Longitudinal determination of skin collagen glycation and glycoxidation rates predicts early death in C57BL/6NNIA mice.

Abstract

In 1988, the National Institute on Aging launched a 10-year program aimed at identification of biomarkers of aging. Previous results from our laboratory showed that pentosidine, an advanced glycation product, formed in skin collagen at a rate inversely related to maximum life span across several mammalian species. As part of the Biomarkers Program, we investigated the hypothesis that longitudinal determination of glycation and glycoxidation rates in skin collagen could predict longevities in ad libitum-fed (AL) and caloric restricted (CR) mice. C57BL/6NNia male mice were biopsied at age 20 months and at natural death. Glycation (furosine method) was assessed by gas chromatography/mass spectrometry (GC/MS) and the glycoxidation products carboxymethyllysine (CML) and pentosidine were determined by GC/MS and HPLC, respectively. CR vs. AL significantly (P<0.0001) increased both mean (34 vs. 27 months) and maximum (47 vs. 31 months) life spans. Skin collagen levels of furosine (pmol/micromol lysine) were approximately 2.5-fold greater than CML levels and 100-fold greater than pentosidine. Individual accumulation rates modeled as linear equations were significantly (P<0.001) inhibited by CR vs. AL for all parameters and in all cases varied inversely with longevity (P<0.1 to <0.0001). The incidence of three tissue pathologies (lymphoma, dermatitis, and seminal vesiculitis) was found to be attenuated by CR and the latter pathology correlated significantly with longevities (r=0.54, P=0. 002). The finding that markers of skin collagen glycation and glycoxidation rates can predict early deaths in AL and CR C57BL/6NNia mice strongly suggests that an age-related deterioration in glucose tolerance is a life span-determining process.