These pathological actions of TNF-α are aggravated by aging, smoking, and obesity, which are associated with a chronic low-grade increase in TNF-α [46], suggesting that a positive feedback loop may occur in some clinical settings that accentuate the vascular damaging effects of both TNF-α and the more traditional vascular risk factors. This evidence concerns the gene TNF and obesity due to melanocortin 4 receptor deficiency.