Identifying Advanced Glycation End Products as a Major Source of Oxidants in Aging: Implications for the Management and/or Prevention of Reduced Renal Function in Elderly Persons

Abstract

Summary Aging is characterized by increasing inflammation and oxidant stress (OS). Reduced renal function was present in more than 20% of normal-aged individuals sampled in the National Health and Nutrition Examination Survey (NHANES) cross-sectional study of the US population. Longitudinal studies in the United States and Italy showed that renal function does not decline in some individuals, suggesting that a search for causes of the loss of renal function in some persons might be indicated and interventions to reduce this outcome should be sought. Because advanced glycation end products (AGEs) induce both inflammation and OS, accumulate with age, and primarily are excreted by the kidney, one outcome of reduced renal function in aging could be decreased AGE disposal. The build-up of AGEs with reduced renal function could contribute to inflammation, increased oxidant stress, and accumulation of AGEs in aging. In fact, results from a longitudinal study of normal aging adults in Italy showed that the most significant correlation with mortality was the level of renal function. A clear link between inflammation, OS, AGEs, and chronic disease was shown in studies of mice that showed that reduction of AGE levels by drugs or decreased intake of AGEs reduces chronic kidney disease (CKD) and cardiovascular disease of aging. The data support a role for AGEs in the development of renal lesions in aging mice and reveal that AGEs in the diet are very important contributors to renal and cardiovascular lesions. AGEs signal through two receptors, one of which is anti-inflammatory (AGER1) and the other is proinflammatory (RAGE). Overexpression of AGER1 protects against OS and acute vascular injury. The reduction of AGEs in the diet is as efficient in preventing aging-related cardiovascular and renal lesions in mice as that seen with calorie restriction. Studies in normal adults of all ages and those with CKD suggest that the findings in mice may be directly applicable to both aging and CKD. Namely, the dietary content of AGEs determines the serum levels of AGEs and inflammatory mediators and urine AGE levels in both normal subjects and CKD patients. Importantly, reduction of AGEs controls these changes in both normal subjects and CKD patients, and the phenotypic changes in AGER1 are reduced in CKD patients by decreasing the amount of AGEs consumed with the diet. These data suggest that the changes in renal function in normal aging may be subject to control and this subject deserves renewed attention.

AGE restriction in diabetes mellitus: a paradigm shift

“…Whether epigenetic changes could be traced to the increased AGE content of modern food and whether this could play a part in the high incidence of diabetes mellitus was tested in transgenerational studies in C57B6 mice exposed to an AGE-restricted or methylglyoxal-supplemented diet and monitored for five generations (F0 to F5). 118,154 A striking observation was made in that by the fifth generation, methylglyoxal-fed F5-mice developed insulin resistance followed by diabetes mellitus at 16–18 months of age, whereas AGE-restricted F5-mice did not develop these changes until the age of 36 months or more (H. Vlassara, unpublished work). This acceleration of T2DM onset in methylglyoxal-fed mice over five generations (by more than one-third of a normal life cycle) could not be attributed to genetic effects, an argument similar to that raised by the doubling of obesity in humans within one generation.…”

Age dependent accumulation patterns of advanced glycation end product receptor (RAGE) ligands and binding intensities between RAGE and its ligands differ in the liver, kidney, and skeletal muscle

“…The AGEs-RAGE pathway is a primary contributor to kidney aging [13]. The accumulation of AGEs and a progressive decline in renal function during aging may induce the release of inflammatory mediators and the generation of reactive oxygen species (ROS) [10, 11].…”

Glycation‐altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age‐related disease (in nondiabetics)

“…These data, along with epidemiologic observations, elicited our hypothesis that over time, elevated postprandial blood sugar levels, due to consuming high GI diets, is mechanistically linked to the intracellular accumulation of AGEs in the retina (Chiu, 2011a). Furthermore, we posited that this dGI-induced accumulation of AGEs would be related to retina cellular and tissue damage because conditions which favor formation of such AGEs were previously associated with cytotoxicity, disease, oxidative stress, senescence and aging, and diminished cell viability (Tessier et al , 1999; Ihnat et al , 2007; Goligorsky et al , 2009; Guix et al , 2009; Vlassara et al , 2009; Wei et al , 2009; Ahmed et al , 2010). …”