Aging of the world population has made prolongation of health a more important priority than ever. Several models of extended health and delayed aging such as caloric restriction and mouse models of dwarfism demonstrate low blood glucose. However, these models have complex physiology and it is not known whether low blood glucose is important to their prolonged health and extended lifespan. Of potential value to understanding the relationship between blood glucose and aging is a transgenic mouse line, designated Inshex, with a healthy phenotype but permanently low blood glucose, 25-50% lower than normal mice. The mouse was originally developed mice to study pancreatic ?-cells and diabetes. The Inshex transgene produced a left shift in the pancreatic ?-cell insulin secretion response to glucose but the final phenotype is hypoglycemia with almost normal serum insulin levels. This proposal will use Inshex mice to test if blood glucose influences aging. Inshex mice are healthy, of normal size and fertile. Blood glucose is reduced at 500 days of age. The first goals of this project are to confirm that blood glucose stays low permanently and that reduced blood glucose extends longevity. Lifespan will be determined in cohorts of 30 male Inshex and 30 non-transgenic littermates that will be followed undisturbed to determine the age when mice become moribund and require euthanasia. A veterinary pathologist will assess the cause of morbidity. Over the course of their lives mice will be observed daily and weighed monthly. In separate cohorts of Inshex and control mice, blood and urine samples will be obtained at 3 month intervals to measure blood glucose, HbA1c, plasma free fatty acids and urine albumin to creatinine ratio. Groups of mice will be sacrificed at 5, 10 and 20 months of age. The day before sacrifice mice will be placed in metabolic chambers to determine respiratory quotient by indirect calorimetry and simultaneously measure ambulatory activity. Unlike other mouse models with low glucose initial results indicate that Inshex mice have a normal respiratory quotient. After the metabolic chamber, animals will be anesthetized for DEXA scan measurement of body composition and for obtaining a large blood sample to measure metabolic hormones implicated in modulation of aging (insulin, IGF1 or growth hormone). Aging is the leading cause for loss of renal function in people. A preliminary analysis indicated less glomerular scarring in 400-500 day Inshex kidneys. The beneficial effect of Inshex low glucose on kidney structure and function will be confirmed by examining renal histology of control and Inshex mice sacrificed at 5, 10 and 20 months and by comparing age associated leakage of albumin into the urine. These studies will demonstrate whether low blood glucose extends function of the kidney and lifespan of the mouse.
Lowbloodglucoseiscommontoseveralcomplexmodelsofextendedhealthandlifebutitisnotknown iflowglucoseisimportanttoprolongedhealthoranon?essentialby?product.Thisprojectwilltesta novelmousemodelwhichhaslowbloodglucoseastheprimarydifferencefromnormalmicetotestif lowbloodglucoseissufficienttoextendlongevity.
