are caused by mainly atherosclerosis, the hardening and narrowing of arteries over the years by lipid deposition in the vascular bed. Despite the significant advances in interventions for revascularization and intensive medical care, patients with CAD or PAD who undergo percutaneous transluminal angioplasty have a persistent high rate of myocardial infarction, amputation, and death. Therefore, new therapeutic strategies are urgently needed for these patients. To overcome this unmet need, therapeutic angiogenesis using angiogenic growth factors has evolved in an attempt to stimulate the growth of new vasculature to compensate for tissue ischemia. After nearly 20 years of investigation, there is growing evidence of successful or unsuccessful gene therapy for ischemic heart and limb disease. This review will discuss basic and clinical data of therapeutic angiogenesis studies employing angiogenic growth factors for PAD patients and will draw conclusions on the basis of our current understanding of the biological processes of new vascularization

Critical roles of cold shock domain protein A as an endogenous angiogenesis inhibitor in skeletal muscle

PublisherAngiogenesis is regulated by the local balance between angiogenic stimulators and inhibitors and is maintained by muscle-derived angiogenic factors in ischemic tissues. AIMS: Our objectives were to investigate the effect of cold shock domain protein A (CSDA) as an endogenous angiogenesis inhibitor and to develop a novel strategy of therapeutic angiogenesis by blocking CSDA expression. RESULTS: In human skeletal muscle cells, CSDA was upregulated during hypoxia when cells were damaged and apoptosis was induced. CSDA expression could repress the activity of hypoxia inducible factor-1α and nuclear factor κB, because CSDA can competitively bind the hypoxia response element and the nuclear factor κB-binding element. As a result, vascular endothelial growth factor-A, interleukin-6, and interleukin-8 secretions from skeletal muscle cells were decreased. Further, CSDA depletion increased the secretion level of these angiogenic factors. In a hindlimb ischemia model, transfer of short-hairpin RNA targeting CSDA ameliorated ischemia without direct transfer of angiogenic factors. In this ischemic tissue, vascular endothelial growth factor-A, interleukin-6, and CXCL2 protein levels were increased. INNOVATION AND CONCLUSION: CSDA appears to play a critical role as an endogenous angiogenesis inhibitor in skeletal muscle, and RNA interference targeting of CSDA is a promising gene therapy strategy for treating peripheral arterial disease