Extending healthy ageing: nutrient sensitive pathway and centenarian population

Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.

TOR-driven aging: speeding car without brakes.

This article discusses that the traditional analogy of an aging organism with a rusting (albeit self-repairing) car is misleading. The true analogy is a speeding car that enters a low-speed zone and damages itself because it does not and cannot slow down. For such a car without brakes (and actually without a driver), aging from rusting never occurs. Using simple analogies (although turning gerontology upside down), this article discusses the origin of aging, how overactivation of the mTOR (Target of Rapamycin) pathway causes aging, why aging causes damage (organ damage) not damage causes aging, the link between aging and age-related diseases, slow aging versus aging tolerance and suppression of aging with rapamycin.

Sociodemographic and Lifestyle Statistics of Oldest Old People (>80 Years) Living in Ikaria Island: The Ikaria Study

Background. There are places around the world where people live longer and they are active past the age of 100 years, sharing common behavioral characteristics; these places (i.e., Sardinia in Italy, Okinawa in Japan, Loma Linda in California and Nicoya Peninsula in Costa Rica) have been named the “Blue Zones”. Recently it was reported that people in Ikaria Island, Greece, have also one of the highest life expectancies in the world, and joined the “Blue Zones”. The aim of this work work was to evaluate various demographic, lifestyle and psychological characteristics of very old (>80 years) people participated in Ikaria Study. Methods. During 2009, 1420 people (aged 30+) men and women from Ikaria Island, Greece, were voluntarily enrolled in the study. For this work, 89 males and 98 females over the age of 80 yrs were studied (13% of the sample). Socio-demographic, clinical, psychological and lifestyle characteristics were assessed using standard questionnaires and procedures. Results. A large proportion of the Ikaria Study's sample was over the age of 80; moreover, the percent of people over 90 were much higher than the European population average. The majority of the oldest old participants reported daily physical activities, healthy eating habits, avoidance of smoking, frequent socializing, mid-day naps and extremely low rates of depression. Conclusion. Modifiable risk factors, such as physical activity, diet, smoking cessation and mid-day naps, might depict the “secrets” of the long-livers; these findings suggest that the interaction of environmental, behavioral together with clinical characteristics may determine longevity. This concept must be further explored in order to understand how these factors relate and which are the most important in shaping prolonged life.

Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis

Healthy life span is rapidly increasing and human aging seems to be postponed. As recently exclaimed in Nature, these findings are so perplexing that they can be dubbed the 'longevity riddle'. To explain current increase in longevity, I discuss that certain genetic variants such as hyper-active mTOR (mTarget of Rapamycin) may increase survival early in life at the expense of accelerated aging. In other words, robustness and fast aging may be associated and slow-aging individuals died prematurely in the past. Therefore, until recently, mostly fast-aging individuals managed to survive into old age. The progress of civilization (especially 60 years ago) allowed slow-aging individuals to survive until old age, emerging as healthy centenarians now. I discuss why slow aging is manifested as postponed (healthy) aging, why the rate of deterioration is independent from aging and also entertain hypothetical use of rapamycin in different eras as well as the future of human longevity.

Longevity and diet. Myth or pragmatism?

Licorice and licochalcone-A induce autophagy in LNCaP prostate cancer cells by suppression of Bcl-2 expression and the mTOR pathway.

Licorice is a common Chinese medicinal herb with antitumor activity. Some components in licorice root have been shown to induce cell cycle arrest or apoptosis in cancer cells. This paper demonstrates for the first time that licorice Glycyrrhiza glabra and its component licochalcone-A (LA) can induce autophagy in addition to apoptosis in human LNCaP prostate cancer cells. Exposure of cells to licorice or LA resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine (MDC) staining, formation of acidic vesicular organelles (AVOs), and autophagosome membrane association of microtubule-associated protein 1 light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, as well as ultrastructural observation of autophagic vacuoles by transmission electron microscopy. Autophagy induction was accompanied by down-regulation of Bcl-2 and inhibition of the mammalian target of rapamycin (mTOR) pathway. In summary, licorice can induce caspase-dependent and autophagy-related cell death in LNCaP cells.

Advanced glycation end products as biomarkers and gerontotoxins - A basis to explore methylglyoxal-lowering agents for Alzheimer's disease?

Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we put forward the hypothesis that advanced glycation end products (AGEs) and their precursors, including methylglyoxal, are both biomarkers and causative agents ("gerontotoxins") characteristic for this disorder. Accumulation of AGEs is a normal feature of aging, but is accelerated in AD, where AGEs can be detected in amyloid plaques and neurofibrillary tangles. AGE modification may explain many of the neuropathological and biochemical features of AD such as extensive protein cross-linking, inflammation, oxidative stress and neuronal cell death. We suggest that methylglyoxal is one of the major carbonyl species responsible for the formation of AGEs. We propose that one promising pharmacological approach to prevent the formation of AGEs would be to lower the methylglyoxal concentration. This can be achieved, for example, by decreasing the concentration of methylglyoxal precursors such as d-glyceraldehyde-3-phosphate by allowing a higher flux through the pentose phosphate pathway or by increasing methylglyoxal detoxification through the glyoxalase system. Alternatively, methylglyoxal could be scavenged by various types of carbonyl scavengers. Copyright © 2010 Elsevier Inc. All rights reserved.

Dietary Advanced Glycation End Products and Aging

Advanced glycation end products (AGEs) are a heterogeneous, complex group of compounds that are formed when reducing sugar reacts in a non-enzymatic way with amino acids in proteins and other macromolecules. This occurs both exogenously (in food) and endogenously (in humans) with greater concentrations found in older adults. While higher AGEs occur in both healthy older adults and those with chronic diseases, research is progressing to both quantify AGEs in food and in people, and to identify mechanisms that would explain why some human tissues are damaged, and others are not. In the last twenty years, there has been increased evidence that AGEs could be implicated in the development of chronic degenerative diseases of aging, such as cardiovascular disease, Alzheimer’s disease and with complications of diabetes mellitus. Results of several studies in animal models and humans show that the restriction of dietary AGEs has positive effects on wound healing, insulin resistance and cardiovascular diseases. Recently, the effect of restriction in AGEs intake has been reported to increase the lifespan in animal models. This paper will summarize the work that has been published for both food AGEs and in vivo AGEs and their relation with aging, as well as provide suggestions for future research.

Comparative and meta-analytic insights into life extension via dietary restriction.

Dietary restriction (DR) extends the lifespan of a wide range of species, although the universality of this effect has never been quantitatively examined. Here, we report the first comprehensive comparative meta-analysis of DR across studies and species. Overall, DR significantly increased lifespan, but this effect is modulated by several factors. In general, DR has less effect in extending lifespan in males and also in non-model organisms. Surprisingly, the proportion of protein intake was more important for life extension via DR than the degree of caloric restriction. Furthermore, we show that reduction in both age-dependent and age-independent mortality rates drives life extension by DR among the well-studied laboratory model species (yeast, nematode worms, fruit flies and rodents). Our results suggest that convergent adaptation to laboratory conditions better explains the observed DR-longevity relationship than evolutionary conservation although alternative explanations are possible. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Accelerated Telomere Erosion Is Associated with a Declining Immune Function of Caregivers of Alzheimer’s Disease Patients

Caregivers of Alzheimer’s disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-α and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

Is there more to aging than mitochondrial DNA and reactive oxygen species?

Summary With the aging of the population, we are seeing a global increase in age-related disorders, especially in developed countries. Chronic diseases disproportionately affect the older segment of the population, contributing to disability, a diminished quality of life, and an increase in healthcare costs. Increased life expectancy reflects the success of contemporary medicine, which must now respond to the challenges created by this achievement, including the growing burden of chronic illnesses, injuries, and disabilities. A well-developed theoretical framework is required to understand the molecular basis of aging. This, in turn, is a prerequisite for developing the clinical interventions that will constitute an efficient response to the challenge of age-related health issues. This review critically analyzes the experimental evidence that supports and refutes the Free Radical/Mitochondrial Theory of Aging, which has dominated the field of aging research for almost half a century.

Ageing and eating.

Epidemiological studies propose that extension of the human lifespan or the reduction of age associated diseases may be achieved by physical exercise, caloric restriction, and by consumption of certain substances such as resveratrol, selenium, flavonoids, zinc, omega 3 unsaturated fatty acids, vitamins E and C, Ginkgobiloba extracts, aspirin, green tea catechins, antioxidants in general, and even by light caffeine or alcohol consumption. Though intriguing, these studies only show correlative (not causative) effects between the application of the particular substance and longevity. On the other hand, obesity is yet a strong menace to the western society and it will emerge even more so throughout the next decades according to the prediction of the WHO. Although obesity is considered a severe problem, very little is known about the molecular mechanisms causing the associated degeneration of organs and finally death. Nutrient related adverse consequences for health and thus ageing may be due to a high sugar or high fat diet, excessive alcohol consumption and cigarette smoke amongst others. In this article we examine the interdependencies of eating and ageing and suggest yeast, one of the most successful ageing models, as an easy tool to elucidate the molecular pathways from eating to ageing. The conservation of most ageing pathways in yeast and their easy genetic tractability may provide a chance to discriminate between the correlative and causative effects of nutrition on ageing. 2010 Elsevier B.V. All rights reserved.

Açai Palm Fruit (Euterpe oleracea Mart.) Pulp Improves Survival of Flies on a High Fat Diet

Reducing oxidative damage is thought to be an effective aging intervention. Açai, a fruit indigenous to the Amazon, is rich in phytochemicals that possesses high anti-oxidant activities, and has anti-inflammatory, anti-cancer and anti-cardiovascular disease properties. However, little is known about its potential anti-aging properties especially at the organismal level. Here we evaluated the effect of açai pulp on modulating lifespan in Drosophila melanogaster. We found that açai supplementation at 2% in the food increased the lifespan of female flies fed a high fat diet compared to the non-supplemented control. We measured transcript changes induced by açai for age-related genes. Although transcript levels of most genes tested were not altered, açai increased the transcript level of l(2)efl, a small heat-shock-related protein, and two detoxification genes, gstD1 and mtnA, while decreasing the transcript level of phosphoenolpyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis. Furthermore, açai increased the lifespan of oxidative stressed females caused by sod1 RNAi. This suggests that açai improves survival of flies fed a high fat diet through activation of stress response pathways and suppression of Pepck expression. Açai has the potential to antagonize the detrimental effect of fat in the diet and alleviate oxidative stress in aging.

Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging

Cellular senescence is an in vivo and in vitro phenomenon, accompanied by physiological changes including cessation of division and disturbances of organelle structure and function. Review of the literature was undertaken to determine whether there is evidence that whole organism aging and cell senescence share a common initiation pathway. In vivo aged cells of different lineages, including aged T lymphocytes, show high expression of the INK4A-p16 gene. In cell culture when telomeres are shortened past a key length or state, the Arf/Ink gene system (p16/p14 humans, p16/p19 mice) switches on and activates p53, which suppresses further cell division. The p53 gene is a key tumor suppressor and its deletion or mutation allows cancerous growth. The switching on of p53 also causes changes in fatty acid metabolism, especially down-regulation of both fatty acid synthase and stearoyl-CoA (delta-9) desaturase. The co-suppression of these genes together with enhanced uptake of extracellular fatty acids, leads to raised levels of cellular palmitate and induction of either apoptosis or senescence. In senescent cells, the fatty acid composition of the cellular membranes alters and leads to changes in both structure and function of organelles, especially mitochondria. Animal models of accelerated aging exhibit repression of stearoyl-CoA desaturase activity while anti-aging calorie restriction stimulates the same enzyme system. It is concluded that aging in cells and whole organisms share a common initiation pathway and that cellular senescence is protective against cancer. Healthy longevity is likely to be most enhanced by factors that actively suppress excessive cell division.

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. Antioxid. Redox Signal. 19, 779–787.

Evaluation of the Possible Transmission of BSE and Scrapie to Gilthead Sea Bream (Sparus aurata)

In transmissible spongiform encephalopathies (TSEs), a group of fatal neurodegenerative disorders affecting many species, the key event in disease pathogenesis is the accumulation of an abnormal conformational isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). While the precise mechanism of the PrPC to PrPSc conversion is not understood, it is clear that host PrPC expression is a prerequisite for effective infectious prion propagation. Although there have been many studies on TSEs in mammalian species, little is known about TSE pathogenesis in fish. Here we show that while gilthead sea bream (Sparus aurata) orally challenged with brain homogenates prepared either from a BSE infected cow or from scrapie infected sheep developed no clinical prion disease, the brains of TSE-fed fish sampled two years after challenge did show signs of neurodegeneration and accumulation of deposits that reacted positively with antibodies raised against sea bream PrP. The control groups, fed with brains from uninfected animals, showed no such signs. Remarkably, the deposits developed much more rapidly and extensively in fish inoculated with BSE-infected material than in the ones challenged with the scrapie-infected brain homogenate, with numerous deposits being proteinase K-resistant. These plaque-like aggregates exhibited congophilia and birefringence in polarized light, consistent with an amyloid-like component. The neurodegeneration and abnormal deposition in the brains of fish challenged with prion, especially BSE, raises concerns about the potential risk to public health. As fish aquaculture is an economically important industry providing high protein nutrition for humans and other mammalian species, the prospect of farmed fish being contaminated with infectious mammalian PrPSc, or of a prion disease developing in farmed fish is alarming and requires further evaluation.

A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process.

A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention-most notably salt restriction-may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction possible i...

Available information indicates that long-lived mammals have low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, many studies have consistently shown that dietary restriction (DR) in rodents also decreases mitochondrial ROS (mtROS) production and oxidative damage to mitochondrial DNA and proteins. It has been observed that protein restriction also decreases mtROS generation and oxidative stress in rat liver, whereas neither carbohydrate nor lipid restriction change these parameters. This is interesting because protein restriction also increases maximum longevity in rodents (although to a lower extent than DR) and is a much more practicable intervention for humans than DR, whereas neither carbohydrate nor lipid restriction seem to change rodent longevity. Moreover, it has been found that isocaloric methionine restriction also decreases mtROS generation and oxidative stress in rodent tissues, and this manipulation also increases maximum longevity in rats and mice. In addition, excessive dietary methionine also increases mtROS generation in rat liver. These studies suggest that the reduced intake of dietary methionine can be responsible for the decrease in mitochondrial ROS generation and the ensuing oxidative damage that occurs during DR, as well as for part of the increase in maximum longevity induced by this dietary manipulation. In addition, the mean intake of proteins (and thus methionine) of Western human populations is much higher than needed. Therefore, decreasing such levels to the recommended ones has a great potential to lower tissue oxidative stress and to increase healthy life span in humans while avoiding the possible undesirable effects of DR diets.

Pesticides and human chronic diseases: evidences, mechanisms, and perspectives.

Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action. Copyright © 2013 Elsevier Inc. All rights reserved.

The role of hormesis in life extension by dietary restriction.

The level of food restriction that results in life extension and retarded aging in rodents also enhances their ability to cope with intense stressors. Moreover, this level of dietary restriction (DR) leads to a modest increase in the daily peak concentration of plasma free corticosterone, which strongly points to DR as a low-intensity stressor. These findings suggest that hormesis plays a role in the life-extending and anti-aging actions of DR. The evidence for and against this possibility is considered, and it is concluded that hormesis does have an important role.

Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on mor...

Long-term caloric restriction (CR) is a robust means of reducing age-related diseases and extending life span in multiple species, but the effects in humans are unknown. The low caloric intake, long life expectancy, and the high prevalence of centenarians in Okinawa have been used as an argument to support the CR hypothesis in humans. However, no long-term, epidemiologic analysis has been conducted on traditional dietary patterns, energy balance, and potential CR phenotypes for the specific cohort of Okinawans who are purported to have had a calorically restricted diet. Nor has this cohort's subsequent mortality experience been rigorously studied. Therefore, we investigated six decades of archived population data on the elderly cohort of Okinawans (aged 65-plus) for evidence of CR. Analyses included traditional diet composition, energy intake, energy expenditure, anthropometry, plasma DHEA, mortality from age-related diseases, and current survival patterns. Findings include low caloric intake and negative energy balance at younger ages, little weight gain with age, life-long low BMI, relatively high plasma DHEA levels at older ages, low risk for mortality from age-related diseases, and survival patterns consistent with extended mean and maximum life span. This study lends epidemiologic support for phenotypic benefits of CR in humans and is consistent with the well-known literature on animals with regard to CR phenotypes and healthy aging.

Loving-Kindness Meditation practice associated with longer telomeres in women.

Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity. Copyright © 2013 Elsevier Inc. All rights reserved.

Diet promotes sleep duration and quality.

Sleep, much like eating, is an essential part of life. The mechanisms of sleep are only partially clear and are the subject of intense research. There is increasing evidence showing that sleep has an influence on dietary choices. Both cross-sectional and epidemiologic studies have demonstrated that those who sleep less are more likely to consume energy-rich foods (such as fats or refined carbohydrates), to consume fewer portions of vegetables, and to have more irregular meal patterns. In this narrative review, we pose the opposite question: can ingested food affect sleep? The purpose of this review is to discuss the evidence linking diet and sleep and to determine whether what we eat and what kind of nutrients we obtain from the food consumed before bedtime matter. In addition, scientific evidence behind traditional sleep-promoting foods such as milk and some herbal products is briefly described. These are reviewed using data from clinical trials, mostly in healthy subjects. In addition, we discuss the possible mechanisms behind these observations. Lastly, we summarize our findings that emerging evidence confirms a link between diet and sleep. Overall, foods impacting the availability of tryptophan, as well as the synthesis of serotonin and melatonin, may be the most helpful in promoting sleep. Although there are clear physiological connections behind these effects, the clinical relevance needs to be studied further. Copyright © 2012 Elsevier Inc. All rights reserved.

Alzheimer's disease is incurable but preventable.

The dramatic rising incidence and costs of Alzheimer's disease (AD) require that research efforts and funding be primarily directed on either finding a cure or applying preventive measures to curb this disorder. A cure for AD appears unlikely when significant cognitive loss has occurred because the neuronal networks that controlled the perturbed cognitive abilities are either dead or irreversibly damaged and replacing them, even if it were technically possible, would not reconstruct the intellectual identity of the host. Prevention of risk factors to sporadic AD is a more realistic stratagem and treatment, when indicated, ideally should begin in cognitively intact individuals as part of a mass screening effort. Prevention of modifiable risk factors to AD is cost-effective because it reduces hospice or hospital stay, repeated doctor visits, and long-term care. Presently, neurocognitive and neuroimaging tests are used with partial success in identifying persons at higher risk of AD but these tests can not pinpoint either a cause or a specific intervention that could attenuate disease progress. We previously proposed that carotid artery ultrasound +echocardiography together with ankle-brachail index (CAUSE+ABI) as mass screening tests in asymptomatic persons could detect not only cardio-cerebrovascular risk factors to AD, but also identify an indicated intervention. CAUSE+ABI are simple to perform, cost-effective, non-invasive, and reasonably accurate for the intended purpose. Additionally, detection of cardio-cerebrovasacular abnormalities long before expression of cognitive deterioration allows higher success rate with earlier treatment. Evidence-based medicine is recommended for optimizing clinical decision-making in evaluating AD risk factors and their treatment.

The association between physical activity in leisure time and leukocyte telomere length.

BACKGROUND: Physical inactivity is an important risk factor for many aging-related diseases. Leukocyte telomere dynamics (telomere length and age-dependent attrition rate) are ostensibly a biological indicator of human aging. We therefore tested the hypothesis that physical activity level in leisure time (over the past 12 months) is associated with leukocyte telomere length (LTL) in normal healthy volunteers. METHODS: We studied 2401 white twin volunteers, comprising 2152 women and 249 men, with questionnaires on physical activity level, smoking status, and socioeconomic status. Leukocyte telomere length was derived from the mean terminal restriction fragment length and adjusted for age and other potential confounders. RESULTS: Leukocyte telomere length was positively associated with increasing physical activity level in leisure time (P< .001); this association remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work. The LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases, respectively; P= .006). This finding was confirmed in a small group of twin pairs discordant for physical activity level (on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins; P= .03). CONCLUSIONS: A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.

The Restriction of Zoonotic PERV Transmission by Human APOBEC3G

The human APOBEC3G protein is an innate anti-viral factor that can dominantly inhibit the replication of some endogenous and exogenous retroviruses. The prospects of purposefully harnessing such an anti-viral defense are under investigation. Here, long-term co-culture experiments were used to show that porcine endogenous retrovirus (PERV) transmission from pig to human cells is reduced to nearly undetectable levels by expressing human APOBEC3G in virus-producing pig kidney cells. Inhibition occurred by a deamination-independent mechanism, likely after particle production but before the virus could immortalize by integration into human genomic DNA. PERV inhibition did not require the DNA cytosine deaminase activity of APOBEC3G and, correspondingly, APOBEC3G-attributable hypermutations were not detected. In contrast, over-expression of the sole endogenous APOBEC3 protein of pigs failed to interfere significantly with PERV transmission. Together, these data constitute the first proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. These studies suggest that human APOBEC3G-transgenic pigs will provide safer, PERV-less xenotransplantation resources and that analogous cross-species APOBEC3-dependent restriction strategies may be useful for thwarting other endogenous as well as exogenous retrovirus infections.

Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens.

Females live longer than males. Work from our laboratory has shown that this may be due to the up-regulation of longevity-associated genes by estrogens. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein kinase and nuclear factor kappa B signalling pathways, resulting in an up-regulation of antioxidant enzymes. Estrogen administration, however, has serious undesirable effects and of course, cannot be administered to males because of its powerful feminizing effects. Thus, we tested the effect of genistein, a phytoestrogen of high nutritional importance whose structure is similar to estradiol, on the regulation of the expression of antioxidant, longevity-related genes and consequently on oxidant levels in mammary gland tumour cells in culture. Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of up-regulating antioxidant genes, by hormonal and dietary manipulations, to increase longevity is discussed.

Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens.

Using data from 16 published reports, the authors correlated macroscopic disc degeneration grades with age, sex, and spine level in 600 lumbar intervertebral discs from 273 cadavers (ages: 0-96 years). Male discs were more degenerated than female discs at most ages; significantly so in the second, fifth, sixth, and seventh decades. On average, L4-L5 and L3-L4 level discs showed more degeneration than discs at other lumbar levels. These macroscopic findings corroborate radiographic data from epidemiologic studies. The calculations suggest that higher mechanical stress, perhaps combined with longer nutritional pathways, may be responsible for the earlier degeneration of male discs.

Recent advances in berry supplementation and age-related cognitive decline.

PURPOSE OF REVIEW: To summarize recent findings and current concepts in the beneficial effects of berry consumption on brain function during aging. RECENT FINDINGS: Berryfruit supplementation has continued to demonstrate efficacy in reversing age-related cognitive decline in animal studies. In terms of the mechanisms behind the effects of berries on the central nervous system, recent studies have demonstrated the bioavailability of berry polyphenols in several animal models. These studies have revealed that flavonoids and polyphenols from berries do accumulate in the brain following long-term consumption. Finally, several compelling studies have revealed that berries can influence cell-signaling cascades both in vivo and in cell culture systems. These studies underscore the developing theory that berries and antioxidant-rich foods may be acting as more than just oxygen radical neutralizers in the aging central nervous system. SUMMARY: Antioxidant-rich berries consumed in the diet can positively impact learning and memory in the aged animal. This effect on cognition is thought to be due to the direct interaction of berry polyphenols with aging neurons, reducing the impact of stress-related cellular signals and increasing the capacity of neurons to maintain proper functioning during aging.

Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits

Summary Anti-Gal is the most abundant natural antibody in humans, constituting ∼ 1% of immunoglobulins. Anti-Gal is naturally produced also in apes and Old World monkeys. The ligand of anti-Gal is a carbohydrate antigen called the ‘α-gal epitope’ with the structure Galα1-3Galβ1-4GlcNAc-R. The α-gal epitope is present as a major carbohydrate antigen in non-primate mammals, prosimians and New World monkeys. Anti-Gal can contributes to several immunological pathogeneses. Anti-Gal IgE produced in some individuals causes allergies to meat and to the therapeutic monoclonal antibody cetuximab, all presenting α-gal epitopes. Aberrant expression of the α-gal epitope or of antigens mimicking it in humans may result in autoimmune processes, as in Graves' disease. α-Gal epitopes produced by Trypanosoma cruzi interact with anti-Gal and induce ‘autoimmune like’ inflammatory reactions in Chagas' disease. Anti-Gal IgM and IgG further mediate rejection of xenografts expressing α-gal epitopes. Because of its abundance, anti-Gal may be exploited for various clinical uses. It increases immunogenicity of microbial vaccines (e.g. influenza vaccine) presenting α-gal epitopes by targeting them for effective uptake by antigen-presenting cells. Tumour lesions are converted into vaccines against autologous tumour-associated antigens by intra-tumoral injection of α-gal glycolipids, which insert into tumour cell membranes. Anti-Gal binding to α-gal epitopes on tumour cells targets them for uptake by antigen-presenting cells. Accelerated wound healing is achieved by application of α-gal nanoparticles, which bind anti-Gal, activate complement, and recruit and activate macrophages that induce tissue regeneration. This therapy may be of further significance in regeneration of internally injured tissues such as ischaemic myocardium and injured nerves.

Appealing to Vanity: Could Potential Appearance Improvement Motivate Fruit and Vegetable Consumption?

Fruit and vegetable consumption is inadequate among adults in the United States; this contributes to preventable morbidity and mortality. More effective dietary intervention strategies are needed. Recently, interventions that advertise the consequences of behavior for appearance have been successful in modifying sun-exposure habits and tobacco use. Such an approach might also facilitate dietary improvement. Consumption of carotenoid-rich fruit and vegetables positively affects skin color, which influences perceptions of health and attractiveness, and promoting such an effect may motivate target audiences to increase consumption of this important food group. This approach represents a novel direction for the field and is potentially suitable for cost-effective, population-level dissemination through the visual media.

A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam

As root symbionts of cycad trees, cyanobacteria of the genus Nostoc produce β-methylamino-l-alanine (BMAA), a neurotoxic nonprotein amino acid. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. However, because BMAA is polar and nonlipophilic, a mechanism for its biomagnification through increasing trophic levels has been unclear. We report that BMAA occurs not only as a free amino acid in the Guam ecosystem but also can be released from a bound form by acid hydrolysis. After first removing free amino acids from tissue samples of various trophic levels (cyanobacteria, root symbioses, cycad seeds, cycad flour, flying foxes eaten by the Chamorro people, and brain tissues of Chamorros who died from amyotrophic lateral sclerosis/Parkinsonism dementia complex), we then hydrolyzed the remaining fraction and found BMAA concentrations increased 10- to 240-fold. This bound form of BMAA may function as an endogenous neurotoxic reservoir, accumulating and being transported between trophic levels and subsequently being released during digestion and protein metabolism. Within brain tissues, the endogenous neurotoxic reservoir can slowly release free BMAA, thereby causing incipient and recurrent neurological damage over years or even decades, which may explain the observed long latency period for neurological disease onset among the Chamorro people. The presence of BMAA in brain tissues from Canadian patients who died of Alzheimer's disease suggests that exposure to cyanobacterial neurotoxins occurs outside of Guam.

Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly?

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence - a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in 'inflammaging', a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A possible role for lutein and zeaxanthin in cognitive function in the elderly.

Epidemiologic studies suggest that dietary lutein and zeaxanthin may be of benefit in maintaining cognitive health. Among the carotenoids, lutein and zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment (MP) in the eye. They also preferentially accumulate in the human brain. Lutein and zeaxanthin in macula from nonhuman primates were found to be significantly correlated with their concentrations in matched brain tissue. Therefore, MP can be used as a biomarker of lutein and zeaxanthin in primate brain tissue. This is of interest given that a significant correlation was found between MP density and global cognitive function in healthy older adults. An examination of a relation between cognition and lutein and zeaxanthin concentrations in the brain tissue of decedents from a population-based study in centenarians found that zeaxanthin concentrations in brain tissue were significantly related to antemortem measures of global cognitive function, memory retention, verbal fluency, and dementia severity after adjustment for age, sex, education, hypertension, and diabetes. In univariate analyses, lutein was related to recall and verbal fluency, but the strength of the associations was attenuated with adjustment for covariates. However, lutein concentrations in the brain were significantly lower in individuals with mild cognitive impairment than in those with normal cognitive function. Last, in a 4-mo, double-blinded, placebo-controlled trial in older women that involved lutein supplementation (12 mg/d), alone or in combination with DHA (800 mg/d), verbal fluency scores improved significantly in the DHA, lutein, and combined-treatment groups. Memory scores and rate of learning improved significantly in the combined-treatment group, who also showed a trend toward more efficient learning. When all of these observations are taken into consideration, the idea that lutein and zeaxanthin can influence cognitive function in older adults warrants further study.

Upregulation of lymphocyte apoptosis as a strategy for preventing and treating autoimmune disorders: a role for whole-food vegan diets, fish oil an...

Induced apoptosis of autoreactive T-lymphocyte precursors in the thymus is crucial for the prevention of autoimmune disorders. IGF-I and prolactin, which are lymphocyte growth factors, may have the potential to suppress apoptosis in thymocytes and thus encourage autoimmunity; conversely, dietary fish oil rich in omega-3 fats appears to upregulate apoptosis in lymphocytes. Since whole-food vegan diets may downregulate systemic IGF-I activity, it is proposed that such a diet, in conjunction with fish oil supplementation and treatment with dopamine agonists capable of suppressing prolactin secretion, may have utility for treating and preventing autoimmune disorders. This prediction is consistent with the extreme rarity of autoimmune disorders among sub-Saharan black Africans as long as they followed their traditional quasi-vegan lifestyles, and with recent ecologic studies correlating risks for IDDM and for multiple sclerosis mortality with animal product and/or saturated fat consumption. Moreover, there is evidence that vegan or quasi-vegan diets are useful in the management of rheumatoid arthritis, multiple sclerosis, and possibly SLE. The dopamine agonist bromocryptine exerts anti-inflammatory effects in rodent models of autoimmunity, and there is preliminary evidence that this drug may be clinically useful in several human autoimmune diseases; better tolerated D2-specific agonists such as cabergoline may prove to be more practical for use in therapy. The moderate clinical utility of supplemental fish oil in rheumatoid arthritis and certain other autoimmune disorders is documented. It is not unlikely that extra-thymic anti-inflammatory effects contribute importantly to the clinical utility of vegan diets, bromocryptine, and fish oil in autoimmunity. The favorable impact of low latitude or high altitude on autoimmune risk may be mediated by superior vitamin D status, which is associated with decreased secretion of parathyroid hormone; there are theoretical grounds for suspecting that parathyroid hormone may inhibit apoptosis in thymocytes. Androgens appear to up-regulate thymocyte apoptosis, may be largely responsible for the relative protection from autoimmunity enjoyed by men, and merit further evaluation for the management of autoimmunity in women. It will probably prove more practical to prevent autoimmune disorders than to reverse them once established; a whole-food vegan diet, coupled with fish oil and vitamin D supplementation, may represent a practical strategy for achieving this prevention, while concurrently lowering risk for many other life-threatening 'Western' diseases. Copyright 2001 Harcourt Publishers Ltd.

Bridging the gap in life expectancy of the aborigines in Taiwan.

BACKGROUND: Similar to the general population in Taiwan, the health of aborigines has steadily improved over the last 30 years, but the gap remains wide, especially in males, despite an infusion of substantial medical resources. The objectives of this study are to quantify the contribution of major causes of death to the gap in life expectancy and to propose initiatives to bridge the health gap between aborigines and the general population. METHODS: This study included residents (slightly over 200000) from 30 'aboriginal townships' in Taiwan. The gap in life expectancy between aborigines and the general population was analysed by decomposing these gaps according to major causes of deaths. This analysis quantifies the contribution of different causes of deaths to the gap in life expectancy between the two populations. RESULTS: The overall mortality of aborigines in these townships was approximately 70% higher than the respective male and female general populations over the past 30 years. Mortality from infectious disease, cirrhosis of the liver, accidents, and suicide are substantially higher than the general population. The gap in life expectancy at birth in males was 8.5 years during 1971-1973, increasing to 13.5 years by 1998-2000, however, the gap in females remained relatively stable (8.0 years and 8.4 years, respectively). Of the 13.5-year difference in life expectancy in males, the differential mortality from diseases of the digestive system (mainly due to cirrhosis of the liver), accidents (from both motor vehicle and non-motor vehicle accidents), and infectious and parasitic disease contributed half (50%) of the gap in life expectancy. In females, the above primarily preventable causes of deaths accounted for 41% of the life expectancy gap. CONCLUSIONS: Based on the findings of this study, we suggest that future focus should be in the area of primary prevention in order to reduce the incidence of infectious and parasitic diseases, liver cirrhosis, and accidents.

The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease.

It is a pleasure and an honor to contribute a paper to a special issue of the Journal of the American College of Nutrition honoring Stanley Wallach and Pearl Small. In this brief review I advance the hypothesis that copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.

Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases.

Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual.

Xenohormesis: health benefits from an eon of plant stress response evolution

Xenohormesis is a biological principle that explains how environmentally stressed plants produce bioactive compounds that can confer stress resistance and survival benefits to animals that consume them. Animals can piggyback off products of plants' sophisticated stress response which has evolved as a result of their stationary lifestyle. Factors eliciting the plant stress response can judiciously be employed to maximize yield of health-promoting plant compounds. The xenohormetic plant compounds can, when ingested, improve longevity and fitness by activating the animal's cellular stress response and can be applied in drug discovery, drug production, and nutritional enhancement of diet.

Intensive meditation training, immune cell telomerase activity, and psychological mediators.

BACKGROUND: Telomerase activity is a predictor of long-term cellular viability, which decreases with chronic psychological distress (Epel et al., 2004). Buddhist traditions claim that meditation decreases psychological distress and promotes well-being (e.g., Dalai Lama and Cutler, 2009). Therefore, we investigated the effects of a 3-month meditation retreat on telomerase activity and two major contributors to the experience of stress: Perceived Control (associated with decreased stress) and Neuroticism (associated with increased subjective distress). We used mediation models to test whether changes in Perceived Control and Neuroticism explained meditation retreat effects on telomerase activity. In addition, we investigated whether two qualities developed by meditative practice, increased Mindfulness and Purpose in Life, accounted for retreat-related changes in the two stress-related variables and in telomerase activity. METHODS: Retreat participants (n=30) meditated for ∼6 h daily for 3 months and were compared with a wait-list control group (n=30) matched for age, sex, body mass index, and prior meditation experience. Retreat participants received instruction in concentrative meditation techniques and complementary practices used to cultivate benevolent states of mind (Wallace, 2006). Psychological measures were assessed pre- and post-retreat. Peripheral blood mononuclear cell samples were collected post-retreat for telomerase activity. Because there were clear, a priori hypotheses, 1-tailed significance criteria were used throughout. RESULTS: Telomerase activity was significantly greater in retreat participants than in controls at the end of the retreat (p<0.05). Increases in Perceived Control, decreases in Neuroticism, and increases in both Mindfulness and Purpose in Life were greater in the retreat group (p<0.01). Mediation analyses indicated that the effect of the retreat on telomerase was mediated by increased Perceived Control and decreased Neuroticism. In turn, changes in Perceived Control and Neuroticism were both partially mediated by increased Mindfulness and Purpose in Life. Additionally, increases in Purpose in Life directly mediated the telomerase group difference, whereas increases in Mindfulness did not. CONCLUSIONS: This is the first study to link meditation and positive psychological change with telomerase activity. Although we did not measure baseline telomerase activity, the data suggest that increases in perceived control and decreases in negative affectivity contributed to an increase in telomerase activity, with implications for telomere length and immune cell longevity. Further, Purpose in Life is influenced by meditative practice and directly affects both perceived control and negative emotionality, affecting telomerase activity directly as well as indirectly. Copyright © 2010 Elsevier Ltd. All rights reserved.

Longevity. The allostatic load of dietary restriction.

Restriction of food intake by 10-50% of ad libitum on a per unit of weight or energy content basis can extend the lifespan of a wide variety of species and prevent or delay age-related disease. This review first briefly summarizes the data delineating mortality trajectories of various species' populations maintained on restricted diets to provide insight into the effects of nutrient deprivation on distinct components of the aging process. Next, I discuss a number of important studies that have addressed the question whether it is the lack of calories and/or specific nutrients that determines the longevity response to dietary restriction. Finally, I review the evidence for hormesis as a proximate mechanism underpinning the impact of dietary restriction on lifespan. In aggregate, the currently available demographic data suggest that dietary restriction can both slow the age-related progressive accumulation of cellular damage and also enhance the ability of organisms to cope with irreversible injury. Restriction of essential nutrients as well as calories may affect life expectancy, perhaps in a species specific fashion. Hormesis, i.e. an evolutionary conserved stress response routine providing protection against a wide variety of (other) hazards in response to low levels of stress, is very likely to contribute to the beneficial health effects of dietary restriction. Copyright Â© 2011 Elsevier Inc. All rights reserved.

A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: Effects on mental health, cognition, and telomerase activity

BACKGROUND This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms. METHODS Thirty-nine family dementia caregivers (mean age 60.3 years old (SD=10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 minutes per day for eight weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre- and post-intervention. RESULTS The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared to the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score (MCS) of the SF-36 scale; compared to 31.2% and 19% respectively in the relaxation group (pp<0.05). The meditation group showed 43% improvement in telomerase activity compared to 3.7% in the relaxation group (p=0.05). CONCLUSION This pilot study found that brief daily meditation practices by family dementia caregivers can lead to improved mental and cognitive functioning, and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample.

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation.

AIMS/HYPOTHESIS: Defects in pancreatic beta cell turnover are implicated in the pathogenesis of type 2 diabetes by genetic markers for diabetes. Decreased beta cell neogenesis could contribute to diabetes. The longevity and turnover of human beta cells is unknown; in rodents <1 year old, a half-life of 30 days is estimated. Intracellular lipofuscin body (LB) accumulation is a hallmark of ageing in neurons. To estimate the lifespan of human beta cells, we measured beta cell LB accumulation in individuals aged 1-81 years. METHODS: LB content was determined by electron microscopical morphometry in sections of beta cells from human (non-diabetic, n = 45; type 2 diabetic, n = 10) and non-human primates (n = 10; 5-30 years) and from 15 mice aged 10-99 weeks. Total cellular LB content was estimated by three-dimensional (3D) mathematical modelling. RESULTS: LB area proportion was significantly correlated with age in human and non-human primates. The proportion of human LB-positive beta cells was significantly related to age, with no apparent differences in type 2 diabetes or obesity. LB content was low in human insulinomas (n = 5) and alpha cells and in mouse beta cells (LB content in mouse <10% human). Using 3D electron microscopy and 3D mathematical modelling, the LB-positive human beta cells (representing aged cells) increased from >or=90% (<10 years) to >or=97% (>20 years) and remained constant thereafter. CONCLUSIONS/INTERPRETATION: Human beta cells, unlike those of young rodents, are long-lived. LB proportions in type 2 diabetes and obesity suggest that little adaptive change occurs in the adult human beta cell population, which is largely established by age 20 years.

From the Cover: Accelerated telomere shortening in response to life stress

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets “under the skin” remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress— both perceived stress and chronicity of stress—is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.

Rapalogs in cancer prevention

Common cancer is an age-related disease. Slow aging is associated with reduced and delayed carcinogenesis. Calorie restriction (CR), the most studied anti-aging intervention, prevents cancer by slowing down the aging process. Evidence is emerging that CR decelerates aging by deactivating MTOR (Target of Rapamycin). Rapamycin and other rapalogs suppress cellular senescence, slow down aging and postpone age-related diseases including cancer. At the same time, rapalogs are approved for certain cancer treatments. Can cancer prevention be explained by direct targeting of cancer cells? Or does rapamycin prevent cancer indirectly through slowing down the aging process? Increasing evidence points to the latter scenario.

Blueberry anthocyanins: protection against ageing and light-induced damage in retinal pigment epithelial cells.

Retinal pigment epithelium (RPE) cells are vital for retinal health. However, they are susceptible to injury with ageing and exposure to excessive light, including UV (100-380 nm) and visible (380-760 nm) radiation. To evaluate the protective effect of blueberry anthocyanins on RPE cells, in vitro cell models of replicative senescent and light-induced damage were established in the present study. After purification and fractionation, blueberry anthocyanin extracts (BAE) were yielded with total anthocyanin contents of 31·0 (SD 0·5) % and were used in this study. Replicative senescence of RPE cells was induced by repeatedly passaging cells from the fourth passage to the tenth. From the fifth passage, cultured RPE cells began to enter a replicative senescence, exhibiting reduced cell proliferation along with an increase in the number of β-galactosidase-positive cells. RPE cells maintained high cell viability (P < 0·01) and a low (P < 0·01) percentage of β-galactosidase-positive cells when treated with 0·1 μg/ml BAE. In contrast, after exposure to 2500 (SD 500) lx light (420-800 nm) for 12 h, RPE cells in the positive control (light exposure, no BAE treatment) exhibited premature senescence, low (P < 0·01) cell viability and increased (P < 0·01) vascular endothelial growth factor (VEGF) release compared with negative control cells, which were not subjected to light irradiation and BAE exposure. Correspondingly, BAE is beneficial to RPE cells by protecting these cells against light-induced damage through the suppression of ageing and apoptosis as well as the down-regulation of the over-expressed VEGF to normal level. These results demonstrate that BAE is efficacious against senescence and light-induced damage of RPE cells.

Blueberries and neuronal aging.

As the population of people in the United States over the age of 65 years continues to increase, so too will the incidence of age-related pathologies, including decreases in cognitive and motor function. In cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Evidence is accumulating that consumption of blueberries may be one strategy to forestall or even reverse age-related neuronal deficits, as well as their subsequent behavioral manifestations, in order to increase healthy aging. Research suggests that the polyphenolic compounds found in blueberries exert their beneficial effects either through their ability to lower oxidative stress and inflammation or directly by altering the signaling involved in neuronal communication. These interventions, in turn, may protect against age-related deficits in cognitive and motor function. Appropriately, the US Department of Agriculture has figured prominently in these discoveries, through the efforts of two USDA researchers who worked for the department 100 years apart. Copyright © 2012 S. Karger AG, Basel.

Radioprotective effects of Zingiber officinale Roscoe (ginger): past, present and future.

Radiation is an important modality in treating people with cancer especially when surgical intervention is impracticable or might debilitate the patient. However, effective use of ionizing radiation is compromised by the side effects that result from radiation-induced damage to normal tissue. The use of radioprotective compounds, which can selectively protect normal tissues against radiation injury is of immense use because in addition to association with protecting the normal tissue, it will also permits use of higher doses of radiation to obtain better cancer control and possible cure. However, till date no ideal radioprotectors are available as most synthetic compounds are toxic at their optimal concentrations. Plants commonly used as dietary and or therapeutic agents have recently been the focus of attention since in most cases they are non-toxic and are easily accepted for human use. Ginger, the rhizomes of Zingiber officinale Roscoe (Zingiberaceae), has widely been used as both culinary and medicinal agent. Preclinical studies carried out in the last decade has shown that ginger and its phytochemicals dehydrozingerone, zingerone possess radioprotective effects in laboratory animals and in cultured cells in vitro. The hydroalcoholic extract of ginger rhizome when administered either through intraperitoneal or oral route was effective in protecting against gamma radiation-induced sickness and mortality. The phytochemicals dehydrogingerone and zingerone present in ginger are also shown to protect mice against radiation-induced sickness and mortality. Mechanistic studies have indicated that the free radical scavenging, antioxidant affects, anti-inflammatory and anti-clastogenic effects may contribute towards the observed protection. Additionally, studies with tumor bearing mice have also shown that zingerone selectively protects the normal tissues against the tumoricidal effects of radiation. This review for the first time summarizes the results related to the radioprotective properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a radioprotective agent.

Effects of Aerobic Exercise on Mild Cognitive Impairment

Objectives To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design Six-month, randomized, controlled, clinical trial. Setting Veterans Affairs Puget Sound Health Care System clinical research unit. Participants Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age,70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions This study provides support, using rigorous controlled methodology, for a potent nonpharma-cologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

Macronutrient balance and lifespan

Dietary restriction (DR) without malnutrition is widely regarded to be a universal mechanism for prolonging lifespan. It is generally believed that the benefits of DR arise from eating fewer calories (termed caloric restriction, CR). Here we argue that, rather than calories, the key determinant of the relationship between diet and longevity is the balance of protein to non-protein energy ingested. This ratio affects not only lifespan, but also total energy intake, metabolism, immunity and the likelihood of developing obesity and associated metabolic disorders. Among various possible mechanisms linking macronutrient balance to lifespan, the nexus between the TOR and AMPK signaling pathways is emerging as a central coordinator.

Stress and Telomere Biology: A Lifespan Perspective

In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes ver the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.

Treating aging: progress toward dietary restriction mimetics

During the last decade, biogerontologists have labored to understand the biological basis of the aging process by studying the genes and signaling pathways that regulate it. But the last year has seen a breakthrough in a different direction: toward treatments that might slow aging by mimicking the effects of dietary restriction.

mTOR is a key modulator of ageing and age-related disease

Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of ‘when’ rather than ‘if’. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.

Telomeres, lifestyle, cancer, and aging

Purpose of review There has been growing evidence that lifestyle factors may affect the health and lifespan of an individual by affecting telomere length. The purpose of this review was to highlight the importance of telomeres in human health and aging and to summarize possible lifestyle factors that may affect health and longevity by altering the rate of telomere shortening. Recent findings Recent studies indicate that telomere length, which can be affected by various lifestyle factors, can affect the pace of aging and onset of age-associated diseases. Summary Telomere length shortens with age. Progressive shortening of telomeres leads to senescence, apoptosis, or oncogenic transformation of somatic cells, affecting the health and lifespan of an individual. Shorter telomeres have been associated with increased incidence of diseases and poor survival. The rate of telomere shortening can be either increased or decreased by specific lifestyle factors. Better choice of diet and activities has great potential to reduce the rate of telomere shortening or at least prevent excessive telomere attrition, leading to delayed onset of age-associated diseases and increased lifespan. This review highlights the role of telomeres in aging and describes the lifestyle factors which may affect telomeres, human health, and aging.

Cancer and aging: from the kinetics of biological parameters to the kinetics of cancer incidence and mortality.

Epidemiologic and biological data strongly support the existence of a strict link between cancer and aging. In spite of the relevance of the problem, there were numerous pitfalls in epidemiologic investigation until a few years ago. An apparent decrease of cancer incidence in old age was revealed to be a misconception based on lack of sufficient appreciation for changing population size. But not all problems are solved by using age-specific cancer incidence, as recently stressed by some authors. At very advanced ages a slowing of the rate of increase of age-specific cancer incidence is clearly demonstrated. These findings apparently clash with the majority of biological data and suggest that some mechanism may develop at advanced ages capable of decreasing cancer susceptibility. In this paper, it will be shown that just a slowing-down kinetics is predicted for cancer incidence by using a mathematical model of mortality kinetics recently proposed in the gerontologic field. The slowing of the increasing rate or even a decreasing trend of cancer incidence of an aging population is compatible with a continuously accelerating pace of loss of physiological capacity of the single subjects, as with advancing age there is a selection of individuals with better physiological functions.

Insect food for astronauts: gas exchange in silkworms fed on mulberry and lettuce and the nutritional value of these insects for human consumption ...

In this study, silkworm moth (Bombyx mori L.) larvae were regarded as an animal protein source for astronauts in the bioregenerative life support system during long-term deep space exploration in the future. They were fed with mulberry and stem lettuce leaves during the first three instars and the last two instars, respectively. In addition, this kind of environmental approach, which utilised inedible biomass of plants to produce animal protein of high quality, can likewise be applied terrestrially to provide food for people living in extreme environments and/or impoverished agro-ecosystems, such as in polar regions, isolated military bases, ships, submarines, etc. Respiration characteristics of the larvae during development under two main physiological conditions, namely eating and not-eating of leaves, were studied. Nutrient compositions of silkworm powder (SP), ground and freeze-dried silkworms on the 3rd day of the 5th instar larvae, including protein, fat, vitamins, minerals and fatty acids, were measured using international standard methods. Silkworms' respiration rates, measured when larvae were eating mulberry leaves, were higher than those of similar larvae that hadn't eaten such leaves. There was a significant difference between silkworms fed on mulberry leaves and those fed on stem lettuce in the 4th and 5th instars (P<0.01). Amounts of CO2 exhaled by the silkworms under the two physiological regimes differed from each other (P<0.01). There was also a significant difference between the amount of O2 inhaled when the insects were under the two physiological statuses (P<0.01). Moreover, silkworms' respiration quotient under the eating regime was larger than when under the not-eating regime. The SP was found to be rich in protein and amino acids in total; 12 essential vitamins, nine minerals and twelve fatty acids were detected. Moreover, 359 kcal could be generated per 100 gram of SP (dry weight).

The microbiome and obesity: is obesity linked to our gut flora?

The human gut is a lush microbial ecosystem containing about 100 trillion microorganisms, whose collective genome, the microbiome, contains 100-fold more genes than the entire human genome. The symbiosis of our extended genome plays a role in host homeostasis and energy extraction from diet. In this article, we summarize some of the studies that have advanced the understanding of the microbiome and its effects on metabolism, obesity, and health. Metagenomic studies demonstrated that certain mixes of gut microbiota may protect or predispose the host to obesity. Furthermore, microbiota transplantation studies in germ-free murine models showed that the efficient energy extraction traits of obese-type gut flora are transmissible. The proposed methods by which the microbiome may contribute to obesity include increasing dietary energy harvest, promoting fat deposition, and triggering systemic inflammation. Future treatments for obesity may involve modulation of gut microbiota using probiotics or prebiotics.

Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet

Modern diets are largely heat-processed and as a result contain high levels of advanced glycation end products (AGEs). Dietary advanced glycation end products (dAGEs) are known to contribute to increased oxidant stress and inflammation, which are linked to the recent epidemics of diabetes and cardiovascular disease. This report significantly expands the available dAGE database, validates the dAGE testing methodology, compares cooking procedures and inhibitory agents on new dAGE formation, and introduces practical approaches for reducing dAGE consumption in daily life. Based on the findings, dry heat promotes new dAGE formation by >10- to 100-fold above the uncooked state across food categories. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In contrast, carbohydrate-rich foods such as vegetables, fruits, whole grains, and milk contain relatively few AGEs, even after cooking. The formation of new dAGEs during cooking was prevented by the AGE inhibitory compound aminoguanidine and significantly reduced by cooking with moist heat, using shorter cooking times, cooking at lower temperatures, and by use of acidic ingredients such as lemon juice or vinegar. The new dAGE database provides a valuable instrument for estimating dAGE intake and for guiding food choices to reduce dAGE intake.

Methionine dependency and cancer treatment.

Conventional chemotherapies have showed their limits, notably for patients with advanced cancer. New therapeutic strategies must be identified, and the metabolic abnormalities of cancer cells offer such opportunities. Many human cancer cell lines and primary tumors have absolute requirements for methionine, an essential amino acid. In contrast, normal cells are relatively resistant to exogenous methionine restriction. The biochemical mechanism for methionine dependency has been studied extensively, but the fundamental mechanism remains unclear. A number of investigators have attempted to exploit the methionine dependence of tumors for therapeutic effects in vivo. To reduce in vivo methionine in plasma and tumours, dietary and pharmacological treatments have been used. Methionine-free diet or methionine-deprived total parenteral nutrition causes regression of a variety of animal tumours. Alternatively, methionine depletion was achieved by the use of methioninase. This enzyme specifically degrades methionine and inhibits tumour growth in preclinical models. Because of potential toxicity and quality of life problems, prolonged methionine restriction with diet or with methioninase is not suitable for clinical use. Methionine restriction may find greater application in association with various chemotherapeutic agents. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs. The experimental results accumulated during the last three decades suggest that methionine restriction can become an additional cancer therapeutic strategy, notably in association with chemotherapy.

Curcumin in Cell Death Processes: A Challenge for CAM of Age-Related Pathologies

Curcumin, the yellow pigment from the rhizoma of Curcuma longa, is a widely studied phytochemical which has a variety of biological activities: anti-inflammatory and anti-oxidative. In this review we discuss the biological mechanisms and possible clinical effects of curcumin treatment on cancer therapy, and neurodegenerative diseases such as Alzheimer's Disease, with particular attention to the cell death processes induced by curcumin. Since oxidative stress and inflammation are major determinants of the aging process, we also argue that curcumin can have a more general effect that slows down the rate of aging. Finally, the effects of curcumin can be described as xenohormetic, since it activates a sort of stress response in mammalian cells.

Exercise and longevity.

Aging is a natural and complex physiological process influenced by many factors, some of which are modifiable. As the number of older individuals continues to increase, it is important to develop interventions that can be easily implemented and contribute to "successful aging". In addition to a healthy diet and psychosocial well-being, the benefits of regular exercise on mortality, and the prevention and control of chronic disease affecting both life expectancy and quality of life are well established. We summarize the benefits of regular exercise on longevity, present the current knowledge regarding potential mechanisms, and outline the main recommendations. Exercise can partially reverse the effects of the aging process on physiological functions and preserve functional reserve in the elderly. Numerous studies have shown that maintaining a minimum quantity and quality of exercise decreases the risk of death, prevents the development of certain cancers, lowers the risk of osteoporosis and increases longevity. Training programs should include exercises aimed at improving cardiorespiratory fitness and muscle function, as well as flexibility and balance. Though the benefits of physical activity appear to be directly linked to the notion of training volume and intensity, further research is required in the elderly, in order to develop more precise recommendations, bearing in mind that the main aim is to foster long-term adherence to physical activity in this growing population. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?

The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.

Aluminum involvement in the progression of Alzheimer's disease.

The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD.

Aging is not programmed

Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways such as mTOR. Ironically, this is often misunderstood as a sort of programmed aging. In contrast, aging is a purposeless quasi-program or, figuratively, a shadow of actual programs. “The brightest flame casts the darkest shadow.” -George Martin

At the crossroad of lifespan, calorie restriction, chromatin and disease: meeting on sirtuins.

Longevity, lifespan, cancer, cellular transformation, energy, calorie restriction, diabetes--what can tie together such a diversity of hot topics in biomedical research? Emerging findings suggest that the answer lies in understanding the functions of the recently discovered family of proteins known as Sirtuins. Barcelona hosted the first scientific meeting completely focused on these evolutionary conserved protein deacetylases, bringing together experts in the biochemistry to cellular biology, mice models, drug targeting and pathophysiology of these molecules. Their work, summarized here, establishes the Sirtuins as major players in cellular homeostasis and human diseases that act through a whole range of biochemical substrates and physiological processes. Undoubtedly, this is an increasingly expanding field that it is here to stay and growth.

Insights into the beneficial effect of caloric/ dietary restriction for a healthy and prolonged life

Over the last several years, new evidence has kept pouring in about the remarkable effect of caloric restriction (CR) on the conspicuous bedfellows- aging and cancer. Through the use of various animal models, it is now well established that by reducing calorie intake one can not only increase life span but, also, lower the risk of various age related diseases such as cancer. Cancer cells are believed to be more dependent on glycolysis for their energy requirements than normal cells and, therefore, can be easily targeted by alteration in the energy-metabolic pathways, a hallmark of CR. Apart from inhibiting the growth of transplantable tumors, CR has been also shown to inhibit the development of spontaneous, radiation, and chemically induced tumors. The question regarding the potentiality of the anti-tumor effect of CR in humans has been in part answered by the resistance of a cohort of women, who had suffered from anorexia in their early life, to breast cancer. However, human research on the beneficial effect of CR is still at an early stage and needs further validation. Though the complete mechanism of the anti-tumor effect of CR is far from clear, the plausible involvement of nutrient sensing pathways or IGF-1 pathways proposed for its anti-aging action cannot be overruled. In fact, cancer cell lines, mutant for proteins involved in IGF-1 pathways, failed to respond to CR. In addition, CR decreases the levels of many growth factors, anabolic hormones, inflammatory cytokines, and oxidative markers that are deregulated in several cancers. In this review, we discuss the anti-tumor effect of CR, describing experiments done in vitro in tumor models and in vivo in mouse models in which the tumor was induced by means of radiation or chemical exposure, expressing oncogenes or deleting tumor suppression genes. We also discuss the proposed mechanisms of CR anti-tumor action. Lastly, we argue the necessity of gene expression studies in cancerous versus normal cells upon CR.

Spending on vegetable and fruit consumption could reduce all-cause mortality among older adults

Background Few studies have evaluated the linkage between food cost and mortality among older adults. This study considers the hypothesis that greater food expenditure in general, and particularly on more nutritious plant and animal-derived foods, decreases mortality in older adults. Methods This study uses the 1999–2000 Elderly Nutrition and Health Survey in Taiwan and follows the cohort until 2008, collecting 24-hr dietary recall data for 1781 participants (874 men and 907 women) aged 65 y or older. Using monthly mean national food prices and 24-hr recall, this study presents an estimate of daily expenditures for vegetable, fruit, animal-derived, and grain food categories. Participants were linked to the national death registry. Results Of the 1781 original participants, 625 died during the 10-y follow-up period. Among the 4 food categories, the fourth and fifth expenditure quintiles for vegetables and for fruits had the highest survival rates. After adjusting for co-variates, higher (Q4) vegetable and higher fruit (Q4) food expenditures referent to Q1 were significantly predictive of reduced mortality (HR = 0.55, 95% CI: 0.39-0.78 and HR = 0.64, 95% CI: 0.42–0.99, respectively) and the risk decreased by 12% and 10% for every NT$15 (US$0.50) increase in their daily expenditures. Animal-derived and grain food spending was not predictive of mortality. Conclusion Greater and more achievable vegetable and fruit affordability may improve food security and longevity for older adults.

Electric light causes cancer? Surely you're joking, Mr. Stevens.

Night is no longer dark in the modern world, and the Milky Way has disappeared. Electric light has benefits but there are also a few detriments. These are (1) loss of the night sky, (2) wasted energy, (3) harm to animal and plant life, (4) and perhaps increases in some severe human maladies such as cancers of breast and prostate. The science on phototransduction for the circadian system and on clock gene function is evolving rapidly, and it provides a rationale for the idea that circadian disruption from light at night could cause disease. Direct evidence from humans and rodent models has also accumulated to the point where the idea is no longer fanciful. Although it may seem logical now, the journey on the path from electric light to breast cancer has been a tortuous one, at least for me.

From the Cover: Caloric restriction improves memory in elderly humans

Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m2) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < −0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.

Oral implications of the vegan diet: observational study.

AIM: The aim of this study was to investigate oral changes in subjects who have assumed a vegan diet for a long time (at least 18 months), that is to say, a diet completely lacking in meat and animal derivatives. METHODS: A sample of 15 subjects was analyzed, all from northern Italy and aged 24 to 60 year, composed of 11 men and 4 women who had been following a vegan diet for a minimum of 18 months to a maximum of 20 years. In parallel with the study sample, a control group (15 subjects) with the same criteria of age, sex, and place of origin all following an omnivorous diet was chosen. The sample answered a questionnaire that investigated their eating habits, the frequency with which they eat meals, the main foodstuffs assumed, oral hygiene habits, and any painful symptomatology of the teeth or more general problems in the oral cavity. The sample was then subject to objective examination in which the saliva pH was measured and the teeth were checked for demineralization of the enamel, white spots, and caries (using KaVo DIAGNOdent) with particular attention being paid to the localization of these lesions, and lastly, sounding was carried out to detect any osseous defects and periodontal pockets. RESULTS: The study revealed greater incidence of demineralization and white spots in the vegan subjects compared to the omnivorous ones localized at the neck of the teeth and on the vestibular surfaces of dental elements (with the exception of the lower anterior group). The saliva pH, more acid in the omnivorous patients, ranged between four and six. Changes in oral conditions in both groups of subjects were observed. CONCLUSION: In order to research into the cause-effect relationship of the vegan diet on the oral cavity effectively, the sample needs to be studied for a longer period of time and the results re-evaluated.

Age and systemic acid-base equilibrium: analysis of published data.

To investigate whether systemic acid-base equilibrium changes with aging in normal adult humans, we reviewed published articles reporting the acid-base composition of arterial, arterialized venous, or capillary blood in age-identified healthy subjects. We extracted or calculated blood hydrogen ion concentration ([H+]), plasma bicarbonate concentration ([HCO3(-)]), blood PCO2, and age, and computed a total of 61 age-group means, distributed among eight 10-year intervals from age 20 to 100 years. Using linear regression analysis, we found that with increasing age, there is a significant increase in the steady-state blood [H+] (p < .001), and reduction in steady-state plasma [HCO3(-)] (p < .001), indicative of a progressively worsening low-level metabolic acidosis. Blood PCO2 decreased with age (p < .05), in keeping with the expected respiratory adaptation to metabolic acidosis. Such age-related increasing metabolic acidosis may reflect in part the normal decline of renal function with increasing age. The role of age-related metabolic acidosis in the pathogenesis of the degenerative diseases of aging warrants consideration.

BEYOND THE PALEOLITHIC PRESCRIPTION: INCORPORATING DIVERSITY AND FLEXIBILITY IN THE STUDY OF HUMAN DIET EVOLUTION

Evolutionary paradigms of human health and nutrition center on the evolutionary discordance or “mismatch” model whereby human bodies, reflecting adaptations established in the Paleolithic era, are ill-suited to modern industrialized diets resulting in rapidly increasing rates of chronic metabolic disease. Whereas this model remains useful, we argue that its utility in explaining the evolution of human dietary tendencies is limited. The assumption that human diets are mismatched to our evolved biology implies that they are instinctual or genetically determined and rooted in the Paleolithic. We review current research indicating that human eating habits are primarily learned through behavioral, social and physiological mechanisms starting in utero and extending throughout the life course. Those adaptations that appear to be strongly genetic likely reflect Neolithic, rather than Paleolithic, adaptations and are significantly influenced by human niche-constructing behavior. Incorporating a broader understanding of the evolved mechanisms by which humans learn and imprint eating habits and the reciprocal effects of those habits on physiology would provide useful tools for structuring more lasting nutrition interventions.

Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer's disease, diabetes mellitus, and no...

Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

The rise and fall of horror autotoxicus and forbidden clones.

Cui and associates show that healthy individuals have natural autoantibodies (NAAs) specific for myeloperoxidase, proteinase 3, and glomerular basement membrane (GBM) with the same specificity as anti-neutrophil cytoplasmic antibodies and anti-GBM antibodies that are pathogenic. Although Ehrlich proposed horror autotoxicus and Burnet envisioned elimination of forbidden clones, NAAs are present in all healthy individuals and play beneficial homeostatic roles. Pathogenic autoimmunity is dysregulation of natural homeostatic autoimmunity rather than onset of a previously absent self-recognition.

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1–7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics. Initial studies in yeasts, nematodes, and flies indicated a strong connection of SIRT with the life-prolonging effects of calorie restriction (CR), a robust experimental intervention for longevity in a range of organisms. However, subsequent studies reported controversial findings regarding SIRT roles in the effect of CR. This review describes the functional roles of mammalian SIRTs and discusses their relevance to mechanisms underlying the longevity effect of CR.

Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53.

BACKGROUND: Centenarians are exceptionally long living individuals who escaped the most common age-related diseases. In particular they appear to be effectively protected from cancers. The mechanisms that underlie this protection are quite complex and still largely unclear. AIM: To critically analyse the literature in order to propose a unifying hypothesis that can account for this cancer protection in centenarians. METHODS: Review of the scientific literature regarding three main players in tumourigenesis such as IGF-1, inflammation and p53, and centenarians. RESULTS: Centenarians appear to be characterised by low IGF-1-mediated responses and high levels of anti-inflammatory cytokines such as IL-10 and TGF-beta, a condition that results in protection from cancer. Both inflammation and IGF-1 pathway converge on the tumour suppressor p53. Accordingly, some studies indicate that genetic variants of p53 are associated with human longevity by providing protection from cancer mortality. CONCLUSIONS: The available data let us to hypothesise that among other possible mechanisms, well-preserved p53-mediated responses are likely a key factor contributing to protection from cancer in centenarians.

Dietary Restriction, Growth Factors and Aging: from yeast to humans

Dietary restriction (DR) and reduced growth factor signaling both elevate resistance to oxidative stress, reduce macromolecular damage, and increase lifespan in model organisms. In rodents, both DR and decreased growth factor signaling reduce the incidence of tumors and slow down cognitive decline and aging. DR reduces cancer and cardiovascular disease and mortality in monkeys, and reduces metabolic traits associated with diabetes, cardiovascular disease and cancer in humans. Neoplasias and diabetes are also rare in humans with loss of function mutations in the growth hormone receptor. DR and reduced growth factor signaling may thus slow aging by similar, evolutionarily conserved, mechanisms. We review these conserved anti-aging pathways in model organisms, discuss their link to disease prevention in mammals, and consider the negative side effects that might hinder interventions intended to extend healthy lifespan in humans.

Epidemiologic Investigation of Immune-Mediated Polyradiculoneuropathy among Abattoir Workers Exposed to Porcine Brain

Background In October 2007, a cluster of patients experiencing a novel polyradiculoneuropathy was identified at a pork abattoir (Plant A). Patients worked in the primary carcass processing area (warm room); the majority processed severed heads (head-table). An investigation was initiated to determine risk factors for illness. Methods and Results Symptoms of the reported patients were unlike previously described occupational associated illnesses. A case-control study was conducted at Plant A. A case was defined as evidence of symptoms of peripheral neuropathy and compatible electrodiagnostic testing in a pork abattoir worker. Two control groups were used - randomly selected non-ill warm-room workers (n = 49), and all non-ill head-table workers (n = 56). Consenting cases and controls were interviewed and blood and throat swabs were collected. The 26 largest U.S. pork abattoirs were surveyed to identify additional cases. Fifteen cases were identified at Plant A; illness onsets occurred during May 2004–November 2007. Median age was 32 years (range, 21–55 years). Cases were more likely than warm-room controls to have ever worked at the head-table (adjusted odds ratio [AOR], 6.6; 95% confidence interval [CI], 1.6–26.7), removed brains or removed muscle from the backs of heads (AOR, 10.3; 95% CI, 1.5–68.5), and worked within 0–10 feet of the brain removal operation (AOR, 9.9; 95% CI, 1.2–80.0). Associations remained when comparing head-table cases and head-table controls. Workers removed brains by using compressed air that liquefied brain and generated aerosolized droplets, exposing themselves and nearby workers. Eight additional cases were identified in the only two other abattoirs using this technique. The three abattoirs that used this technique have stopped brain removal, and no new cases have been reported after 24 months of follow up. Cases compared to controls had higher median interferon-gamma (IFNγ) levels (21.7 pg/ml; vs 14.8 pg/ml, P<0.001). Discussion This novel polyradiculoneuropathy was associated with removing porcine brains with compressed air. An autoimmune mechanism is supported by higher levels of IFNγ in cases than in controls consistent with other immune mediated illnesses occurring in association with neural tissue exposure. Abattoirs should not use compressed air to remove brains and should avoid procedures that aerosolize CNS tissue. This outbreak highlights the potential for respiratory or mucosal exposure to cause an immune-mediated illness in an occupational setting.

Ten years of life: Is it a matter of choice?

BACKGROUND: Relative risk estimates suggest that effective implementation of behaviors commonly advocated in preventive medicine should increase life expectancy, although there is little direct evidence. OBJECTIVE: To test the hypothesis that choices regarding diet, exercise, and smoking influence life expectancy. METHODS: A total of 34 192 California Seventh-Day Adventists (75% of those eligible) were enrolled in a cohort and followed up from 1976 to 1988. A mailed questionnaire provided dietary and other exposure information at study baseline. Mortality for all subjects was ascertained by matching to state death tapes and the National Death Index. RESULTS: California Adventists have higher life expectancies at the age of 30 years than other white Californians by 7.28 years (95% confidence interval, 6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88 years) in women, giving them perhaps the highest life expectancy of any formally described population. Commonly observed combinations of diet, exercise, body mass index, past smoking habits, and hormone replacement therapy (in women) can account for differences of up to 10 years of life expectancy among Adventists. A comparison of life expectancy when these factors take high-risk compared with low-risk values shows independent effects that vary between 1.06 and 2.74 years for different variables. The effect of each variable is assessed with all others at either medium- or high-risk levels. CONCLUSIONS: Choices regarding diet, exercise, cigarette smoking, body weight, and hormone replacement therapy, in combination, appear to change life expectancy by many years. The longevity experience of Adventists probably demonstrates the beneficial effects of more optimal behaviors.

Curcumin and neurodegenerative diseases

Over the last ten years curcumin has been reported to be effective against a wide variety of diseases and is characterized as having anti-carcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, and anti-infectious properties. Recent studies performed in both vertebrate and invertebrate models have been conducted to determine whether curcumin was also neuroprotective. The efficacy of curcumin in several pre-clinical trials for neurodegenerative diseases has created considerable excitement mainly due to its lack of toxicity and low cost. This suggests that curcumin could be a worthy candidate for nutraceutical intervention. Since aging is a common risk factor for neurodegenerative diseases, it is possible that some compounds that target aging mechanisms could also prevent these kinds of diseases. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent aging-associated changes in cellular proteins that lead to protein insolubility and aggregation. This loss in protein homeostasis is associated with several age-related diseases. Recently, curcumin has been found to help maintain protein homeostasis and extend lifespan in the model invertebrate Caenorhabditis elegans. Here, we review the evidence from several animal models that curcumin improves healthspan by preventing or delaying the onset of various neurodegenerative diseases.

Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR

DR (dietary restriction), or reduced food intake without malnutrition, is associated with extended longevity, improved metabolic fitness and increased stress resistance in a wide range of organisms. DR is often referred to as calorie restriction, implying that reduced energy intake is responsible for its widespread and evolutionarily conserved benefits. However, recent data indicate dietary amino acid restriction as a key mediator of DR benefits. In fruitflies, an imbalance in essential amino acid intake is thought to underlie longevity benefits of DR. In mammals, reduced dietary protein or essential amino acid intake can extend longevity, improve metabolic fitness and increase stress resistance. In the present paper we review two evolutionarily conserved signal transduction pathways responsible for sensing amino acid levels. The eIF2α (eukaryotic initiation factor 2α) kinase GCN2 (general amino acid control non-derepressible 2) senses the absence of one or more amino acids by virtue of direct binding to uncharged cognate tRNAs. The presence of certain amino acids, such as leucine, permits activation of the master growth regulating kinase TOR (target of rapamycin). These two signal transduction pathways react to amino acid deprivation by inhibiting general protein translation while at the same time increasing translation of specific mRNAs involved in restoring homoeostasis. Together, these pathways may contribute to the regulation of longevity, metabolic fitness and stress resistance.

Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients.

Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-beta (1-42) (Abeta) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Abeta plaques [5]. The natural product curcuminoids enhanced brain clearance of Abeta in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Abeta uptake using fluorescence and confocal microscopy. At baseline, the intensity of Abeta uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Abeta uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain.

Aspartame-induced fibromyalgia, an unusual but curable cause of chronic pain.

We report for the first time an unusual musculoskeletal adverse effect of aspartame in two patients. A 50-year-old woman had been suffering from widespread pain and fatigue for more than 10 years leading to the diagnosis of fibromyalgia. During a vacation in a foreign country, she did not suffer from painful symptoms since she had forgotten to take her aspartame. All of the symptoms reappeared in the days following her return when she reintroduced aspartame into her daily diet. Thus, aspartame was definitively excluded from her diet, resulting in a complete regression of the fibromyalgia symptoms. A 43-year-old man consulted for a 3-year history of bilateral forearm, wrist, and hand and cervical pain with various unsuccessful treatments. A detailed questioning allowed to find out that he had been taking aspartame for three years. The removal of aspartame was followed by a complete regression of pain, without recurrence. We believe that these patients' chronic pain was due to the ingestion of aspartame, a potent flavouring agent, widely used in food as a calorie-saver. The benefit/ risk ratio of considering the diagnosis of aspartame-induced chronic pain is obvious: the potential benefit is to cure a disabling chronic disease, to spare numerous laboratory and imaging investigations, and to avoid potentially harmful therapies; the potential risk is to temporarily change the patient's diet. Thus, practitioners should ask patients suffering from fibromyalgia about their intake of aspartame. In some cases, this simple question might lead to the resolution of a disabling chronic disease.

Early life stress and telomere length: Investigating the connection and possible mechanisms

How can adverse experiences in early life, such as maltreatment, exert such powerful negative effects on health decades later? The answer may lie in changes to DNA. New research suggests that exposure to stress can accelerate the erosion of DNA segments called telomeres. Shorter telomere length correlates with chronological age and also disease morbidity and mortality. Thus, telomere erosion is a potential mechanism linking childhood stress to health problems later in life. However, an array of mechanistic, methodological, and basic biological questions must be addressed in order to translate telomere discoveries into clinical applications for monitoring health and predicting disease risk. This paper covers the current state of the science and lays out new research directions.

An anthroposophic lifestyle and intestinal microflora in infancy.

The intestinal flora is considered to have an impact on the development of the immune system. In the anthroposophic lifestyle, a diet comprising vegetables spontaneously fermented by lactobacilli, and a restrictive use of antibiotics, anti-pyretics and vaccinations, is typical. The aim of this study was to assess the gut flora in infants in relation to certain lifestyle characteristics associated with anthroposophy. Sixty-nine children < 2 years of age with an anthroposophic lifestyle, and 59 infants of a similar age with a traditional lifestyle, were clinically examined and questionnaire replies assessed. Fecal samples were analyzed by bacterial enumeration, bacterial typing through biochemical fingerprinting and by measuring microflora-associated characteristics (MACs). The numbers of colony-forming units (CFU)/g of feces were significantly higher for enterococci and lactic acid bacteria in children who had never been exposed to antibiotics (5.5 x 107 vs. 2.1 x 107; p < 0.001 and 10 x 107 vs. 4.1 x 107; p < 0.01, respectively). Furthermore, the number of enterococci was significantly higher in breastfed and vegetarian infants (p < 0.01). The diversity (Simpson's diversity index) of lactobacilli, as determined by biochemical fingerprinting, was higher in infants born at home than in those born in hospital (p < 0.01). Several MACs were related to specific lifestyle features, and infants with an anthroposophic lifestyle had a higher proportion of acetic acid and a lower proportion of propionic acid in their stool as compared to the control children. In conclusion, lifestyle factors related to the anthroposophic way of life influenced the composition of the gut flora in the infants. These differences may contribute to the lower prevalence of atopic disease previously observed in children in anthroposophic families.

The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy.

Recent studies confirm that dietary methionine restriction increases both mean and maximal lifespan in rats and mice, achieving "aging retardant" effects very similar to those of caloric restriction, including a suppression of mitochondrial superoxide generation. Although voluntary caloric restriction is never likely to gain much popularity as a pro-longevity strategy for humans, it may be more feasible to achieve moderate methionine restriction, in light of the fact that vegan diets tend to be relatively low in this amino acid. Plant proteins - especially those derived from legumes or nuts - tend to be lower in methionine than animal proteins. Furthermore, the total protein content of vegan diets, as a function of calorie content, tends to be lower than that of omnivore diets, and plant protein has somewhat lower bioavailability than animal protein. Whole-food vegan diets that moderate bean and soy intake, while including ample amounts of fruit and wine or beer, can be quite low in methionine, while supplying abundant nutrition for health (assuming concurrent B12 supplementation). Furthermore, low-fat vegan diets, coupled with exercise training, can be expected to promote longevity by decreasing systemic levels of insulin and free IGF-I; the latter effect would be amplified by methionine restriction - though it is not clear whether IGF-I down-regulation is the sole basis for the impact of low-methionine diets on longevity in rodents.

Effect of low saturated fat diet in early and late cases of multiple sclerosis.

144 multiple sclerosis patients took a low-fat diet for 34 years. For each of three categories of neurological disability (minimum, moderate, severe) patients who adhered to the prescribed diet (less than or equal to 20 g fat/day) showed significantly less deterioration and much lower death rates than did those who consumed more fat than prescribed (greater than 20 g fat/day). The greatest benefit was seen in those with minimum disability at the start of the trial; in this group, when those who died from non-MS diseases were excluded from the analysis, 95% survived and remained physically active.

Cognitive performance among the elderly in relation to the intake of plant foods. The Hordaland Health Study.

Fruits and vegetables are among the most nutritious and healthy of foods, and are related to the prevention of many chronic diseases. The aim of the study was to examine the relationship between intake of different plant foods and cognitive performance in elderly individuals in a cross-sectional study. Two thousand and thirty-one elderly subjects (aged 70-74 years; 55% women) recruited from the general population in Western Norway underwent extensive cognitive testing and completed a comprehensive FFQ. The cognitive test battery covered several domains (Kendrick Object Learning Test, Trail Making Test--part A, modified versions of the Digit Symbol Test, Block Design, Mini-Mental State Examination and Controlled Oral Word Association Test). A validated and self-reported FFQ was used to assess habitual food intake. Subjects with intakes of >10th percentile of fruits, vegetables, grain products and mushrooms performed significantly better in cognitive tests than those with very low or no intake. The associations were strongest between cognition and the combined intake of fruits and vegetables, with a marked dose-dependent relationship up to about 500 g/d. The dose-related increase of intakes of grain products and potatoes reached a plateau at about 100-150 g/d, levelling off or decreasing thereafter, whereas the associations were linear for mushrooms. For individual plant foods, the positive cognitive associations of carrots, cruciferous vegetables, citrus fruits and high-fibre bread were most pronounced. The only negative cognitive association was with increased intake of white bread. In the elderly, a diet rich in plant foods is associated with better performance in several cognitive abilities in a dose-dependent manner.

Organically Grown Food Provides Health Benefits to Drosophila melanogaster

The “organic food” market is the fastest growing food sector, yet it is unclear whether organically raised food is nutritionally superior to conventionally grown food and whether consuming organic food bestows health benefits. In order to evaluate potential health benefits of organic foods, we used the well-characterized fruit fly Drosophila melanogaster as a model system. Fruit flies were raised on a diets consisting of extracts of either conventionally or organically raised produce (bananas, potatoes, raisins, soy beans). Flies were then subjected to a variety of tests designed to assess overall fly health. Flies raised on diets made from organically grown produce had greater fertility and longevity. On certain food sources, greater activity and greater stress resistance was additionally observed, suggesting that organic food bestows positive effects on fly health. Our data show that Drosophila can be used as a convenient model system to experimentally test potential health effects of dietary components. Using this system, we provide evidence that organically raised food may provide animals with tangible benefits to overall health.

Dietary intake of berries and flavonoids in relation to cognitive decline

Objective Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women. Methods Beginning in 1980, a semi-quantitative food frequency questionnaire was administered every four years to Nurses’ Health Study participants. In 1995–2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at two-year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariable-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes. Results Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (e.g., for a global score averaging all six cognitive tests, for blueberries: p-trend=0.014 and mean difference=0.04 [95% CI=0.01, 0.07] comparing extreme categories of intake; for strawberries: p-trend= 0.022 and mean difference=0.03 [95% CI=0.00, 0.06] comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we find for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends= 0.015 and 0.053, respectively, for the global score). Interpretation Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.

Neuroprotective effect of the natural iron chelator, phytic acid in a cell culture model of Parkinson's disease.

Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease (PD) patients. Because excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons in PD, we determined the protective effect of a naturally occurring iron chelator, phytic acid (IP6), on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in immortalized rat mesencephalic/dopaminergic cells. Cell death was induced with MPP(+) in normal and iron-excess conditions and cytotoxicity was measured by thiazolyl blue tetrazolium bromide (MTT assay) and trypan blue staining. Apoptotic cell death was also measured with caspase-3 activity, DNA fragmentation, and Hoechst nuclear staining. Compared to MPP(+) treatment, IP6 (30 micromol/L) increased cell viability by 19% (P<0.05) and decreased cell death by 22% (P<0.05). A threefold increase in caspase-3 activity (P<0.001) and a twofold increase in DNA fragmentation (P<0.05) with MPP(+) treatment was decreased by 55% (P<0.01) and 52% (P<0.05), respectively with IP6. Cell survival was increased by 18% (P<0.05) and 42% (P<0.001) with 30 and 100 micromol/L of IP6, respectively in iron-excess conditions. A 40% and 52% (P<0.001) protection was observed in caspase-3 activity with 30 and 100 micromol/L IP6, respectively in iron-excess condition. Similarly, a 45% reduction (P<0.001) in DNA fragmentation was found with 100 micromol/L IP6. In addition, Hoechst nuclear staining results confirmed the protective effect of IP6 against apoptosis. Similar protection was also observed with the differentiated cells. Collectively, our results demonstrate a significant neuroprotective effect of phytate in a cell culture model of PD.

Death by design: where curcumin sensitizes drug-resistant tumours.

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours.

Do all sedentary activities lead to weight gain: sleep does not.

PURPOSE OF REVIEW: To discuss the benefits of having a good night's sleep for body weight stability. RECENT FINDINGS: Experimental studies have shown that short-term partial sleep restriction decreases glucose tolerance, increases sympathetic tone, elevates cortisol concentrations, decreases the satiety hormone leptin, increases the appetite-stimulating hormone ghrelin, and increases hunger and appetite. Short sleep duration might increase the risk of becoming obese, because it does not allow the recovery of a hormonal profile facilitating appetite control. Lack of sleep could also lead to weight gain and obesity by increasing the time available for eating and by making the maintenance of a healthy lifestyle more difficult. Furthermore, the increased fatigue and tiredness associated with sleeping too little could lessen one's resolve to follow exercise regimens. SUMMARY: Short sleep duration appears to be a novel and independent risk factor for obesity. With the growing prevalence of chronic sleep restriction, any causal association between reduced sleep and obesity would have substantial importance from a public health standpoint. Future research is needed to determine whether sleep extension in sleep-deprived obese individuals will influence appetite control and/or reduce the amount of body fat.

Much meat, much malady: changing perceptions of the epidemiology of hepatitis E.

Hepatitis E, which is caused by hepatitis E virus (HEV), may now be considered a zoonosis as well as an anthroponosis. Pigs, boars and deer have been identified as reservoirs, and their flesh and entrails--as meat and offal--as vehicles of HEV transmission. Shellfish also act as vehicles. Dietary, gastronomic and culinary preferences influence how extensively HEV conveyed by these vehicles can be inactivated before their ingestion by the host. Another route of infection is paved by HEV that is enterically shed by humans and by live animals into the environment. Although anthroponotic transmission of HEV is primarily environmental, zoonotic transmission may proceed along both foodborne and environmental routes.

Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal.

Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. Evidence indicates that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. A new mechanism by which physiological and pharmacological blood levels of melatonin inhibit cancer growth in vivois via a melatonin-induced suppression of tumor linoleic acid (LA) uptake and its metabolism to the important mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin suppresses cAMP formation and inhibits tumor uptake of LA and its metabolism to 13-HODE via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. It has been postulated that in industrialized societies, light at night, by suppressing melatonin production, poses a new risk for the development of breast cancer and, perhaps, other cancers as well. In support of this hypothesis, light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of rat hepatoma and human breast cancer xenografts. Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth via the mechanisms described above. The nocturnal melatonin signal organizes tumor metabolism and growth within circadian time structure that can be further reinforced by appropriately timed melatonin supplementation. Dietary melatonin supplementation working in concert with the endogenous melatonin signal has the potential to be a new preventive/therapeutic strategy to optimize the host/cancer balance in favor of host survival and quality of life.

Dieldrin-induced neurotoxicity: relevance to Parkinson's disease pathogenesis.

Parkinson's disease (PD) is increasingly recognized as a neurodegenerative disorder strongly associated with environmental chemical exposures. Recent epidemiological data demonstrate that environmental risk factors may play a dominant role as compared to genetic factors in the etiopathogenesis of idiopathic Parkinson's disease. Identification of key genetic defects such as alpha-synuclein and parkin mutations in PD also underscores the important role of genetic factors in the disease. Thus, understanding the interplay between genes and environment in PD may be critical to unlocking the mysteries of this 200-year-old neurodegenerative disease. Pesticides and metals are the most common classes of environmental chemicals that promote dopaminergic degeneration. The organochlorine pesticide dieldrin has been found in human PD postmortem brain tissues, suggesting that this pesticide has potential to promote nigral cell death. Though dieldrin has been banned, humans continue to be exposed to the pesticide through contaminated dairy products and meats due to the persistent accumulation of the pesticide in the environment. This review summarizes various neurotoxic studies conducted in both cell culture and animals models following dieldrin exposure and discusses their relevance to key pathological mechanisms associated with nigral dopaminergic degeneration including oxidative stress, mitochondrial dysfunction, protein aggregation, and apoptosis.

mTORC1 activity as a determinant of cancer risk--rationalizing the cancer-preventive effects of adiponectin, metformin, rapamycin, and low-protein ...

Increased plasma levels of adiponectin, metformin therapy of diabetes, rapamycin administration in transplant patients, and lifelong consumption of low-protein plant-based diets have all been linked to decreased risk for various cancers. These benefits may be mediated, at least in part, by down-regulated activity of the mTORC1 complex, a key regulator of protein translation. By boosting the effective availability of the translation initiator eIF4E, mTORC1 activity promotes the translation of a number of "weak" mRNAs that code for proteins, often up-regulated in cancer, that promote cellular proliferation, invasiveness, and angiogenesis, and that abet cancer promotion and chemoresistance by opposing apoptosis. Measures which inhibit eIF4E activity, either directly or indirectly, may have utility not only for cancer prevention, but also for the treatment of many cancers in which eIF4E drives malignancy. Since eIF4E is overexpressed in many cancers, strategies which target eIF4E directly--some of which are now being assessed clinically--may have the broadest efficacy in this regard. Many of the "weak" mRNAs coding for proteins that promote malignant behavior or chemoresistance are regulated transcriptionally by NF-kappaB and/or Stat3, which are active in a high proportion of cancers; thus, regimens concurrently targeting eIF4E, NF-kappaB, and Stat3 may suppress these proteins at both the transcriptional and translational levels, potentially achieving a very marked reduction in their expression. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cooking frequency may enhance survival in Taiwanese elderly.

OBJECTIVE: To investigate the association between cooking behaviour and long-term survival among elderly Taiwanese. DESIGN: Cohort study. The duration of follow-up was the interval between the date of interview and the date of death or 31 December 2008, when censored for survivors. Information used included demographics, socio-economic status, health behaviours, cooking frequencies, physical function, cognitive function, nutrition knowledge awareness, eating out habits and food and nutrient intakes. These data were linked to death records. Cox proportional-hazards models were used to evaluate cooking frequency on death from 1999 to 2008 with related covariate adjustments. SETTING: Elderly Nutrition and Health Survey in Taiwan, 1999-2000. SUBJECTS: Nationally representative free-living elderly people aged ≥65 years (n 1888). RESULTS: During a 10-year follow-up, 695 participants died. Those who cooked most frequently were younger, women, unmarried, less educated, non-drinkers of alcohol, non-smokers, without chewing difficulty, had spouse as dinner companion, normal cognition, who walked or shopped more than twice weekly, who ate less meat and more vegetables. Highly frequent cooking (>5 times/week, compared with never) predicted survival (hazard ratio (HR) = 0·47; 95 % CI, 0·36, 0·61); with adjustment for physical function, cognitive function, nutrition knowledge awareness and other covariates, HR was 0·59 (95 % CI, 0·41, 0·86). Women benefited more from cooking more frequently than did men, with decreased HR, 51 % v. 24 %, when most was compared with least. A 2-year delay in the assessment of survivorship led to similar findings. CONCLUSIONS: Cooking behaviour favourably predicts survivorship. Highly frequent cooking may favour women more than men.

Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence

Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries. The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20 and 50% compared with non-eaters. In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk. Those that have been tested experimentally are (i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids; (ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons; (iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously; (iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water. Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.