Gut microbial DNA and immune checkpoint gene Vsig4/CRIg are key antagonistic players in healthy aging and age-associated development of hypertension and diabetes

ABSTRACT: Aging is associated with the development of insulin resistance and hypertension. Aim of this study was to identify factors regulating these processes. We studied mice with complete knockout (KO) of the neuroendocrine prohormone Chromogranin A (CgA) as a model for healthy aging. These mice display two opposite aging phenotypes: hypertension but heightened insulin sensitivity at young age, whereas the blood pressure normalizes at older age and insulin sensitivity further improves. In comparison, aging WT mice gradually lost glucose tolerance and insulin sensitivity and developed hypertension. Quantitative RT-PCR revealed increased (~35-fold) accumulation of bacterial DNA in the heart of 2-yr-old WT mice compared to only ~2-fold increase in age-matched CgA-KO mice. Similarly, RNA sequencing showed increased expression of the Vsig4 gene (which removes bacterial DNA) in the liver of 2-yr-old CgA-KO mice, which possibly accounts for the very low accumulation of microbial DNA in the heart. The reversal of hypertension in aging CgA-KO mice is possibly due to (i) low accumulation of microbial DNA (i.e., reduced inflammation), and (ii) decreased spillover of norepinephrine (measured by ultra-pressure liquid chromatography) in the heart and kidneys. The reverse is true for aging WT mice. Moreover, while aging WT mice had increased inflammation with higher plasma TNF-⍺, IFN-ɣ, CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging CgA-KO mice. We conclude that Vsig4 plays a crucial role in “healthy aging” by counteracting age-associated insulin resistance and hypertension.

ORGANISM(S): Mus musculus

PROVIDER: GSE217145 | GEO | 2022/11/09

REPOSITORIES: GEO