We examined the ability of pyridoxamine (PM), an inhibitor of formation of advanced glycation end products (AGEs) and lipoxidation end products (ALEs), to protect against diabetes-induced retinal vascular lesions. The effects of PM were compared with the antioxidants vitamin E (VE) and R-␣-lipoic acid (LA) in streptozotocin-induced diabetic rats. Animals were given either PM (1 g/l drinking water), VE (2,000 IU/kg diet), or LA (0.05%/kg diet). After 29 weeks of diabetes, retinas were examined for pathogenic changes, alterations in extracellular matrix (ECM) gene expression, and accumulation of the immunoreactive AGE/ALE N -(carboxymethyl)lysine (CML). Acellular capillaries were increased more than threefold, accompanied by significant upregulation of laminin immunoreactivity in the retinal microvasculature. Diabetes also increased mRNA expression for fibronectin (2-fold), collagen IV (1.6-fold), and laminin ␤ chain (2.6-fold) in untreated diabetic rats compared with nondiabetic rats. PM treatment protected against capillary drop-out and limited laminin protein upregulation and ECM mRNA expression and the increase in CML in the retinal vasculature. VE and LA failed to protect against retinal capillary closure and had inconsistent effects on diabetes-related upregulation of ECM mRNAs. These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy.

Progress in gerontological research has been promoted through the use of numerous animal models, which have helped identify possible mechanisms of aging and age-related chronic diseases and evaluate possible interventions with potential relevance to human aging and disease. Further development of nonhuman primate models, particularly rhesus monkeys, could accelerate this progress, because their closer genetic relationship to humans produces a highly similar aging phenotype. Because the relatively long lives of primates increase the administrative and economic demands on research involving them, new emphasis has emerged on increasing the efficient use of these valuable resources through cooperative, interdisciplinary research.As gerontological research continues to gain both visibility and interest within the broader scientific community, the relevance of various model systems for eventual application of findings to humans has become a critical issue. Although rodents remain the most widely used animal model for gerontology, an increasing use of invertebrates has provided many new insights into aging processes, especially regarding possible longevity genes (1). Given the complexity of human physiology, however, models more phylogenetically similar to humans are needed. Advantages and Disadvantages of Nonhuman Primate ModelsResearch using nonhuman primates can provide a valuable approach for elucidating the nature and causes of aging processes observed in humans as well as evaluating potential interventions. An ongoing longitudinal study of aging and nutrition in rhesus monkeys (Macaca mulatta) conducted since 1987 by the National Institute on Aging (NIA), as well as studies conducted at other sites, has revealed much about aging and age-related disease in these monkeys and has shed light on the advantages and disadvantages of their use in gerontological research. Because of their genetic homology to humans (92.5 to 95%), many biological similarities are observed in the profile of aging. Another advantage is that rhesus monkeys are well adapted for laboratory research, including established husbandry, nutrition, breeding practices, and veterinary medicine. Disadvantages of rhesus monkeys include their current limited availability, costs of procurement and maintenance, and genetic heterogeneity. In addition, cross-species risks of disease transmission exist, and issues of animal welfare require constant vigilance. Research in monkeys is only as good as their physical and emotional health.The major scientific disadvantage is that rhesus monkeys are long-lived. Sexual maturity occurs at 3 to 5 years of age, median life-span is 25 years, and maximum life-span is 40 years (2, 3). With an estimated maximum life-span of 122 years in humans (4), the rate of aging in rhesus monkeys is roughly three times as fast. Thus, rhesus monkeys offer a distinct advantage over long-term human aging research, but longitudinal studies in these primates require a major investment of time, resources, and effort. Scope of Rhesus Monkey Res...

Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia. PM inhibited AGE/ALE formation and hyperlipidemia and protected against renal and vascular pathology in a nondiabetic model.

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Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13-14 month-old) mice that co-express two mutations related to familial AD, amyloid precursor protein (APP) and presenilin 1 (PS1), were fed balanced diets with 40% fewer calories than ad libitum-fed controls. Following 18 weeks of treatment, mice were killed and brains processed for quantification of total volume of amyloid-beta (Aβ) in the hippocampal formation and the overlying neocortex. Computerized stereology confirmed that CR reduced the total Aβ volume by about one-third compared to that in age-matched controls. Thus, CR appears to attenuate the accumulation of AD-type neuropathology in two cortical brain regions of middle-aged dtg APP/ PS1 mice. These findings support the view that CR could be a potentially effective, non-pharmacology strategy for reducing relatively heavy Aβ deposition in older adult dtg APP/ PS1 mice, and possibly afford similar protection against the onset and progression of AD in older adult humans.

Aims/hypothesis. This study was designed to determine whether inhibition of formation of AGE and advanced lipoxidation end-products (ALE) is a mechanism of action common to a diverse group of therapeutic agents that limit the progress of diabetic nephropathy. We compared the effects of the ACE inhibitor enalapril, the antioxidant vitamin E, the thiol compound lipoic acid, and the AGE/ALE inhibitor pyridoxamine on the formation of AGE/ALE and protection against nephropathy in streptozotocin diabetic rats. Methods. Renal function and AGE/ALE formation were evaluated in rats treated with the agents listed above. Plasma was monitored monthly for triglycerides, cholesterol, creatinine and TNF-α, and 24-h urine samples were collected for measurement of albumin and total protein excretion. After 29 weeks, renal expression of mRNA for extracellular matrix proteins was measured, and AGE/ALE were quantified in skin and glomerular and tubular collagen. Results. Diabetic animals were both hyperglycaemic and dyslipidaemic, and showed evidence of early nephropathy (albuminuria, creatinaemia). All interventions limited the progression of nephropathy, without affecting glycaemia. The order of efficacy was: pyridoxamine (650 mg·kg −1 ·day −1 ) > vitamin E (200 mg·kg −1 ·day −1 ) > lipoic acid (93 mg·kg −1 ·day −1 ) enalapril (35 mg·kg −1 ·day −1 ). Pyridoxamine also significantly inhibited AGE/ALE accumulation in tissues; effects of other agents were mixed, but the degree of renoprotection was consistent with their effects on AGE/ALE formation. Conclusions/interpretation. All interventions inhibited the progression of nephropathy at the doses studied, but the maximal benefit was achieved with pyridoxamine, which also limited dyslipidaemia and AGE/ALE formation. These experiments indicate that the more effective the renoprotection, the greater the inhibition of AGE/ALE formation. For optimal protection of renal function, it would be beneficial to select drugs whose mechanism of action includes inhibition of AGE/ALE formation.

Calorie restriction (CR) is a reliable antiaging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that had been fed either ad libitum (AL) or 40% calorie restricted based on AL consumption. Rats were assigned to one of three diet groups that received three skin punch wounds along the dorsal interscapular region (12-mm diameter near the front limbs) of the back as follows: (1) CR (n=8) were wounded and maintained on CR until they healed, (2) AL (n=5) were wounded and maintained on AL until wound closure was completed, and (3) CR rats were refed (RF, n=9) AL for 48 h prior to wounding and maintained on AL until they healed. We observed that young rats on CR healed more slowly while CR rats refed for 48 h prior to wounding healed as fast as AL fed rats, similar to a study reported in aged CR and RF mice (Reed et al. 1996). Our data suggest that CR subjects, regardless of age, fail to heal well and that provision of increased nutrition to CR subjects prior to wounding enhances the healing process.

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