Sataro Goto

Biological significance of protein modifications in aging and calorie restriction

By virtue of the progress in proteomics, the involvement of posttranslational modifications in aging has been more clearly demonstrated in recent years. We describe here that (1) carbonylation, a hallmark of protein oxidation in general, is paradoxically decreased in histone with aging and increased by calorie restriction (CR), (2) acetylation of lysine 9 and phosphorylation of serine 10 in histone H3 are decreased and increased, respectively, with aging, and (3) the acetylation level of multiple extranuclear proteins decreases significantly with aging, and the change was not only retarded but increased remarkably by CR in rat liver. Based on these findings, we discuss possible implications of the posttranslational protein modifications in biochemical processes underlying aging and CR‐induced extension of life span.

Exercise training increases anabolic and attenuates catabolic and apoptotic processes in aged skeletal muscle of male rats

Aging results in significant loss of mass and function of the skeletal muscle, which negatively impacts the quality of life. In this study we investigated whether aerobic exercise training has the potential to alter anabolic and catabolic pathways in the skeletal muscle. Five and twenty eight month old rats were used in the study. Aging resulted in decreased levels of follistatin/mTOR/Akt/Erk activation and increased myostatin/Murf1/2, proteasome subunits, and protein ubiquitination levels. In addition, TNF-α, reactive oxygen species (ROS), p53, and Bax levels were increased while Bcl-2 levels were decreased in the skeletal muscle of aged rats. Six weeks of exercise training at 60% of VO2max reversed the age-associated activation of catabolic and apoptotic pathways and increased anabolic signaling. The results suggest that the age-associated loss of muscle mass and cachexia could be due to the orchestrated down-regulation of anabolic and up-regulation of catabolic and pro-apoptotic processes. These metabolic changes can be attenuated by exercise training.

Nitric oxide: Is it the cause of muscle soreness?

Skeletal muscle hosts all of the isoforms of nitric oxide synthase (NOS). It is well documented that nitric oxide (NO) regulates force generation and satellite cell activation, and therefore, damage repair of skeletal muscle. NO can also activate nociceptors of C-fibers, thereby causing the sensation of pain. Although delayed-onset of muscle soreness (DOMS) is associated with decreased maximal force generation, pain sensation and sarcomere damage, there is a paucity of research linking NO and DOMS. The present mini-review attempts to elucidate the possible relationship between NO and DOMS, based upon current literature.

Voluntary Exercise Can Ameliorate Insulin Resistance by Reducing iNOS-Mediated S-Nitrosylation of Akt in the Liver in Obese Rats

Voluntary exercise can ameliorate insulin resistance. The underlying mechanism, however, remains to be elucidated. We previously demonstrated that inducible nitric oxide synthase (iNOS) in the liver plays an important role in hepatic insulin resistance in the setting of obesity. In this study, we tried to verify our hypothesis that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. Twenty-one Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats were randomly assigned to a sedentary group or exercise group subjected to voluntary wheel running for 20 weeks. The voluntary exercise significantly reduced the fasting blood glucose and HOMA-IR in the OLETF rats. In addition, the exercise decreased the amount of iNOS mRNA in the liver in the OLETF rats. Moreover, exercise reduced the levels of S-nitrosylated Akt in the liver, which were increased in the OLETF rats, to those observed in the LETO rats. These findings support our hypothesis that voluntary exercise improves insulin resistance, at least partly, by suppressing the iNOS expression and subsequent S-nitrosylation of Akt, a key molecule of the signal transduction pathways in glucose metabolism in the liver.

Cardiorespiratory fitness, body mass index, and cancer mortality: a cohort study of Japanese men

BackgroundThe aim of this study is to investigate the independent and joint effects of cardiorespiratory fitness (CRF) and body mass index (BMI) on cancer mortality in a low body mass index population.MethodsWe evaluated CRF and BMI in relation to cancer mortality in 8760 Japanese men. The median BMI was 22.6xa0kg/m2 (IQR: 21.0-24.3). The mean follow-up period was more than 20xa0years. Hazard ratios and 95% CI were obtained using a Cox proportional hazards model while adjusting for several confounding factors.ResultsUsing the 2nd tertile of BMI (21.6-23.6xa0kg/m2) as reference, hazard ratios and 95% CI for the lowest tertile of BMI (18.5-21.5) were 1.26 (0.87–1.81), and 0.92 (0.64–1.34) for the highest tertile (23.7-37.4). Using the lowest tertile of CRF as reference, hazard ratios and 95% CIs for 2nd and highest tertiles of CRF were 0.78 (0.55–1.10) and 0.59 (0.40–0.88). We further calculated hazard ratios according to groups of men cross-tabulated by tertiles of CRF and BMI. Among men in the second tertile of BMI, those belonging to the lowest CRF tertile had a 53% lower risk of cancer mortality compared to those in the lowest CRF tertile (hazard ratio: 0.47, 95% CI: 0.23-0.97). Among those in the highest BMI tertile, the corresponding hazard ratio was 0.54 (0.25-1.17).ConclusionThese results suggest that high CRF is associated with lower cancer mortality in a Japanese population of men with low average BMI.

Dietary restriction increases site-specific histone H3 acetylation in rat liver: Possible modulation by sirtuins

We studied dietary restriction (DR) related changes of site-specific acetylation of histone H3 in rat livers to explore a possible link to histone modifications and sirtuin levels with anti-aging effects of DR. The acetylation at lysine residue 9, 27 and 56 in H3 was 20-30% higher in DR animals compared with ad libitum fed counterparts. SIRT6, one of histone deacetylases, was significantly decreased by DR and thereby may be involved in an increase in the histone acetylation. Our findings suggest that upregulation of chromatin activities through increased histone acetylation is a mechanism of anti-aging effects of DR.

The biological mechanisms of aging: A historical and critical overview

This overview describes the historical background and modern versions of selected theories of the mechanisms of biological aging, including the mutation or genome instability theory, the free radical or oxidative stress theory, the mitochondrial theory, the error catastrophe theory, the altered protein or protein homeostasis dysregulation theory, the dysdifferentiation or epigenetic theory and the hyperfunction theory. The author has been involved in the development of some of these theories, which are therefore described in more detail. A discussion on the definition of aging and general comments on aging theory are included. The most popular theory of aging, the free radical or oxidative theory, was proposed more than 50 years ago but has recently faced severe criticism. To date, no single theory has been able to successfully explain the mechanisms of aging. We are thus awaiting the appearance of a new paradigm or an integration of the existing theories for a better understanding of the mechanisms of aging.

Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages

IntroductionTo examine whether the mutagenic potential of lung exposure to air-borne environmental mutagens is age dependent, we administered 1xa0mg of benzo[a]pyrene intratracheally to 11- and 24-month old (middle-aged and old, respectively) gpt delta transgenic mice that harbor gpt (guanine phosphoribosyltransferase) genes integrated in the genomic DNA as a target for mutation detection, and then analyzed the benzo[a]pyrene-induced and spontaneous in vivo mutations and mutation spectrum in the lungs.ResultsThe mutant frequencies in the lungs of the 11- and 24-month–old control (vehicle-treated) gpt delta mice were 1.14u2009±u20090.22u2009×u200910−5 and 1.00u2009±u20090.20u2009×u200910−5, respectively, which are significantly higher than that observed for the control 3-month–old (young) mice (0.59u2009±u20090.13u2009×u200910−5) in our previous studies, indicating that spontaneous mutation in the lung increases with age. The mutant frequencies in 11- and 24-month–old mice treated with benzo [a] pyrene were 1.5- and 2.3-fold, respectively, that of the age-matched control mice, and 4.3-fold that of the 3-month–old mice in our previous studies. Analysis of mutation spectra showed that both G:C to A:T transitions and G:C to T:A transversions were predominant in the lungs of control mice at all ages. In benzo [a] pyrene-treated mice in our previous studies, G:C to T:A transversions were the predominant type of mutation (55xa0%) at 3xa0months. Here we found that their frequency was dramatically reduced to 18xa0% by 24xa0months, and the G:C to A:T transitions became the predominant type of mutation in 24-month–old mice (41xa0% [16xa0% at CpG sites]).ConclusionsOur findings suggest that susceptibility to benzo[a]pyrene is highest in young mice and is elevated again in old age. The elevation of G:C to A:T transitions was observed following benzo [a] pyrene administration in the lungs of aged mice, and accelerated cytidine deamination is speculated to contribute to this elevation.

Exogenous nicotinamide supplementation and moderate physical exercise can attenuate the aging process in skeletal muscle of rats

Nicotinamide (NAM) could enhance the availability of NAD+ and be beneficial to cell function. However, NAM can inhibit the activities of SIRT1 and PARP. The effect of NAM supplementation on the aging process is not well known. In the present study exogenous NAM (1–0.5% in drinking water) was supplemented for 5xa0weeks and in the last 4xa0weeks moderate treadmill running was given to 5 mo and 28 mo old rats. The content of SIRT1 was not effected by NAM treatment alone. However, the activity of SIRT1, judged from the acetylated p53/p53 ratio, increased in both NAM treated age groups, suggesting beneficial effects of exogenous NAM. This was confirmed by the finding of increased PGC-1α and pCREB/CREB ratio in the gastrocnemius muscle of old but not young NAM treated animals. Our data suggest NAM administration can attenuate the aging process in skeletal muscle of rats, but NAM administration together with exercise training might be too great challenge to cope with in the old animals, since it leads to decreased levels of SIRT1.

Epigenetic Modulation of Gene Expression by Exercise

Physical activity has long-lasting beneficial effects by inducing metabolic adaptation, retarding biological ageing and reducing the risk of various age-related disorders and lifestyle-associated diseases such as type 2 diabetes mellitus, cancer, cardiovascular disorders and various types of inflammation, thereby extending healthy lifespan. Recent studies revealed that epigenetic mechanisms such as DNA methylation, histone modifications and microRNA expression are involved in exercise-induced adaptive responses. In this chapter, we first describe the processes of DNA methylation, histone modifications and microRNA, and then overview the effect of exercise on these epigenetic regulatory mechanisms. Finally, we discuss the relevance of epigenetics to ageing.