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Insulin resistance is common with aging and is associated with the inflammatory response in both humans and rodents. A number of peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have been tested for their abilities to attenuate insulin resistance and type 2 diabetes. However, there is no study on the effects of PPARα/γ dual agonists on inflammation and insulin resistance during aging. In the present study, we investigated the ability of 2-[4-(5-chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908), a newly synthesized novel PPARα/γ dual agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rats. Twenty-month-old rats were divided into four groups: ad libitum fed, ad libitum fed supplemented with MHY908 (1 mg and 3 mg/kg/day for 4 weeks), and 40% calorie restricted. Six-month-old ad libitum fed rats were used as an age control. The aged rats supplemented with MHY908 showed reduced serum glucose, triglyceride, and insulin levels, as well as reduced liver triglyceride levels. MHY908 brought about a reduction in endoplasmic reticulum stress and activation of the c-Jun N-terminal kinase in the livers of aged rats, which consequently improved insulin signaling. In the kidneys of aged rats, the efficacy of MHY908 as a potent anti-inflammatory agent was shown by its suppression of NF-κB activation through inhibition of the Akt/IκB kinase signaling pathway. Therefore, the major finding of this study is that MHY908 acts as a therapeutic agent against age-related inflammation associated with insulin resistance by activating PPARα and PPARγ, thus attenuating endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Stresses, such as exposure to ultraviolet radiation and those associated with aging, are known to cause premature cellular senescence that is characterized by growth arrest and morphological and gene expression changes. This study was designed to investigate the protective effect of Sirtuin1 (SIRT1) on the UVB-induced premature senescence. Under in vitro experimental conditions, exposure to a subcytotoxic dose of UVB enhanced human skin fibroblasts senescence, as characterized by increased β-galactosidase activity and increased levels of senescence-associated proteins. However, adenovirus-mediated SIRT1 overexpression significantly protected fibroblasts from UVB-induced cellular deterioration. Exposure to UVB-induced cell senescence was associated with oxidative stress and p38 mitogen-activated protein kinase activation. Molecular analysis demonstrated that deacetylation of Forkhead box O3α (FOXO3α) by SIRT1 changed the transcriptional activity of FOXO3α and increased resistance to the oxidative stress. In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB. Further study demonstrated that SIRT1 activation inhibited cell senescence in the skin of the HR1 hairless mouse exposed to UVB. The study identifies a new role for SIRT1 in the UVB-induced senescence of skin fibroblats and provides a potential target for skin protection through molecuar insights into the mechanisms responsible for UVB-induced photoaging. [ABSTRACT FROM AUTHOR]

Using proteomic techniques, we investigated peroxynitrite (ONOO-) and 4-hydroxy-2-nonenal (HNE) modified serum proteins from young and old Fischer 344 rats. Two-dimensional gel electrophoresis/western blot analysis of nitrotyrosine and HNE-histidine revealed that serum proteins were differentially modified by ONOO- and HNE. Among them, 16 of the modified proteins, identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), are involved in blood coagulation, lipid transport, blood pressure regulation, and protease inhibition. Furthermore, nitration and HNE adduction were found to increase with age, lending support to the oxidative stress hypothesis of aging. Our data showed that proteomic techniques can be valuable tools in the study of protein profiling modifications during aging. [ABSTRACT FROM AUTHOR]

Betaine is an important human nutrient obtained from various foods. In the present study, we assessed the anti-inflammatory effect of betaine on nuclear factor-kappaB (NF-kappaB) during aging. Sprague-Dawley (SD) rats, ages 7 and 21 months, were used in this study. The older rats were fed betaine. To elucidate the effect of betaine on oxidative stress-induced NF-kappaB and its signaling pathway at molecular levels, YPEN-1 cells were used. Results showed that betaine suppressed NF-kappaB and its related gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), and intracellular cell adhesion molecule-1 (ICAM-1) in aged kidney. Furthermore, betaine attenuated oxidative stress-induced NF-kappaB via nuclear factor-inducing kinase/IkappaB kinase (NIK/IKK) and mitogen-activated protein kinases (MAPKs) in the YPEN-1 cells. On the basis of these results, we concluded that betaine suppressed the age-related NF-kappaB activities associated with upregulated NIK/IKK and MAPKs that were induced by oxidative stress. Thus, betaine might be useful as a preventive agent against the activation of NF-kappaB induced during inflammation and aging. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily of transcription factors, are key regulators in various pathophysiological processes related to energy metabolism including lipid, carbohydrate metabolism, and inflammation. At present, little information is on the effect of age and calorie restriction (CR) on PPARs. In the present study, we investigated how age and CR (60% of the ad libitum intake) modulate PPARs in kidneys obtained from Fischer 344 rats, ages 13 and 25 months. Results showed that nuclear protein, mRNA level, and DNA binding activity of PPARs decreased with age, while CR blunted the reduction. Our findings were verified in separate experiments in which rats were injected with lipopolysaccharide, with the result of increased susceptibility to inflammation. Based on these findings, we conclude that the altered expression of PPARs may be due to increased oxidative stress with age, and that CR prevents these decreases through its antioxidative action. [ABSTRACT FROM AUTHOR]

The relevance of prostanoids to inflammation, thrombosis, and cardiovascular diseases is well known. The present study attempts to explore age effects on prostanoids and their biosynthesis cascade. Results from comparing prostanoid levels between young (6 months) and old (24 months) Fischer 344 rats showed rises of prostaglandin E2 (PGE2), PGI2, and thromboxane A2 (TXA2) levels in the old rats. Correlating evidence showed gene expression up-regulation of several prostanoid synthase enzymes in old rat aorta. Further, we found that expression of the antioxidant enzyme glutathione peroxidase was raised by age in the aorta, while superoxide dismutase and catalase expression showed no significant change during aging in the aorta. Moreover, calorie restriction (CR) was found to attenuate age-related prostanoid changes by suppressing inflammatory activities. In conclusion, the data from this study indicated that age-related increases in prostanoids and their biosynthesis might be closely associated with a weakened antioxidant capacity. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX) is the key rate-limiting enzyme in the prostaglandin synthetic pathway. Two isoforms of COX have been identified: a constitutive COX-1 and an inducible COX-2, which is activated in response to various stimuli. We investigated the changes of COX-1 and COX-2 in rat heart during aging. We measured the age-related changes in the mRNA and protein levels of COX by using reverse-transcription polymerase chain reaction and Western blotting, respectively. COX-2 mRNA and protein levels increased with age, whereas those of COX-1 showed no change. The COX activity determined by prostaglandin E(2) production increased with age. Because the COX-catalyzed arachidonate cascade is an important source of reactive oxygen species (ROS) generation, changes in ROS generation and lipid peroxidation were also assessed. The amount of ROS generated by the COX pathway increased with age, as did the total ROS generation and lipid peroxidation. These results show that COX-2 activity increases with age, partially because of elevated transcriptional expression and protein content, and they suggest that increased COX-2 can play a role in oxidative alterations in the aged heart. [ABSTRACT FROM AUTHOR]

Investigates the effect of duration and age of initiation of dietary restriction (DR) on the spontaneous occurrence of leukemia in male rats. Relative onset rate; Onset and progression; Statistical analyses; Pathological examination and classification of leukemia; Care and dietary programs for rats.

The effects of aging and of food restriction at different times during life on rat adipocyte responses to glucagon and epinephrine were explored by studying hormone-stimulated lipolysis, hormone binding, and phosphodiesterase activity. The times of food restriction were: (a) from 6 weeks of age, (b) limited to early life, and(c) beginning in young adult life. Hormone-sensitive lipolysis is lost with age. Food restriction from 6 weeks of age prevents this loss, and food restriction started in adult life causes the recovery of this lipolysis. Hormone binding studies reveal that: (a) changes in glucagon-stimulated lipolysis parallel changes in glucagon binding; (b) glucagon binding and glucagon-stimulated lipolysis correlate inversely with cell size; (c) changes in epinephrine-stimulated lipolysis are not due to changes in (β-adrenergic binding; and (d) neither β adrenergic binding nor epinephrine-promoted lipolysis correlate with fat cell size. Phosphodiesterase activity is not influenced by diet, making it unlikely to be a postreceptor component lost with age. [ABSTRACT FROM PUBLISHER]

The aims of this research were (a) to compare food restriction initiated in adult life of male Fischer 344 rats with that limited to early life or involving most of the life span on physical, metabolic, and longevity characteristics and (b) to study a similar level of protein restriction without caloric restriction on these characteristics. Food restriction (60% of the ad libitum intake) initiated at 6 months of age markedly increased life span as did a similar restriction started at 6 weeks of age, but food restriction limited to early life (6 weeks to 6 months of age) and protein restriction caused only a small increase in longevity. Food restriction does not act by reducing the intake of calories or other nutrient per gram of body mass, a finding not in accord with classic views. A progressive decrease in spontaneous locomotive activity with age occurred in ad libitum fed but not restricted rats [ABSTRACT FROM PUBLISHER]

The aim of this study was to explore the effects of nutritional manipulations on the occurrence and progression of age-related pathologic lesions in male Fischer 344 rats. The following nutritional regimens were studied: (a) ad libitum feeding, (b) food restriction initiated at 6 weeks of age, (c) food restriction initiated at 6 months of age, (d) food restriction limited to a period of early life (6 weeks to 6 months of age), (e) protein restriction without caloric restriction. The major age-related lesions observed were chronic nephropathy, cardiomyopathy, and neoplasia. Food restriction initiated at 6 months of age was as effective as food restriction initiated at 6 weeks of age in slowing the progression of chronic nephropathy and cardiomyopathy and in delaying the occurrence of neoplasia. Food restriction limited to early life was much less effective. Protein restriction in the absence of caloric restriction did not delay the occurrence of neoplasia, but it did retard chronic nephropathy and cardiomyopathy, although much less effectively than caloric restriction involving a similar level of protein restriction. [ABSTRACT FROM PUBLISHER]

A life-span study was carried out on longevity, pathologic lesions, growth, lean body mass and selected aspects of muscle of barrier-maintained SPF fischer 344 rats fed either ad (Group A) or 60% of the ad intake (Group R). Food restriction was as effective in prolonging the life of already long-lived SPF rats as previously shown for rats maintained in conventional facilities. Food restriction not only increased the mean length of life but also acted to extend life span since more than 60% of the Group R rats lived longer than the longest lived Group A rat. Renal lesions occurred at an earlier age in Group A rats than in Group R rats and progressed more rapidly. Death of most Group A rats was associated with severe renal lesions while few Group R rats showed such lesions at death. Food restriction was also found to delay or prevent interstitial cell tumors of the testes, bile duct hyperplasia, myocardial fibrosis and myocardial degeneration. Gastrocnemius muscle mass declined in advanced age and food restriction delayed this decline. Interestingly, however, lean body mass did not progressively decline with increasing age but rather decline occurred only after the onset of the terminal disease process. [ABSTRACT FROM PUBLISHER]

The objective of this study was to determine the effect of dietary restriction on the spontaneous occurrence and the progression of leukemia in male F344 rats. The analysis involved both sacrificed rats and those that died spontaneously. These rats had been either ad libitum fed (AL) or restricted to approximately 60% of the ad libitum intake (DR) from 6 weeks of age. Dietary restriction delayed spontaneous death due to this disease by delaying the occurrence of leukemia. However, dietary restriction did not retard its progression, i.e., the time between occurrence and death. [ABSTRACT FROM PUBLISHER]

The influence of dietary manipulations on fatal neoplasms in male Fischer 344 rats was assessed. Particular attention was paid to leukemia and pituitary adenoma because they are the most common potentially fatal neoplasms that occur in this rat strain. The only dietary manipulation which depressed the mortality rates due to neoplastic disease was that involving a reduction in energy intake. Reduction of mineral or protein or fat intake without a reduction of energy had, at most, marginal effects on fatal neoplastic disease. [ABSTRACT FROM PUBLISHER]

The influence of replacing dietary casein with soy protein on longevity and age-related pathologic lesions of male Fischer 344 rats was investigated. Caloric intake and body weights were similar for rats on the two diets. Rats on the soy protein-containing diet had a median length of life of 844 days compared to 730 days for those on the caseincontaining diet (p < .002), and the ages of the 10th percentile survivors were 937 and 857 days, respectively (p > .02). The progression of chronic nephropathy was markedly retarded by replacing casein with soy protein. Only 7% of the rats dying spontaneously on the soy protein-containing diet exhibited end-stage chronic nephropathy compared to 41 % of the rats on the casein-containing diet. Clearly, the soy protein-containing diet enables ad libitum fed male Fischer 344 rats to be used as a model for aging research without the occurrence of renal failure as a major confounding problem [ABSTRACT FROM PUBLISHER]

The influence of restricting either the fat or the mineral component of the diet to the same extent as they are restricted in the life-prolonging, food-restriction paradigm but without restricting calories was studied in regard to longevity and age-related pathologic lesions of barrier-maintained male Fischer 344 rats. Neither the restriction of fat nor the restriction of mineral influenced the median length of life or maximum life span as indicated by the age of the 10th percentile survivors. Restricting the dietary fat did retard the development of chronic nephropathy and associated lesions, but it also increased the prevalence of lymphoma and leukemia. The development of chronic nephropathy was not significantly affected by restricting the mineral component of the diet. [ABSTRACT FROM PUBLISHER]