ABSTRACT Aging is associated with the development of metabolic disorders, including insulin resistance and hypertension. Young mice that are negative for the neuroendocrine prohormone Chromogranin A (CgA knockout, CgA-KO) display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice. In comparison, aging wild-type (WT) mice gradually lost glucose tolerance and insulin sensitivity. Moreover, while aging WT mice had increased inflammation with higher plasma TNF-α, IFN-γ and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging CgA-KO mice. CgA-KO mice also showed increased expression of mitochondrial and nuclear-encoded complex I genes, implying that they were healthier than WT mice. Most intriguingly, the hypertension in CgA-KO mice was spontaneously reversed with aging. Supplementation of CgA-KO mice with pancreastatin, a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension. We conclude that age-related insulin resistance and hypertension are caused by CgA.

Chromogranin A plays a crucial role in the age-related development of insulin resistance and hypertension