Methionine restriction improves renal insulin signalling in aged kidneys

Abstract

Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190 days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.

Sex differences in the response to dietary restriction in rodents

“…A recent study of 10mo old male and female C57BL/6J wild-type mice demonstrated sex specific differences in kidney gene expression as a function of an 8-week MetR diet (0.172%). Females significantly upregulated FGF-21 and its co-receptor, b-Klotho, which controls energy expenditure, while male mice significantly upregulated SIRT-1 with potential renoprotective effects on lipid and glucose metabolism [35]. These sex differences in response to MetR diet may help explain the sexual dimorphism in the acute-to-chronic kidney disease transition [36].…”

Potent long-acting rhFGF21 analog for treatment of diabetic nephropathy in db/db and DIO mice

“…An earlier study has shown that rhFGF21 treatment significantly ameliorated functional and morphological glomerular abnormalities induced by chronic diabetic injury in db/db mice [32]. However,the clinical use of rhFGF21 for diabetic kidney injuries has been hampered by its poor in-vivo stability, a daily IP injection of 25 μg/kg rhFGF21 for 3 months was required to ameliorate renal injury in db/db mice.…”

Health Recommendations for the Elderly in the Viewpoint of Traditional Persian Medicine

“…It is proposed that one probable mechanism of low methionine diet on extending lifespan is diminishing tissue oxidative stress through decreasing mitochondrial ROS generation and subsequent DNA and protein damage (41). A recent study also showed renoprotecrive effect of MR-diet in rats (42). TPM recommended foods for the elderly such as honey, leek, lettuce, yellow carrot, vegetable porridges, ginger, light broth and barley soup contain low methionine and seem to be healthy based on the recent evidence.…”