Lifelong soya consumption in males does not increase lifespan but increases health span under a metabolic stress such as type 2 diabetes mellitus.

Soya consumption can decrease oxidative stress in animal models. Moreover, phytoestrogens such as genistein, present in soya, can mimic some of the beneficial effects of estrogens and are devoid of significant side effects, such as cancer. In this study, we have performed a controlled lifelong study with male OF1 mice that consumed either a soya-free diet or a soya-rich diet. We show that, although we found an increase in the expression and activity of antioxidant enzymes in soya-consuming mice, it did not increase lifespan. We reasoned that the soya diet could not increase lifespan in a very healthy population, but perhaps it could extend health span in stressed animals such as type 2 diabetic Goto Kakizaki (GK) rats. Indeed, this was the case: we found that male GK rats consuming a soya-rich diet developed the disease at a lower rate and, therefore, lived longer than soya-free diet-consuming rats.

Sex Differences in Age-Associated Type 2 Diabetes in Rats-Role of Estrogens and Oxidative Stress.

Females live longer than males, and the estrogens are one of the reasons for this difference. We reported some years ago that estrogens are able to protect rats against oxidative stress, by inducing antioxidant genes. Type 2 diabetes is an age-associated disease in which oxidative stress is involved, and moreover, some studies show that the prevalence is higher in men than in women, and therefore there are sex-associated differences. Thus, the aim of this study was to evaluate the role of estrogens in protecting against oxidative stress in type 2 diabetic males and females. For this purpose, we used Goto-Kakizaki rats, which develop type 2 diabetes with age. We found that female diabetic rats showed lower glycaemia levels with age than did diabetic males and that estrogens enhanced insulin sensitivity in diabetic females. Moreover, glucose uptake, measured by positron emission tomography, was higher in the female brain, cerebellum, and heart than in those from male diabetic rats. There were also sex-associated differences in the plasma metabolic profile as determined by metabolomics. The metabolic profile was similar between estrogen-replaced and control diabetic rats and different from ovariectomized diabetic rats. Oxidative stress is involved in these differences. We showed that hepatic mitochondria from females produced less hydrogen peroxide levels and exhibited lower xanthine oxidase activity. We also found that hepatic mitochondrial glutathione oxidation and lipid oxidation levels were lower in diabetic females when compared with diabetic males. Ovariectomy induced oxidative stress, and estrogen replacement therapy prevented it. These findings provide evidence for estrogen beneficial effects in type 2 diabetes and should be considered when prescribing estrogen replacement therapy to menopausal women.

Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging.

Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging.

PTEN mediates the antioxidant effect of resveratrol at nutritionally relevant concentrations.

INTRODUCTION: Antioxidant properties of resveratrol have been intensively studied for the last years, both in vivo and in vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant. AIMS: In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect. METHODS: We used mammary gland tumor cells (MCF-7), which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibitor (bpV: bipy). Hydrogen peroxide levels were determined by fluorimetry, PTEN levels and Akt phosphorylation by Western Blotting, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Resveratrol treatment for 48 h lowered peroxide levels in MCF-7, even at low nutritional concentrations (1 nM). This effect was mediated by the activation of PTEN/Akt pathway, which resulted in an upregulation of catalase and MnSOD mRNA levels. CONCLUSION: Resveratrol acts as an antioxidant at nutritionally relevant concentrations by inducing the expression of antioxidant enzymes, through a mechanism involving PTEN/Akt signaling pathway.

Early, but not late onset estrogen replacement therapy prevents oxidative stress and metabolic alterations caused by ovariectomy.

AIMS: The usefulness of estrogen replacement therapy (ERT) in preventing oxidative stress associated with menopause is controversial. We aimed to study if there is a critical time window for effective treatment of the effects of ovariectomy with estrogens at the molecular, metabolic, and cellular level. RESULTS: Our main finding is that early, but not late onset of ERT prevents an ovariectomy-associated increase in mitochondrial hydrogen peroxide levels, oxidative damage to lipids and proteins, and a decrease in glutathione peroxidase and catalase activity in rats. This may be due to a change in the estrogen receptor (ER) expression profile: ovariectomy increases the ER α/ß ratio and immediate estrogen replacement prevents it. Positron emission tomography analysis shows that ovariectomy decreases the brain glucose uptake in vivo and that estrogen administration is beneficial, but only if administered immediately after deprivation. Ovariectomy decreases GLUT-1 and 3 glucose transporters in the brain, and only early onset estrogen administration prevents it. Plasma from rats treated with estrogens immediately after ovariectomy show similar metabolomics profiles as controls. INNOVATION: We provide molecular basis for the recommendation of early onset ERT and explain its lack of effectiveness if a significant time period elapses after ovariectomy and probably after the onset of menopause. CONCLUSION: Only early, but not late onset administration of estrogens after ovariectomy has beneficial effects at molecular levels on oxidative stress, brain glucose uptake, and metabolomic profiles.

The free radical theory of aging revisited: the cell signaling disruption theory of aging.

SIGNIFICANCE: The free radical theory of aging has provided a theoretical framework for an enormous amount of work leading to significant advances in our understanding of aging. Up to the turn of the century, the theory received abundant support from observations coming from fields as far apart as comparative physiology or molecular biology. RECENT ADVANCES: Work from many laboratories supports the theory, for instance showing that overexpression of antioxidant enzymes results in increases in life-span. But other labs have shown that in some cases, there is an increased oxidative stress and increased longevity. The discovery that free radicals can not only cause molecular damage to cells, but also serve as signals; led to the proposal that they act as modulators of physiological processes. For instance, reactive oxygen species (ROS) stimulate physiological adaptations to physical exercise. CRITICAL ISSUES: A critical blow to the free radical theory of aging came from epidemiological studies showing that antioxidant supplementation did not lower the incidence of many age-associated diseases but, in some cases, increased the risk of death. Moreover, recent molecular evidence has shown that increasing generation of ROS, in some cases, increases longevity. FUTURE DIRECTIONS: Gerontologists interested in free radical biology are at a crossroads and clearly new insights are required to clarify the role of ROS in the process of aging. The hurdles are, no doubt, very high, but the intellectual and practical promise of these studies is of such magnitude that we feel that all efforts will be generously rewarding.

Centenarians, but not octogenarians, up-regulate the expression of microRNAs.

Centenarians exhibit extreme longevity and a remarkable compression of morbidity. They have a unique capacity to maintain homeostatic mechanisms. Since small non-coding RNAs (including microRNAs) are implicated in the regulation of gene expression, we hypothesised that longevity of centenarians may reflect alterations in small non-coding RNA expression. We report the first comparison of microRNAs expression profiles in mononuclear cells from centenarians, octogenarians and young individuals resident near Valencia, Spain. Principal Component Analysis of the expression of 15,644 mature microRNAs and, 2,334 snoRNAs and scaRNAs in centenarians revealed a significant overlap with profiles in young individuals but not with octogenarians and a significant up-regulation of 7 small non-coding RNAs in centenarians compared to young persons and notably 102 small non-coding RNAs when compared with octogenarians. We suggest that the small non-coding RNAs signature in centenarians may provide insights into the underlying molecular mechanisms endowing centenarians with extreme longevity.