Chromogranin A is an aging risk factor

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PROJECT SUMMARY Chromogranin A (CgA) is a component of dense core vesicles of endocrine and neuroendocrine cells and neurons that control the storage of neurotransmitters and hormones. CgA is a prohormone which is processed into peptide hormones with distinct biological functions. Two of these peptides, catestatin (CST: hCgA352-372) and pancreastatin (PST: hCgA250-301), exhibit diametrically opposite functions: CST is anti- hypertensive, anti-inflammatory, and anti-diabetic, whereas PST is pro-inflammatory, pro-hypertensive and pro-diabetic. High levels of CgA are present in the blood of patients with malignancies, inflammatory diseases, and neurological disorders, and their levels rise as their clinical conditions worsen. Although Chga (gene encoding CgA)-null mice have been available for nearly 20 years and have been widely studied, the impact of CgA on aging has not been investigated. We found that CgA-KO mice develop hypertension at a young age, but it reverses beyond the age of 12 months. We also noted that a few unused CgA-KO mice (all male) that were kept aside lived at least 40 months. We also found that mRNA levels of lipoprotein lipase (LPL), which controls triglyceride levels and V-set and immunoglobulin domain containing 4 (Vsig4), which control bacterial clearance via autophagy, are low in the heart and liver of CgA-KO young mice but high in old mice. We further found that leakage of bacterial DNA to other different organs in older WT mice. These preliminary observations imply that CgA is an aging-inducing factor, but it has a positive role at early ages through maintenance of lipid metabolism. We propose that differential processing of CgA into CST and PST would determine aging through regulation of factors involved in metabolism and inflammation. This proposal aims to investigate the validity of our hypothesis by assessing the lifespan, growth, mitochondrial health, energy expenditure of a larger cohort of WT and CgA-KO males and females. We will further determine the factors critical for CgA-induced aging and the pathways involved in the spontaneous reversal of hypertension and lifespan extension of CgA-KO mice with emphasis on the lipoprotein-adipokine, catecholamine-adrenergic receptor and Vsig-4-autophagy signaling axes in four different tissues. The proposed research will be led by two Co-PIs: Dr. Mahata, a physiologist whose research focuses on hypertension, insulin resistance and immunometabolism, and Dr. Ghosh, a biochemist who studies inflammatory responses through the IKK-NF-B signaling pathways. If the hypotheses prove to be correct, long-term studies to determine the underlying mechanisms of CgA-induced aging will be conducted. Experiments proposed here will also help to determine if CgA can be targeted for therapy against inflammatory disorders, aging-related and neurological disorders by lowering CgA transcripts at an older age to reduce the pathogenic repercussions.