Article

Caloric restriction, caloric restriction mimetics, and healthy aging in Okinawa: controversies and clinical implications

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Since then, life expectancy of Okinawans declined due to factors that include the increasing Westernization of the lifestyle [3][4][5]. Prevalence data of centenarians in the Okinawa archipelago with its 1.3 million inhabitants are variable, but estimates from the Okinawa International University in Ginowan, Okinawa, suggest approximately 50 centenarians per 100,000 persons [6], amounting to about 650 centenarians in Okinawa. This is about 4-5 times the average for most Western countries [6]. ...
... Prevalence data of centenarians in the Okinawa archipelago with its 1.3 million inhabitants are variable, but estimates from the Okinawa International University in Ginowan, Okinawa, suggest approximately 50 centenarians per 100,000 persons [6], amounting to about 650 centenarians in Okinawa. This is about 4-5 times the average for most Western countries [6]. The longevity of Okinawans has been linked to various conditions, including the local cuisine-the "Okinawa diet" [5]. ...
... If not accompanied by nutritional deficiencies, the caloric restriction implicated in Okinawan longevity is reproducible in animal models for delaying morbidity and extending average and maximum lifespan. However, the effects in humans require specific attention [64], since the antiaging effect appears robust until the restriction reaches about half the typical calorie intake of the studied animal models [6,66]. In one human epidemiology study of Japanese-American men on calorie intake, there was a trend toward lower mortality of participants who consumed 15% less calories than the group mean, whereas an increased mortality was observed in individuals, whose caloric intake was below 50% of the group mean [66]. ...
Article
Full-text available
The longevity of the population in the Okinawa Islands of Japan has been ascribed to genetic factors and the traditional Okinawa cuisine, which is low in calories and high in plant content. This diet includes shell ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) of the ginger family (Zingiberaceae). Due to its local popularity, Alpinia zerumbet has become the subject of a good deal of study at the University of the Ryukyus in Okinawa. Personal local experience and review of the literature now suggest that culinary shell ginger may contribute to longevity among the population in Okinawa. This is supported by its abundant phytochemical content, with antioxidant and anti-obesity properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain (DDK; 80–410 mg g−1 fresh weight), 5,6-dehydrokawain (DK; ≤100 mg g−1), and essential oils, phenols, phenolic acids, and fatty acids (≤150 mg g−1 each). Further, Alpinia zerumbet extends the lifespan in animals by 22.6%. In conclusion, culinary shell ginger may significantly contribute to human longevity in Okinawa.
... Research suggests that dietary patterns associated with a reduced risk of chronic age-associated disease are vegetable and fruit heavy (therefore phytonutrient rich) but reduced in meat, refined grains, saturated fat, sugar and salt [122]. Many characteristics of the traditional Okinawan diet are shared with other healthy dietary patterns, including traditional Asian diets (especially Japanese), native Hawaiian (taro and sweet potatoes), Mediterranean (both vegetable heavy), and the researcher designed dietary approaches to stop hypertension (DASH) and portfolio (cholesterol lowering) diets [119]. Overall, the important shared features of these healthy dietary patterns include: high intake of unrefined carbohydrates, moderate protein intake with emphasis on vegetables and legumes, fish, and lean meats as sources, and a healthy fat profile (higher in mono/polyunsaturated fats, lower in saturated fat; rich in omega-3). ...
... The Okinawans have long been of interest to CR researchers because they may represent the best human example of a naturally calorically restricted population (with optimal nutrition) and the study of their lifespan, healthspan, mortality and morbidity patterns could provide important information on the long-term effects of CR in humans [120]. Some researchers have argued that the Okinawans achieved a long life expectancy for genetic (or other) reasons, but the rapid disappearance of the CR phenotype, as well as the longevity disadvantage in younger Okinawans who did not experience CR suggests otherwise [119]. Populationwide CR was over by the 1960s, and generations thereafter have had a higher BMI across all age strata, as well as more metabolic syndrome and worse cardiovascular risk factors than other Japanese. ...
... CR-mimetics are compounds that provide the physiological benefit of CR without the need for restriction of calories. The traditional Okinawan diet appears to be a rich source of CR-mimetics [119]. In the Okinawan language, the term nuchi gusui, literally means 'food is medicine' and reflects the cultural context wherein commonly consumed dietary items, including foods, herbs and spices are also used as folk medicines. ...
Article
Full-text available
The field of nutrition has evolved rapidly over the past century. Nutrition scientists and policy makers in the developed world have shifted the focus of their efforts from dealing with diseases of overt nutrient deficiency to a new paradigm aimed at coping with conditions of excess-calories, sedentary lifestyles and stress. Advances in nutrition science, technology and manufacturing have largely eradicated nutrient deficiency diseases, while simultaneously facing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a necessary evolution, starting with a reductionist approach, driven by an ambition to understand the mechanisms responsible for the effects of individual nutrients at the cellular and molecular levels. This approach has appropriately expanded in recent years to become more holistic with the aim of understanding the role of nutrition in the broader context of dietary patterns. Ultimately, this approach will culminate in a full understanding of the dietary landscape-a web of interactions between nutritional, dietary, social, behavioral and environmental factors-and how it impacts health maintenance and promotion.
... The possibility of an effect in humans is supported by improvements in various biomarkers of healthy aging, cardiovascular and metabolic health in particular (Das, Balasubramanian, & Weerasekara, 2017;Fontana, Meyer, Klein, & Holloszy, 2004;Most, Tosti, Redman, & Fontana, 2017;Ravussin et al., 2015;Walford, Mock, Verdery, & MacCallum, 2002). The traditional Okinawan diet, which results in a 10%-15% CR vs the average diet of other Japanese, may contribute to these people having the world's longest lifespan and a remarkable healthspan (Bernstein et al., 2004;Willcox & Willcox, 2014;Willcox et al., 2007). There is no question that most people in Western society consume an excess of calories and that this poses a significant hazard to healthspan and lifespan. ...
... Energy restricted diets improve biomarkers and other phenotypes of healthy aging in humans (Civitarese et al., 2007;Fontana et al., 2004;Ravussin et al., 2015;Walford et al., 2002;Willcox & Willcox, 2014;Willcox et al., 2007;Witte, Fobker, Gellner, Knecht, & Fl€ oel, 2009). In the general population, however, adherence to diet-management plans is generally poor. ...
Chapter
Aging is a complex, multifactorial process with significant plasticity. While several biological pathways appear to influence aging, few genes have been identified that are both evolutionarily conserved and have a strong impact on aging and age-related phenotypes. The FoxO3 gene (FOXO3), and its homologs in model organisms, appears especially important, forming a key gene in the insulin/insulin-like growth factor-signaling pathway, and influencing life span across diverse species. We highlight some of the key findings that are associated with FoxO3 protein, its gene and homologs in relation to lifespan in different species, and the insights these findings might provide about the molecular, cellular, and physiological processes that modulate aging and longevity in humans.
... Cooking oil is rarely used in order to enjoy the original taste of the ingredients, which makes them low EI meals (12) . Nevertheless, satisfaction is high with traditional Japanese food, especially traditional Okinawan low EI cuisine (before being Americanised), which is unique and very important for a healthy lifestyle (13) . Thus, Okinawan cuisine may potentially contribute to weight loss in individuals classified as overweight or obese, and for individuals who want to improve their body composition while remaining cautious of salt intake. ...
... At dinner, we supplied the EI meal using Okinawa foodstuff. The Okinawa diet, which is a plant-rich diet with lean protein sources, healthy fats, more nutrient-dense but energy poor vegetables, fruits, and legumes, can help increase the intake of healthenhancing phytonutrients (13) . Our study used Okinawa foodstuff, which is low-carbohydrate and high protein, and may not reflect typical Japanese cuisine (10) . ...
Article
Excess weight loss while minimising fat-free mass (FFM) loss is important for health. Travel is a particular period at risk for weight gain and for which the effects of a short-term intensive weight loss programme have not been studied. Therefore, we studied the effect of a novel, 1-week supervised health travel programme combining high volume, low-to-moderate intensity exercise and energy intake restriction on weight, body composition and health outcomes in adults. Weight was also monitored for 12 weeks after the programme. In all, thirty-six subjects (nineteen men, seventeen women) consisting of sixteen excess-weight (BMI: 27·1 ( sd 1·7) kg/m ² ) and twenty healthy-weight (BMI: 22·3 ( sd 1·8) kg/m ² ) individuals participated. Subjects performed 1 h of slow-paced intermittent jogging three times per d and other leisure activities, whereas consuming only provided foods without water restriction. Body mass significantly decreased from pre- to post-intervention in excess-weight and healthy-weight individuals (−3·5 ( sd 1·5) and −3·5 ( sd 1·3) %, respectively; P <0·001 for both), and losses were maintained at 12 weeks post-intervention in both groups (−6·3 ( sd 3·8) and −1·7 ( sd 4·0) %, respectively; P <0·01 for both). Fat mass also significantly decreased in both groups (excess weight: −9·2 ( sd 4·6) %: healthy weight: −13·4 ( sd 9·0) %; P <0·01 for both), whereas FFM was maintained. Similar improvements were observed for blood biochemistry and pressure in both groups. This short-term weight loss intervention yielded favourable outcomes in both excess- and healthy-weight adults, particularly a 3·5 % weight loss with no significant change to FFM. In addition, participants maintained weight loss for at least 12 weeks. Of multiple programme choices, the Health Tourism weight loss programme’s results indicate that it is a viable option.
... It is not unlikely that the downregulation of metabolism-associated genes illustrates the lifestyle of the LLI when compared to younger controls, attributed to moderate food intake and reduced physical activity (Von Wurmb-Schwark et al., 2010). In this context, it is important to mention the hypothesis of longevity being linked to caloric restriction, which is supported by several prominent observations: For example in Okinawans, caloric restriction and traditional functional food were suggested to play a role in extended lifespan (Willcox & Willcox, 2014). Similarly, caloric restriction has been proposed to have beneficial effects for age-related outcomes in the CALERIE cohort (Ravussin et al., 2015). ...
Article
Full-text available
Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study (eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age.
... It is also featured by the use of healthy fat and high consumption of vegetables, soy and legumes. Therefore the anti-inflammatory and radical-scavenging properties as well as the anti-aging property as a result of the mild calorie restriction of the Okinawan diet are thought to be protective against age-related diseases and mortality (43,44). ...
Article
Introduction Studies examining dietary patterns and inflammageing in relation to mortality are limited. Objective We examined the influence of various dietary patterns on all-cause and cardiovascular disease (CVD) mortality, taking into account demographics, lifestyle factors, and serum inflammatory markers. Methods We conducted multivariate Cox regression analyses using data from a cohort of communitydwelling older Chinese adults (1,406 men, 1,396 women) in Hong Kong. Baseline interviewer administered questionnaires covered dietary intake estimation and dietary pattern generation from the food frequency questionnaire, demographic and lifestyle factors, cognitive function and depressive symptoms. Serum high-sensitivity C-reactive protein (hsCRP) and 25-hydroxyvitamin D (25OHD) were measured. All-cause and CVD mortality data at 14-year follow up were retrieved from an official database. Results In men, higher hsCRP level was associated with lower Diet Quality Index-International (DQI-I) score, Mediterranean-DASH Intervention for Neurodegenerative Delay Diet (MIND) score, Okinawan diet score, “vegetables-fruits” pattern score and “snacks-drinks-milk” pattern score. Higher serum 25OHD level was associated with higher Mediterranean Diet Score (MDS) but lower “snacks-drinks-milk” pattern score. None of the dietary pattern scores was associated with all-cause or CVD mortality after adjusting for all covariates. In women, hsCRP level and serum 25OHD level were not associated with any dietary patterns. Higher DQI-I score (HR=0.77 (95% CIs: 0.59, 0.99) highest vs. lowest tertile, p-trend=0.038) and Okinawan diet score (HR=0.78 (95% CIs: 0.61, 1.00) highest vs lowest tertile, p-trend=0.046) was associated with a lower risk of all-cause mortality, whereas higher MIND score (HR=0.63 (95% CI: 0.36, 1.09) highest vs. lowest tertile, p-trend=0.045) was associated with a reduced risk of CVD morality in the multivariate adjusted model. Conclusion Higher DQI-I score and Okinawan diet score were associated with a lower risk of all-cause mortality, and higher adherence to the MIND diet was related to a reduced risk of CVD mortality in community-dwelling Chinese older women.
... The hypothesis that impairment of autophagy affects the aging process is supported by life time extension on induction of autophagy, e.g., by caloric restriction [61,10,55] or by application of rapamycin [2,19] in different models from yeast to monkeys. In correlation with these data, overexpression of the autophagy-related protein ATG8 increased the life span of Drosophila melanogaster [52] and overexpression of ATG5, ATG8F, or ATG12 expanded the replicative life span of human umbilical vein endothelial cells (HUVEC) [37]. ...
Article
Full-text available
Senescent cells, which are cells in a post-proliferative state, show an increased number of dysfunctional mitochondria and oxidatively damaged and aggregated proteins. The mitochondrial-lysosomal axis theory of aging proposes that the autophago-lysosomal system is unable to cope with the rising amount of damaged organelles and proteins. We used human umbilical vein endothelial cells (HUVEC) as in vitro model system to determine which part/s of the autophago-lysosomal pathway become deficient by aging. Senescent HUVEC contained a much larger population of autophagosomes and lysosomes compared to young cells. Transcriptome analysis comparing young and old cells demonstrated several age-related changes of autophagy gene expression. One reason for the observed increase of autophagosomes was an impairment of the autophagic flux in senescent cells due to reduced V-ATPase activity required for acidification of the lysosomes and thus functionality of lysosomal hydrolases. The hypothesis that reduced mitochondrial ATP production underlies low V-ATPase activity was supported by addition of exogenous ATP. This procedure rescued the lysosomal acidification and restored the autophagic flux. Thus, we propose impaired lysosomal acidification due to ATP shortage which may result from mitochondrial dysfunction as a mechanism underlying the accumulation of dysfunctional cellular constituents during aging.
... Caloric restriction (CR) has also been shown to prevent several chronic degenerative and inflammatory diseases [5] and to prolong life in more primitive species including Escherichia coli and yeast [6]. In humans, the evidence on the positive effects of CR on longevity is indirect; for example the increased life expectancy in the Okinawan population, from the Kyushu Island in Japan, has been attributed at least in part to low calorie intake [7]. Mechanistically, the effect of CR on longevity has been attributed to fasting-induced modulation of neuroendocrine systems, hormetic stress responses, increased systemic production of neurotrophic factors, reduced mitochondrial oxidative stress, decreased pro-inflammatory cytokine production and insulin resistance, as well as decreased aging-associated signals and autophagy promotion [5,8,9]. ...
Article
Full-text available
Intermittent fasting (IF) has been gaining popularity as a means of losing weight. The Ramadan fast (RF) is a form of IF practiced by millions of adult Muslims globally for a whole lunar month every year. It entails a major shift from normal eating patterns to exclusive nocturnal eating. RF is a state of intermittent liver glycogen depletion and repletion. The earlier (morning) part of the fasting day is marked by dominance of carbohydrate as the main fuel, but lipid becomes more important towards the afternoon and as the time for breaking the fast at sunset (iftar) gets closer. The practice of observing Ramadan fasting is accompanied by changes in sleeping and activity patterns, as well as circadian rhythms of hormones including cortisol, insulin, leptin, ghrelin, growth hormone, prolactin, sex hormones, and adiponectin. Few studies have investigated energy expenditure in the context of RF including resting metabolic rate (RMR) and total energy expenditure (TEE) and found no significant changes with RF. Changes in activity and sleeping patterns however do occur and are different from non-Ramadan days. Weight changes in the context of Ramadan fast are variable and typically modest with wise inter-individual variation. As well as its direct relevance to many religious observers, understanding intermittent fasting may have implications on weight loss strategies with even broader potential implications. This review examines current knowledge on different aspects of energy balance in RF, as a common model to learn from and also map out strategies for healthier outcomes in such settings.
... One pound of body fat contains ~3500 stored calories, so to lose a pound a person must cut out ~3500 calories or walk about 36 miles. Caloric restriction prolongs life in animal models, perhaps by reducing oxidative stress; it is thought that the reasons that Okinawa has the highest proportion of centenarians are that the diet resembles the Mediterranean diet [15], and caloric restriction is the norm in that district [16]. ...
Article
Full-text available
Nutrition is far more important in stroke risk than most physcians suppose. Healthy lifestyle choices reduce the risk of stroke by ~80%, and of the factors that increase the risk of stroke, the worst is diet: only ~0.1% of Americans consume a healthy diet, and only 8.3% consume a somewhat healthy diet. The situation is probably not much better in most other countries. A Cretan Mediterranean diet, high in olive oil, whole grains, fruits, vegetables and legumes, and low in cholesterol and saturated fat, can reduce stroke by 40% or more in high-risk patients. The role of the intestinal microbiome in cardiovascular risk is emerging; high levels of toxic metabolites produced by intestinal bacteria from meat (particularly red meat) and egg yolk are renally excreted. Patients with renal impairment, including the elderly, should limit red meat and avoid egg yolk, as should other patients at high risk of stroke. Salt intake should be limited to 2–3 grams per day. Metabolic B12 deficiency is common and usually missed. It has serious neurological consequences, including an increase in the risk of stroke. It now clear that B vitamins to lower homocysteine reduce the risk of stroke, but we should probably be using methylcobalamin instead of cyanocobalamin.
... In obese humans, CR promotes significant weight loss and improves general health (Ard et al., 2017). Of note, the well-documented good health and high incidence of centenarians in the population of the Japanese Okinawa island have been attributed to nutritional cues including a mild and consistent CR ($10%-15%) (Willcox and Willcox, 2014). ...
Article
The increase in life expectancy has boosted the incidence of age-related pathologies beyond social and economic sustainability. Consequently, there is an urgent need for interventions that revert or at least prevent the pathogenic age-associated deterioration. The permanent or periodic reduction of calorie intake without malnutrition (caloric restriction and fasting) is the only strategy that reliably extends healthspan in mammals including non-human primates. However, the strict and life-long compliance with these regimens is difficult, which has promoted the emergence of caloric restriction mimetics (CRMs). We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans. We anticipate that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases.
... Several mechanisms have been proposed to explain this evidence, and the reduction of mitogen stimuli caused at least partly by decreased hormonal levels, such as insulin, insulin-growth factor 1 (IGF-1), and testosterone appears to play a pivotal role [7][8]. This decrease in hormonal production affects also negatively the activity of mitogen pathways, such as mammalian target of rapamycin (mTOR) signalling pathway activated by insulin and FOXO a key checkpoint gene in the insulin-IGF-1 signaling pathway upregulated by CR [9]. Furthermore, caloric restriction (CR) seems to mimic physical exercise activating biological pathways which are stimulated by physical exercise, such as AMP-activated protein kinase (AMPK) signalling pathways, and to increase sirtuin levels [10]. ...
... Increased consumption of energy dense foods and decreased physical activity are the most important culprits implicated in the dramatic increase in obesity prevalence globally. The impact of this obesogenic environment on obesity and its related comorbidities is further intensified by our understanding of the increased longevity and decreased occurrence of chronic diseases in the Okinawan population, related to their favorable nutritional profile and other lifestyle habits, compared to those of the rest of the world [15]. Despite this formidable contribution from energy dense diets, other factors are also believed to contribute to obesity. ...
Article
Full-text available
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with prevalence increasing in parallel with the rising incidence in obesity. Believed to be a “multiple-hit” disease, several factors contribute to NAFLD initiation and progression. Of these, the gut microbiome is gaining interest as a significant factor in NAFLD prevalence. In this paper, we provide an in-depth review of the progression of NAFLD, discussing the mechanistic modes of hepatocyte injury and the potential role for manipulation of the gut microbiome as a therapeutic strategy in the prevention and treatment of NAFLD.
... No biological processes were independent of a nongenetic contribution [141]. Prominent in attainment of longevity might be caloric restriction (CR) and traditional healthy dietary intake [144,145]. ...
Article
Here we summarize the latest data on genetic and epigenetic contributions to human aging and longevity. Whereas environmental and lifestyle factors are important at younger ages, the contribution of genetics appears more important in reaching extreme old age. Genome-wide studies have implicated ~57 gene loci in lifespan. Epigenomic changes during aging profoundly affect cellular function and stress resistance. Dysregulation of transcriptional and chromatin networks is likely a crucial component of aging. Large-scale bioinformatic analyses have revealed involvement of numerous interaction networks. As the young well-differentiated cell replicates into eventual senescence there is drift in the highly regulated chromatin marks towards an entropic middle-ground between repressed and active, such that genes that were previously inactive “leak”. There is a breakdown in chromatin connectivity such that topologically associated domains and their insulators weaken, and well-defined blocks of constitutive heterochromatin give way to generalized, senescence-associated heterochromatin, foci. Together, these phenomena contribute to aging.
... Both interventions similarly reduced the acetylation of multiple cellular proteins including histones (and hence transcriptional programs) and cytoplasmic enzymes (and hence metabolic functions), processes critical for cell homeostasis in aging and starvation ( Figure 1) (5,(9)(10), and effectively induced autophagy, a cytoprotective selfdigestive process and key to longevity (5,40,41). Although there is some reason to assume that caloric restriction favors healthy aging in humans (42), a concept also corroborated by the current analyses, no respective data have so far been available for spermidine. ...
Article
Background: Spermidine administration is linked to increased survival in several animal models. Objective: The aim of this study was to test the potential association between spermidine content in diet and mortality in humans. Design: This prospective community-based cohort study included 829 participants aged 45-84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated food-frequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred. Results: All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake-adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio-adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio-adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age. Conclusion: Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at http://www.clinicaltrials.gov as NCT03378843.
... While there is considerable research investigating the role of dietary stress factors on aging, e.g. caloric restriction or intermittent fasting (Colman et al., 2009;Golbidi et al., 2017;Martin et al., 2006;Shintani et al., 2018;Willcox and Willcox, 2014) a smaller body of literature has been developed for the impact of psychosocial/anxiety (Gaffey et al., 2016;Lai and Lee, 2019;Maestripieri and Hoffman, 2011;Prather et al., 2015;Riga et al., 2004;Schwartz et al., 1995;Stein et al., 2018) and psychoactive (Kirkpatrick and Kennedy, 2018;Lindqvist et al., 2015;Tian et al., 2017;Wadhwa et al., 2019) stressor effects on longevity. It is clear however from these studies that a reliable intersection between psychological and psychoactive stress and the rate of aging/ onset of age-related disease exists . ...
Article
In most species, females live longer than males. An understanding of this female longevity advantage will likely uncover novel anti-aging therapeutic targets. Here we investigated the transcriptomic responses in the hypothalamus - a key organ for somatic aging control - to the introduction of a simple aging-related molecular perturbation, i.e. GIT2 heterozygosity. Our previous work has demonstrated that GIT2 acts as a network controller of aging. A similar number of both total (1079-female, 1006-male) and gender-unique (577-female, 527-male) transcripts were significantly altered in response to GIT2 heterozygosity in early life-stage (2 month-old) mice. Despite a similar volume of transcriptomic disruption in females and males, a considerably stronger dataset coherency and functional annotation representation was observed for females. It was also evident that female mice possessed a greater resilience to pro-aging signaling pathways compared to males. Using a highly data-dependent natural language processing informatics pipeline, we identified novel functional data clusters that were connected by a coherent group of multifunctional transcripts. From these it was clear that females prioritized metabolic activity preservation compared to males to mitigate this pro-aging perturbation. These findings were corroborated by somatic metabolism analyses of living animals, demonstrating the efficacy of our new informatics pipeline.
... PFSP anthocyanins possess a wide range of pharmacological activities such as antioxidant [4], antiinflammatory and anticarcinogenic [5], chemopreventive [6] and antihyperglycemic [7]. Willcox and Willcox [8] demonstrated that sweet potatoes are important staples of the traditional Okinawa (the southernmost prefecture of Japan) diet and are associated with longevity and low incidence of chronic degenerative diseases. However, phenolics are not distributed equally through the plant. ...
Article
Total anthocyanin content (TAC) and total phenolics in "Nhat tím" purple-fleshed sweet potato (PFSP) variety were analyzed as affected by four cooking methods: steaming, baking, roasting, and frying. Moisture content (%), core flesh temperature (°C) and color characteristics of cooked PFSP were evaluated. TAC in steamed, fried (skin-on), roasted, baked, and fried (skin-off) PFSP were 234.18; 217.14; 208.11; 195.25; 173.68 mg/100g dry weight (DW), respectively. Under the same cooking time, steaming was good for the retention of total phenolics and anthocyanins as compared with baking. Cooking by steaming, roasting, baking, skin-on or skin-offfrying produced significant increase (P ≤ 0.05) of TAC and total phenolics as compared to the respective fresh samples. Steaming resulted in the greatest increase of TAC whereas skin-on frying showed a good cooking method to retain high total phenolics (826.47 mg GAE/100g DW) in shred PFSP.
... La restricción calórica (RC) consiste en la reducción, sin llegar a malnutrición, de la ingesta calórica. Esta reducción en humanos estaría alrededor de un 15% menos de calorías por día 44 . La RC reduce la liberación de hormona de crecimiento, de insulina y de factor de crecimiento insulínico tipo 1, produciendo reducción de lipogénesis y de presión sanguínea, así como aumento de la sensibilidad a la insulina 45 . ...
... [85][86][87] For example, the Okinawan region of Japan has one of the longest-lived populations in the world, with a high number of centenarians, and a low risk of age-related diseases. [88][89][90] Their traditional diet is low in calories, very low in fat (especially low in saturated fat), and nutrient-dense, consisting primarily of orange-yellow root vegetables (particularly sweet potatoes), leafy green vegetables, soy foods, and medicinal plants. As their dietary patterns shift away from the traditional plant-centered Okinawan diet and towards a Western one, their life expectancy is declining. ...
Article
Full-text available
Cardiovascular disease remains the world's leading cause of death. Yet, we have known for decades that the vast majority of atherosclerosis and its subsequent morbidity and mortality are influenced predominantly by diet. This paper will describe a health-promoting whole food, plant-based diet; delineate macro- and micro-nutrition, emphasizing specific geriatric concerns; and offer guidance to physicians and other healthcare practitioners to support patients in successfully utilizing nutrition to improve their health.
... La restricción calórica (RC) consiste en la reducción, sin llegar a malnutrición, de la ingesta calórica. Esta reducción en humanos estaría alrededor de un 15% menos de calorías por día 44 . La RC reduce la liberación de hormona de crecimiento, de insulina y de factor de crecimiento insulínico tipo 1, produciendo reducción de lipogénesis y de presión sanguínea, así como aumento de la sensibilidad a la insulina 45 . ...
Article
Full-text available
Alzheimer's disease is the most common cause of dementia in the elderly population. Currently, there are no effective treatments to prevent or delay the natural course of the disease. Numerous studies have provided information about the molecular processes underlying biological ageing and, perhaps more importantly, potential interventions to slow ageing and promote healthy longevity in laboratory model systems. The main issue addressed in this review is whether an intervention that has anti-ageing properties can alter the appearance and/or progression of Alzheimer's disease, a disease in which age is the biggest risk factor. Different anti-ageing interventions have been shown to prevent (and in some cases possibly restore) several parameters recognised as central symptoms to the development of Alzheimer's disease. In addition, they are taking the first steps towards translating these laboratory discoveries into clinical applications. Copyright © 2017 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.
... Caloric restriction is a strategy to decrease the energy supply by reducing the caloric intake from the diet without causing malnutrition (Ding et al., 2017;Li, Zhang, Liu, Chen, & Chen, 2017). This strategy has been used in several organisms from yeast to mammals, increasing lifespan, and maintaining health by delaying agingrelated diseases such as diabetes, cardiovascular diseases, cancer, and dementia (Ma, Wang, Dong, & Zhao, 2018;Willcox & Willcox, 2014). Some of the mechanisms proposed by which caloric restriction exerts its benefits on health are a possible hypermetabolic state and the attenuation of oxidative stress (Sohal & Weindruch, 1996). ...
Article
Full-text available
Resveratrol is a phytochemical that may promote health. However, it has also been reported to be a toxic compound. The molecular mechanism by which resveratrol acts remains unclear. The inhibition of the oxidative phosphorylation (OXPHOS) pathway appears to be the molecular mechanism of resveratrol. Taking this into account, we propose that the cytotoxic properties of resveratrol depend on the energy (e.g., carbohydrates, lipids, and proteins) availability in the cells. In this regard, in a condition with low energy accessibility, resveratrol could enhance ATP starvation to lethal levels. In contrast, when cells are supplemented with high quantities of energy and resveratrol, the inhibition of OXPHOS might produce a low‐energy environment, mimicking the beneficial effects of caloric restriction. This review suggests that investigating a possible complex relationship between caloric intake and the differential effects of resveratrol on OXPHOS may be justified. Practical applications A low‐calorie diet accompanied by significant levels of resveratrol might modify cellular bioenergetics, which could impact cellular viability and enhance the anti‐cancer properties of resveratrol.
... Okinawans are a genetically distinct group with several specific gene variants, some of which may be related to longevity. However, it is also known that Okinawan elders have reduced caloric intake compared to the rest of the Japanese population and have been found to have low mortality from agingrelated diseases [10]. Although the majority of the population is aware of the fact that reduction in caloric intake confers beneficial effects on health, adherence to continuous calorie restricted diets has been poor. ...
... Such prolonged life expectancy has been accompanied by concomitant improvement in overall health and physical functions in older population, reducing the mortality rate in Japanese female centenarians even further in the last decade (19,20). Moreover, studies have shown that the Japanese elderly population, as whole, is lean, with a low body mass index (BMI), which has been shown to be associated with longevity (21,22). Additionally, the susceptibility of overweight individuals, who often suffer from diabetes and hypertension, to severe COVID-19 disease has been established in multiple studies (23). ...
Preprint
Full-text available
Background Hokkaido is the northernmost, least populous, and coldest of the Japanese islands. It was the first prefecture to be affected by COVID-19, while Kanagawa is home to one of the most populous areas of Japan, namely the Tokyo metro area. The Japanese government responded early during the pandemic by identifying infected patients, contact tracing, and performing PCR analysis on anyone who was suspected of having been exposed to SARS-CoV-2. The government has also been publishing information about each individual who tested positive for the virus. Both Hokkaido and Kanagawa started recording COVID-19 cases in the winter of 2020 and have detailed records of thousands of patients, thus providing an invaluable resource for the transmission and behavior of the virus. Methods The current study analyzed the COVID-19 registry data from the Hokkaido and Kanagawa prefectures. The Hokkaido registry contained 1,269 cases (674 (53%) females and 595 (47%) males) recorded between February 14 and July 22, 2020. The Kanagawa registry had 3,123 cases (1,346 (43%) females and 1,777 (57%) males. The final data contained a total of 4,392 cases (2,020 (46%) females and 2,372 (54%) males). By leveraging the information on viral transmission paths available in the registry data, we performed exponential random graph model (ERGM) network analysis to examine demographic and symptomological homophilies of the SARS-CoV-2 viral transmission networks. Results We observed age, symptomatic, and asymptomatic homophilies in both prefectures. Furthermore, those patients who contracted the virus through secondary or tertiary contacts were more likely to be asymptomatic than those who contracted it from primary infection cases. The transmission networks showed that transmission occurred significantly in healthcare settings, as well as in families, although the size of the networks was small in the latter. Most of the transmissions stopped at the primary and secondary levels and no transmission beyond quaternary was observed. We also observed a higher level of asymptomatic transmission in Kanagawa than in Hokkaido. Conclusions Symptom homophilies are an important component of COVID-19 and suggest that nuanced genetic differences in the virus may affect its epithelial cell type range and can thus result in the diversity of symptoms seen in individuals infected by SARS-CoV-2. Moreover, environmental variables such as temperature and humidity may also be playing an important role in the overall pathogenesis of the virus.
... Moderate energy restriction which characterizes the intermittent fasting has been shown to extend the span life of laboratory animals [3,4]. Moreover, a favorable impact of calorie restriction diets on longevity was observed in older Okinawa inhabitants, who gained an additional 6% survival time as compared to other Japanese inhabitants [5]. Some other human studies on calorie restricted diets provide evidence for slower aging [6][7][8][9]. ...
Article
Full-text available
The aim of this study was to determine whether, after 8 days of water-only fasting, there are changes in the efficiency of the lower urinary tract, the concentration of sex hormones, and the symptoms of prostate diseases in a group of middle-aged men (n = 14). For this purpose, before and after 8 days of water-only fasting (subjects drank ad libitum moderately mineralized water), and the following somatic and blood concentration measurements were made: total prostate specific anti-gen (PSA-T), free prostate specific antigen (PSA-F), follicle stimulating hormone (FSH), luteotropic hormone (LH), prolactin (Pr), total testosterone (T-T), free testosterone (T-F), dehydroepiandros-terone (DHEA), sex hormone globulin binding (SHGB), total cholesterol (Ch-T), β-hydroxybutyrate (β-HB). In addition, prostate volume (PV), volume of each testis (TV), total volume of both testes (TTV), maximal urinary flow rate (Qmax), and International Prostate Symptom Score (IPSS) values were determined. The results showed that after 8 days of water-only fasting, Qmax and IPSS improved but PV and TTV decreased significantly. There was also a decrease in blood levels of PSA-T, FSH, P, T-T, T-F, and DHEA, but SHGB concentration increased significantly. These results indicate that 8 days of water-only fasting improved lower urinary tract functions without negative health effects.
... The traditional Okinawan diet, known for healthy aging properties, is rich in marine-based carotenoids such as ASX and fucoxanthin due to the high intake of seaweeds (macroalgae) that include wakame (Undaria pinnatifida), kombu (Laminaria japonica), and hijiki (Hijikia fusiformis), among others, as well as other seafood such as fish and crustaceans [40]. These foods are very low in caloric density but high in nutrient density, and several have been shown to act as caloric restriction (CR) mimetics [41]. ...
Article
Full-text available
In recent years, the scientific interest in natural compounds with geroprotective activities has grown exponentially. Among the various naturally derived molecules, astaxanthin (ASX) represents a highly promising candidate geroprotector. By virtue of the central polyene chain, ASX acts as a scavenger of free radicals in the internal membrane layer and simultaneously controls oxidation on the membrane surface. Moreover, several studies have highlighted ASX's ability to modulate numerous biological mechanisms at the cellular level, including the modulation of transcription factors and genes directly linked to longevity-related pathways. One of the main relevant evolutionarily-conserved transcription factors modulated by astaxanthin is the forkhead box O3 gene (FOXO3), which has been recognized as a critical controller of cell fate and function. Moreover, FOXO3 is one of only two genes shown to robustly affect human longevity. Due to its tropism in the brain, ASX has recently been studied as a putative neuroprotective molecule capable of delaying or preventing brain aging in different experimental models of brain damage or neurodegenerative diseases. Astaxanthin has been observed to slow down brain aging by increasing brain-derived neurotrophic factor (BDNF) levels in the brain, attenuating oxidative damage to lipids, protein, and DNA and protecting mitochondrial functions. Emerging data now suggest that ASX can modulate Nrf2, FOXO3, Sirt1, and Klotho proteins that are linked to longevity. Together, these mechanisms provide support for a role of ASX as a potential geroneuroprotector.
... Calorie restriction (CR), also known as continuous calorie restriction (CCR) involves a consistent reduction in calorie intake. It is typically defined by a decrease of between 10-40% in normal or recommended calorie intake (Chung et al., 2013;Willcox & Willcox, 2014). The beneficial effects of CR on obesity and related diseases have long been recognised across different species, contributing to a significant reduction in morbidity and mortality (Fontana et al., 2010b). ...
Conference Paper
Background: Overweight and obesity is currently a worldwide problem. Calorie restriction (CR) diets, including intermittent fasting (IF) and continuous calorie restriction (CCR), are popular methods of attempting to lose weight and improve health outcomes. Although research has provided inconsistent results, the eating disorder (ED) field are concerned that CR may lead to adverse psychological outcomes, such as disordered eating symptomology. Few studies have explored the psychological and behavioural effects of IF and whether it differs from the effects of CCR. Aims: To compare the effects of beginning the ‘5:2 diet’, a popular IF regime, with beginning a CCR diet on ED symptoms, binge-eating, food cravings and mood. Method: Males and females participating in either IF (500 calories for females, 650 calories for males 2 days/ week) or CCR (15-25% calorie restriction for 7 days/week) were followed for four weeks. ED symptoms, binge-eating, food cravings, and mood were assessed using online self-report measures prior to starting the diets and after four weeks of dieting (N=86). Participant adherence to the diets was measured through food diaries and weight lost. Results: Participants in both diet groups reported reductions in shape concern, weight concern, binge-eating disorder symptoms, food craving and mood symptoms over the four weeks of dieting. The IF group reported greater reductions in shape and weight concern than the CCR group, and lower levels of eating concern after four weeks of dieting compared to the CCR group. Both groups reported increased restraint scores over the four weeks of dieting, and this was significantly higher for the CCR group. Exploration of risk factors demonstrated those who scored highly on dichotomous thinking experienced less reduction of food cravings for the IF group, whereas those who scored low on self-esteem experienced a higher reduction of mood symptoms for the CCR group. Conclusions: Commencing an IF or CCR diet was associated with an increase in restraint and a reduction in numerous symptoms of eating disorders, food craving and adverse mood symptoms in healthy adults. Overall, commencing an IF diet was associated with greater reductions in symptoms of eating disorders.
... The nutrient-sensing pathways are arguably the most important in aging because of the broad influence of metabolism regulated by these pathways on cellular physiology and homeostasis. Caloric restriction, reducing caloric intake without causing malnutrition, is one of the best ways for extending lifespan in model organisms, including yeast, nematodes, fruit flies, and mice, and for protecting against multiple aging-associated diseases in mice and humans (Madeo, Carmona-Gutierrez, Hofer, & Kroemer, 2019;Willcox & Willcox, 2014). The major cellular pathways that respond to calorie restriction are indeed those involved in nutrientsensing, as discussed below (Fig. 3) (López-Otín et al., 2013;Madeo et al., 2019). ...
Article
Aging is a natural biological progress accompanied by the gradual decline in physiological functions, manifested by its close association with an increased incidence of human diseases and higher vulnerability to death. Those diseases include neurological disorders, cardiovascular diseases, diabetes, and cancer, many of which are currently without effective cures. Even though aging is inevitable, there are still interventions that can be developed to prevent/delay the onset and progression of those aging-associated diseases and extend healthspan and/or lifespan. Here, we reviewed decades of research that reveals the molecular pathways underlying aging and forms the biochemical basis for anti-aging drug development. Importantly, due to the vast chemical space of natural products and the rich history of herb medicines in treating human diseases documented in different cultures, natural products have played essential roles in aging research. Using several of the most promising natural products and their derivatives as examples, we discussed how natural products serve as an inspiration resource that helped the identification of key components/pathways underlying aging, their mechanisms of action inside the cell, and the functional scaffolds or targeting mechanisms that can be learned from natural products for drug engineering and optimization. We argue that natural products might eventually provide a solution to aging and aging-associated diseases.
... Such prolonged life expectancy has been accompanied by concomitant improvement in overall health and physical functions in the older population, reducing the mortality rate in Japanese female centenarians even further in the last decade [21,22]. Moreover, studies have shown that the Japanese elderly population, as a whole, is lean, with a low body mass index (BMI), which is associated with longevity [23,24]. Additionally, the susceptibility of overweight individuals, who often suffer from diabetes and hypertension to severe COVID-19 disease, has been established in multiple studies [25]. ...
Article
Full-text available
Kanagawa and Hokkaido were affected by COVID-19 in the early stage of the pandemic. Japan’s initial response included contact tracing and PCR analysis on anyone who was suspected of having been exposed to SARS-CoV-2. In this retrospective study, we analyzed publicly available COVID-19 registry data from Kanagawa and Hokkaido (n = 4392). Exponential random graph model (ERGM) network analysis was performed to examine demographic and symptomological homophilies. Age, symptomatic, and asymptomatic status homophilies were seen in both prefectures. Symptom homophilies suggest that nuanced genetic differences in the virus may affect its epithelial cell type range and can result in the diversity of symptoms seen in individuals infected by SARS-CoV-2. Environmental variables such as temperature and humidity may also play a role in the overall pathogenesis of the virus. A higher level of asymptomatic transmission was observed in Kanagawa. Moreover, patients who contracted the virus through secondary or tertiary contacts were shown to be asymptomatic more frequently than those who contracted it from primary cases. Additionally, most of the transmissions stopped at the primary and secondary levels. As expected, significant viral transmission was seen in healthcare settings.
... Similar observations were made for a long-term ADF cohort (Stekovic et al, 2019) Fasting length and baseline characteristics, such as BMI, age, and glucose levels, have an impact on blood pressure effects (long-term fasting, Grundler et al, 2020). Overall, the impact of dietary regimens on the cardiovascular system may lower long-term CVD risk, at least in healthy individuals, as shown for ADF (Stekovic et al, 2019) and CR (Lefevre et al, 2009) and mirrored by the low CVD rate in CR societies and the Okinawan people (Willcox & Willcox, 2014). ...
Article
Full-text available
Age-associated diseases are rising to pandemic proportions, exposing the need for efficient and low-cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life- and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social-behavioral limitations, CR may be challenging to implement into real life. Thus, CR-mimicking interventions have been developed, including intermittent fasting, time-restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages.
... Moreover, their diet was lower in proteins and rich in fresh vegetables, fruits, sweet potatoes, soy, and fish, which may have a CR mimicking effect. 61 Interestingly, observations on some Okinawan families who moved to Brazil revealed that the adaptation to a Western lifestyle impacted both their diet and physical activity, resulting in an increased body weight and a drop in life expectancy of 17 years. 62 Recently, a 2-year randomized trial known by the eponym of CALERIE, involving nonobese men and women between 21 and 50 years, was conducted to assess CR feasibility, safety, and improvements in terms of quality of life and risk of diseases. ...
Article
Full-text available
There is now sufficient evidence to indicate that aging is associated with the emergence of a clonogenic and neoplastic‐prone tissue landscape, which fuels early stages of cancer development and helps explaining the rise in cancer incidence and mortality in older individuals. Dietary interventions are among the most effective approaches to delay aging and age‐related diseases, including cancer. Reduced caloric intake has been, historically, the most intensely investigated strategy. Recent findings point to a critical role of a long fasting interval in mediating some of the beneficial effects of caloric restriction. Time‐restricted feeding, intermittent fasting, and fasting mimicking diets are being proposed for their potential to prolong healthy life span and to delay late‐onset diseases such as neoplasia. Evidence will be discussed suggesting that the effects of these dietary regimens are mediated, at least in part, through retardation of age‐related functional changes at cell and tissue level, including a delay in the emergence of the neoplastic‐prone tissue microenvironment.
Chapter
Ageing is a complex process in which multiple factors are involved that can contribute to determine whether a person will or not be affected by diseases that are more frequently observed in advanced age. The factors involved comprise genetic, environmental, behavioural, and dietary factors, which influence pathways that regulate the ageing process and the life expectancy, rendering longevity a multifaceted phenomenon. Even if a miraculous elixir or pill is not yet available, there is general agreement that nutrition has a major impact on the overall mortality and on the development of age-related chronic non-communicable diseases. Nutrition research has focused for decades on single nutrients in relation to health outcomes, although people eat food and combinations of foods rather than nutrients in isolation. Even if research on specific nutrients is scientifically valid and may provide key information on the mechanisms of effects, recent attention to the complex synergistic interactions among nutrients, other food constituents, and whole foods, has led to a growing interest in the total dietary patterns. This chapter describes some specific dietary patterns that have been associated with an increased life expectancy and with reductions of incident chronic diseases, thus consenting people to live a longer and healthier life. We describe the main characteristics and available evidence for Mediterranean, vegetarian, Japanese, and Okinawa dietary patterns, confirming the powerful role that nutrition plays in healthy ageing.
Chapter
Intermittent fasting (IF) is widely practiced for health benefits among people of various societies by adopting regimens which vary in terms of dietary patterns and duration of fast. Also, sustained periods of caloric restriction (CR) without malnutrition have been shown to be a potent modulator of lifespan resulting in lower incidence of metabolic disorders like type 2 diabetes, cardiovascular diseases, cancer, and neurological disorders. IF regimens such as alternate day fasting, time restricted feeding, protein restriction etc. have recently emerged as potential alternate approaches to CR which do not involve any major changes in quality and quantity of nutritional intake. This chapter reviews the different regimens of IF and CR used in model organisms and in humans to ascertain their efficacy for metabolic fitness, resistance to age-related diseases and longevity as well as their underlying molecular and cellular mechanisms. Moreover, promoting health-oriented and disease preventive approaches are more viable options for healthy aging and longevity than continuing with disease-oriented research and therapeutic strategies.
Chapter
Oxidative stress has been related to osteoporosis and other pathologies at the bone. Coenzyme Q10 (CoQ10), a lipid-soluble antioxidant present in cell membranes, has been suggested in vitro to reduce intracellular reactive oxygen species (ROS) production at the same time to prevent or reduce osteoclastogenesis. Also, it promotes osteoblast differentiation and proliferation and matrix mineralization. Thus it has been suggested that this effect on osteoclastogenesis could be a consequence of the reduction of intracellular ROS. The protective effect of CoQ10 against bone loss has been also demonstrated in rodents. Age-associated changes in systemic markers of oxidative damage in animals treated with CoQ10 suggest that this antioxidant can reduce not only intracellular ROS alleviating oxidative damage but also osteoclastogenesis and bone resorption triggered by different signals. Additionally, it has been suggested that oxidative stress is the main mechanism explaining bone alterations both in aged rodents and in those with acute sex steroid deficiency.
Article
Zusammenfassung Epidemiologische Studien, unter anderem aus Japan, legen nahe, dass eine Kalorienrestriktion nicht nur im Tierversuch, sondern auch bei Menschen lebensverlängernd wirkt. Unter den zahlreichen Fastenvarianten sind diejenigen mit längerfristigem Fasten am besten geeignet, den Körper in einen Ketosezustand mit hauptsächlicher Fettsäureverbrennung zu bringen. Aktuelle Forschungsansätze drehen sich um die medikamentöse Induktion eines fastenähnlichen Zustands und damit die Aktivierung von Sirtuinen als effektive „Anti-Aging-Enzyme“.
Article
Full-text available
Purpose of Review With the prolongation of life expectancy, the gap between lifespan and “health span,” the disease-free lifespan, has been widening due to the massive burden of age-related chronic diseases and research on healthy aging has been gaining momentum. A growing body of evidence suggests that diet is a strong determinant of healthy aging and consumption of sugar-sweetened beverages (SSB), a major source of added sugars, predicts poor health outcomes in the aging population, including cardiovascular disease, diabetes, and cancer. Evidence further supports a link between sugar-sweetened beverages-triggered pathological processes and biologic factors of aging, including inflammaging, oxidative stress, and alterations in intestinal microbiota. At present, substitution of sugar-sweetened beverages with healthier alternative beverage remains the most robust strategy to limit the deleterious effects of sugar-sweetened beverages on health worldwide and may help achieve healthy longevity. The purpose of this review is to provide an overview of mechanisms by which sugar-sweetened beverages consumption may impact the physiological aging process and how a simple intervention of beverage replacement may promote healthy aging. Recent Findings Recent findings indicate that SSB are associated with accelerated aging phenotype and activate various adverse biological processes such as chronic inflammation, oxidative stress, insulin resistance, and gut dysbiosis. Summary Replacing SSB with healthier beverages may be a reasonable option to reduce the burden of chronic disease in the aging population and even prolong life and healthspan.
Article
Full-text available
Ageing is a natural process characterized by the gradual decline of physiological functions. In the last decades, human lifespan has considerably increased. Consequently, population ageing and the resulting increase of people affected by age-related diseases, is emerging as a major social and economic challenge in developed countries. This scenario has led to an exponential growth of research projects in the field of ageing, with the aim of identifying amenable drug targets and pharmacological interventions to extend human healthy lifespan. Extensive evidence in literature suggests that the dysfunction of autophagy, a highly conserved pathway involved in maintaining cellular homeostasis, is part of the ageing process with roles in the pathobiology of age-related diseases. Moreover, accumulating experimental data from invertebrate and vertebrate animal models demonstrate that intervening to increase lifespan also induces autophagy, suggesting that stimulating such cellular process may represent an effective strategy to increase longevity. Here, we reviewed the literature on autophagy in ageing and age-related diseases, also discussing the perspective of behavioral and pharmacological interventions that may increase healthy lifespan through autophagy stimulation.
Chapter
The certainty of ageing and death has been a major concern of humans since the beginnings of time, with a consequent never‐ending search for methods to combat the consequences of the ageing process and delay the final moment as long as possible. This chapter explores the topic of antiageing therapies from different perspectives. It discusses the rationale behind the possible delay of death, disease, and disability. Then, some of the advances in biogerontological research in animal models and possible translations into humans are explored. The chapter examines the results of epidemiological studies on lifestyle modification proven to be effective in promoting healthy ageing. Disability and functional dependence associated with ageing may be reversible to some extent; however, when the functional reserve becomes extremely depleted, the restoration of normal function is no longer possible.
Article
Full-text available
The study discusses the intermittent fasting diet that is trending nowadays as one of the successful dieting methods that enhances metabolism and helps in weight loss and Islamic fasting that Allah imposed on Muslims more than 1400 years ago. The researcher compares both diets by reviewing several studies that tackled fasting, whether it is for weight loss or as a religious ritual. The studies discussed were from 2010 until 2021. Publications indexed in Scopus, PubMed, Web of Science, Google Scholar, and other renowned databases were covered. The review highlights and discusses the benefits as well as the side effects of both types of fasting. The conclusion of the review indicates that the miracle of the Quran to impose fasting on Muslims is not only to be emphatic with the poor but also because fasting is one of the healthiest food regimes that everyone should follow and adopt as a style of life.
Chapter
Only 20–25% of healthy life expectancy is predetermined by genes; lifestyle and environment play a major role. In the past decades, biogerontological research has significantly contributed to a better understanding of the ageing process that now provides the basis for the development of efficient intervention strategies suitable to increase healthy life expectancy. Based on the most recent biogerontological findings, the authors summarise which interventions at which stage of life are needed to preserve health and prevent or ameliorate disease. Classical lifestyle interventions as well as novel pharmacological substances with mixed proof of efficacy and evidence are discussed. The authors conclude that novel communication strategies, incentives, and regulations need to be developed to promote and force the adoption of a healthy lifestyle in the general population.
Article
Full-text available
Anticipating population ageing to reach a historically unprecedented level in this century and considering the public goal of promoting well-being until old age, research in many fields has started to focus on processes and factors that contribute to healthy ageing. Since human interactions have a tremendous impact on our mental and physical well-being, scientists are increasingly investigating the basic processes that enable successful social interactions such as social affect (empathy, compassion) and social cognition (Theory of Mind). However, regarding the replication crisis in psychological science it is crucial to probe the reproducibility of findings revealed by each specific method. To this end, we aimed to replicate the effect of age on empathy, compassion and Theory of Mind observed in Reiter and colleagues' study (Reiter et al. 2017 Sci. Rep.7, 11046 (doi:10.1038/s41598-017-10669-4)) by using the same ecologically valid paradigm in an independent sample with similar age ranges. We were able to replicate the previously observed results of a preservation or even enhancement in socio-affective processes, but a decline in socio-cognitive processes for older adults. Our findings add to the understanding of how social affect and cognition change across the adult lifespan and may suggest targets for intervention studies aiming to foster successful social interactions and well-being until advanced old age.
Thesis
L’alimentation est un acte naturel qui permet à chacun de se nourrir et d’apporter à l’organisme les composantes essentielles dont il a besoin. Toutes les habitudes alimentaires ne s’équivalent cependant pas, et lorsqu’elle n’est pas équilibrée, l’alimentation peut même se révéler nocive. Tandis que les maladies infectieuses sont en constante diminution dans les pays occidentaux, de nouvelles maladies, non transmissibles, sont-elles en augmentation, comme c’est le cas pour le surpoids ou l’obésité qui touchent respectivement 2 milliards et 650 millions de personnes dans le monde. Les régimes alimentaires dérivent d’habitudes culturelles qui sont parfois historiques, et il est alors intéressant d’étudier les régimes en vogue au paléolithique, à l’Antiquité, et de comment ils ont évolué au fur et à mesure des siècles pour arriver aujourd’hui à une alimentation qui fait place à l’industrialisation et à la mondialisation. Plusieurs modes alimentaires se sont ancrés dans les habitudes culturelles parmi lesquels le régime méditerranéen, véritable patrimoine immatériel de l’UNESCO, et le régime d’Okinawa au Japon, qui sont présents dans des régions possédant un taux élevé de centenaires, mais c’est également le cas d’autres moins sains tel que le régime typique américain. Parallèlement à ces régimes culturels qui définissent certaines populations, d’autres émergent, dérivant d’une extrapolation de recommandations médicales, comme c’est le cas du régime végétarien ou sans gluten. Chacun de ces régimes présente alors un impact significatif sur l’apparition des maladies chroniques non transmissibles que sont les maladies cardiovasculaires et métaboliques. Enfin, il est également possible de noter le lien très étroit entre alimentation et génétique, de nouvelles disciplines apparaissent. C’est le cas de la nutrigénétique qui définit la façon dont les variations génétiques affectent la réponse aux aliments, alors que le terme nutrigénomique est utilisé lorsque l’on parle de l’interaction entre les aliments et les gènes et comment ces derniers sont affectés.
Chapter
This chapter introduces the concept of diets and explains how diets affect health. Diets are composed of foods that range in healthfulness and nutrition. Many different factors influence a person’s diet. Healthy diets meet an individual’s nutritional needs and support overall health. Dietary patterns vary by region, but global diets are less than optimal. These suboptimal diets directly affect nutrition and health outcomes. Poor diets are now considered a top risk factor for death and disability.
Article
Full-text available
Circadian rhythms are 24-h cycles regulated by endogeneous molecular oscillators called the circadian clock. The effects of diet on circadian rhythmicity clearly involves a relationship between factors such as meal timings and nutrients, known as chrononutrition. Chrononutrition is influenced by an individual’s “chronotype”, whereby “evening chronotypes” or also termed “later chronotype” who are biologically driven to consume foods later in the day. Research in this area has suggested that time of day is indicative of having an influence on the postprandial glucose response to a meal, therefore having a major effect on type 2 diabetes. Cross-sectional and experimental studies have shown the benefits of consuming meals early in the day than in the evening on postprandial glycaemia. Modifying the macronutrient composition of night meals, by increasing protein and fat content, has shown to be a simple strategy to improve postprandial glycaemia. Low glycaemic index (GI) foods eaten in the morning improves glycaemic response to a greater effect than when consumed at night. Timing of fat and protein (including amino acids) co-ingested with carbohydrate foods, such as bread and rice, can reduce glycaemic response. The order of food presentation also has considerable potential in reducing postprandial blood glucose (consuming vegetables first, followed by meat and then lastly rice). These practical recommendations could be considered as strategies to improve glycaemic control, rather than focusing on the nutritional value of a meal alone, to optimize dietary patterns of diabetics. It is necessary to further elucidate this fascinating area of research to understand the circadian system and its implications on nutrition that may ultimately reduce the burden of type 2 diabetes.
Article
Objective: We examined the influence of various dietary patterns on cardiorespiratory fitness (CRF) expressed as peak oxygen uptake (VO2peak), taking into account demographics and lifestyle risk factors. Design: Prospective cohort study. Participants and methods: We conducted multivariate linear regression analyses using available data from a cohort of community-dwelling older Chinese adults (752 men, 483 women) in Hong Kong. Baseline interviewer-administered questionnaires covered dietary intake estimation and dietary pattern generation from the food frequency questionnaire, demographic and lifestyle factors, self-reported medical history, as well as frailty status. VO2peak at the 7-year follow-up was measured using symptom-limited maximal exercise testing on an electrically braked bicycle ergometer. Results: In men, baseline Diet Quality Index-International (DQI-I) score (β = 0.044, P = .013) and Okinawan diet score (β = 0.265, P = .014) was independently associated with age-adjusted VO2peak at the 7-year follow-up. The significant association was only retained for the Okinawan diet score in the multivariate adjusted model (β = 0.227, P = .039). Dietary pattern scores including the Dietary Approaches to Stop Hypertension (DASH) score, Mediterranean-DASH Intervention for Neurodegenerative Delay Diet score, Mediterranean Diet Score, and 3 other pattern scores derived by factor analysis were not associated with VO2peak. In women, none of the dietary pattern scores at baseline was associated with VO2peak in both the age-adjusted and multivariate-adjusted models. Conclusions/implications: A higher Okinawan diet score was associated with a higher 7-year CRF in community-dwelling Chinese older men. Further studies are warranted to examine the underlying mechanisms on how the Okinawan diet influences CRF.
Article
Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemo- and immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.
Article
Context: The Ryukyu Islands stretch across a southwestern area of the Japanese Archipelago. Because of their unique geographical and historical backgrounds, Ryukyuans have their own genetic and phenotypic characteristics, which have been disclosed in previous anthropological and biomedical studies. Objective: The history, peopling and biomedical and genetic characteristics of Ryukyuans are reviewed and future research directions are discussed. Conclusion: Morphological and genetic studies have suggested the complex demographic history of Ryukyuans and their relationships with other Asian populations. Knowledge of population formation processes is important to understand the distribution of pathogens. In viral infectious diseases, some strains that may be associated with disease symptoms are specific to Ryukyuans. Dramatic changes in diet have played an important role among Ryukyuans in terms of increases in lifestyle-related diseases and mortality risks. To achieve a better understanding of pathogenic disease factors, further integration of findings regarding the genetic and biomedical characteristics of the Ryukyuans is needed.
Article
Introduction. The construction of old age is a set of strategies to create and implement the image of the desired old age. The article considers biological, psychological and environmental factors from the point of view of their modeling, which lend themselves to the possibility of creating, managing and eliminating certain mechanisms, depending on their role in the structure of aging. Objective. The work is devoted to systematization of scientific data on aging and the mechanisms of maintaining the quality of life during the aging period. The article examines biological, psychological, social and environmental factors that affect the specifics of aging. Methods. Theoretical analysis of modern research in the field of the psychology of aging. Results and conclusions. It has been shown that genetic and physiological mechanisms are not unconditional predictors of aging, but can be modified. At the same time, psychological and social factors lend themselves only to conditional modeling. The most flexible at this stage are various environmental factors that make it possible to significantly correct aging trends. The analysis showed that the factors and mechanisms known at this stage can be conditionally divided into modeled, conditionally modeled and difficult to model. At the same time, among such factors, conditional and easily modeled ones prevail, which allows us to develop the idea of construction of aging at earlier stages. The data indicate that the mechanisms of subjectivity underlie the possibilities of constructing aging, and the basis for the formation of strategies is adequate and positive representations of one’s own aging.
Article
Calorie restriction (CR), the reduction of dietary intake below energy requirements while maintaining optimal nutrition, is the only known nutritional intervention with the potential to attenuate aging. Evidence from observational, preclinical, and clinical trials suggests the ability to increase life span by 1–5 years with an improvement in health span and quality of life lived. CR moderates intrinsic processes of aging through cellular and metabolic adaptations and reducing risk for the development of many cardiometabolic diseases. Yet, implementation of CR may require unique considerations for the elderly and other specific populations. The objectives of this review are to summarize the evidence for CR to modify primary and secondary aging; present caveats for implementation in special populations; describe newer, alternative approaches that have comparative effectiveness and fewer deleterious effects; and provide thoughts on the future of this important field of study. Please see http://www.annualreviews.org/page/journal/pubdates for expected final online publication date for the Annual Review of Nutrition, Volume 40. 2020
Article
Dietary intervention is a safe, broad-spectrum, and low-cost preventive strategy for slow aging. The Okinawan, Mediterranean, and Dietary approaches to stop hypertension (DASH) diets, as well as caloric restriction (CR) and intermittent fasting (IF), are classic and reliable dietary patterns that slow aging by regulating nutrient-sensing pathways, gut microbiota, metabolism, and immunity. Moreover, the proportion of the three macronutrients (carbohydrate, protein and fat) is also vital for slowing aging, but the debates about the appropriate proportion, especially the ratio of carbohydrates and proteins, remain unknown. Strict and lifelong adherence to these regimens is difficult, thereby promoting the emergence of various dietary supplements, including natural CR mimics, probiotics, natural senolytics, vitamins and essential minerals. Combinations of different dietary patterns and supplements with distinct pathways may have additive effects. Individuals’ aging speed and dietary response are highly variable, thus highlighting the need for precise anti-aging dietary intervention. Nutrigenomics plays an important role in personalized dietary strategies. Therefore, this review critically compares the anti-aging effects of various dietary patterns and supplements, analyzes their mechanisms and combined use, and proposes future research directions to achieve personalized dietary strategies for slowing aging.
Article
Full-text available
Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
Article
Full-text available
Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
Article
Full-text available
The World Health Organization (WHO) estimates that 2.3 billion people will be overweight and 700 million obese in 2015. The reasons for this disastrous trend are attributed to the global tendency toward the reduced magnitude of exercise and physical activity and the increased dietary intake of fats, sugars and calories with reduced amount of vitamins and minerals. To prevent life-style-related diseases, like Metabolic Syndrome (MS), researchers' attention is increasingly focusing on some of the so called "functional foods" which may be useful for their prevention and treatment. One of these functional ingredients is fucoxanthin (FX), a characteristic carotenoid present in edible brown seaweeds, such as Undaria pinnatifida (Wakame), Hijikia fusiformis (Hijiki), Laminaria japonica (Ma-Kombu) and Sargassum fulvellum. The increasing popularity of this molecule is certainly due to its anti-obesity effect, primarily detected by murine studies. These works revealed FX mediated induction of uncoupling protein-1 (UCP-1) in abdominal white adipose tissue (WAT) mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Beyond this important role, in recent studies FX has shown a great antioxidant activity, anti-cancer, anti-diabetic and anti-photoaging properties. The aim of this review is to highlight the main effects of FX on human health.
Article
Full-text available
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.
Article
Full-text available
FOXO3 is generally recognized as a "master" gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
Article
Full-text available
The therapeutic potential of natural bioactive compounds such as polysaccharides, especially glycosaminoglycans, is now well documented, and this activity combined with natural biodiversity will allow the development of a new generation of therapeutics. Advances in our understanding of the biosynthesis, structure and function of complex glycans from mammalian origin have shown the crucial role of this class of molecules to modulate disease processes and the importance of a deeper knowledge of structure-activity relationships. Marine environment offers a tremendous biodiversity and original polysaccharides have been discovered presenting a great chemical diversity that is largely species specific. The study of the biological properties of the polysaccharides from marine eukaryotes and marine prokaryotes revealed that the polysaccharides from the marine environment could provide a valid alternative to traditional polysaccharides such as glycosaminoglycans. Marine polysaccharides present a real potential for natural product drug discovery and for the delivery of new marine derived products for therapeutic applications.
Article
Full-text available
Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits.
Article
Full-text available
Astaxanthin (AX), which is produced by some marine animals, is a type of carotenoid that has antioxidative properties. In this study, we initially examined the effects of AX on the aging of a model organism C. elegans that has the conserved intracellular pathways related to mammalian longevity. The continuous treatments with AX (0.1 to 1 mM) from both the prereproductive and young adult stages extended the mean lifespans by about 16-30% in the wild-type and long-lived mutant age-1 of C. elegans. In contrast, the AX-dependent lifespan extension was not observed even in a daf-16 null mutant. Especially, the expression of genes encoding superoxide dismutases and catalases increased in two weeks after hatching, and the DAF-16 protein was translocated to the nucleus in the AX-exposed wild type. These results suggest that AX protects the cell organelle mitochondria and nucleus of the nematode, resulting in a lifespan extension via an Ins/IGF-1 signaling pathway during normal aging, at least in part.
Article
Full-text available
Longevity in Okinawa is considered to be a result of traditional low calorie diet. Le Bourg suggests that Okinawa is an example of severe malnutrition, which is harmful for later generations. We believe that current loss of longevity advantage in Okinawa is a result of diet westernization and that the dietary restriction is a valid way of life extension in humans.
Article
Full-text available
Curcumin is the active ingredient in the herbal medicine and dietary spice, turmeric (Curcuma longa). It has a wide range of biological activities, including anti-inflammatory, antioxidant, chemopreventive, and chemotherapeutic activities. We examined the effects of curcumin on the lifespan and aging in Caenorhabditis elegans, and found that it responded to curcumin with an increased lifespan and reduced intracellular reactive oxygen species and lipofuscin during aging. We analyzed factors that might influence lifespan extension by curcumin. We showed that lifespan extension by curcumin in C. elegans is attributed to its antioxidative properties but not its antimicrobial properties. Moreover, we showed that lifespan extension had effects on body size and the pharyngeal pumping rate but not on reproduction. Finally, lifespan tests with selected stress- and lifespan-relevant mutant strains revealed that the lifespan-extending phenotype was absent from the osr-1, sek-1, mek-1, skn-1, unc-43, sir-2.1, and age-1 mutants, whereas curcumin treatment prolonged the lifespan of mev-1 and daf-16 mutants. Our study has unraveled a diversity of modes of action and signaling pathways to longevity and aging with curcumin exposure in vivo.
Article
Full-text available
Marine microalgae constitute a natural source of a variety of drugs for pharmaceutical, food and cosmetic applications-which encompass carotenoids, among others. A growing body of experimental evidence has confirmed that these compounds can play important roles in prevention (and even treatment) of human diseases and health conditions, e.g., cancer, cardiovascular problems, atherosclerosis, rheumatoid arthritis, muscular dystrophy, cataracts and some neurological disorders. The underlying features that may account for such favorable biological activities are their intrinsic antioxidant, anti-inflammatory and antitumoral features. In this invited review, the most important issues regarding synthesis of carotenoids by microalgae are described and discussed-from both physiological and processing points of view. Current gaps of knowledge, as well as technological opportunities in the near future relating to this growing field of interest, are also put forward in a critical manner.
Article
Full-text available
Insulin-like growth factor 1 (IGF-1) is an anabolic hormone important for growth and development. However, high-circulating serum concentrations in adults are associated with increased risk of postmenopausal breast cancer. Nutritional status and specific foods influence serum IGF-1 concentrations. Breast cancer incidence is typically low in Asian countries where soy is commonly consumed. Paradoxically, soy supplement trials in American women have reported significant increases in IGF-1. Seaweed also is consumed regularly in Asian countries where breast cancer risk is low. We investigated the possibility that seaweed could modify soy-associated increases in IGF-1 in American women. Thirty healthy postmenopausal women (mean age 58 yr) participated in this 14-wk double-blinded, randomized, placebo-controlled crossover clinical trial. Participants consumed 5 g/day placebo or seaweed (Alaria esculenta) in capsules for 7 wk. During the 7th wk, a high-soy protein isolate powder was added (2 mg/kg body weight aglycone equivalent isoflavones). Overnight fasting blood samples were collected after each intervention period. Soy significantly increased serum IGF-1 concentrations compared to the placebo (21.2 nmol/L for soy vs. 16.9 nmol/L for placebo; P = 0.0001). The combination of seaweed and soy significantly reduced this increase by about 40% (21.2 nmol/L for soy alone vs. 19.4 nmol/L; P = 0.01). Concurrent seaweed and soy consumption may be important in modifying the effect of soy on IGF-1 serum concentrations.
Article
Full-text available
Caloric (or dietary) restriction (CR) extends lifespan and lowers risk for age associated diseases in a phylogenetically diverse group of species. Whether prolonged CR increases average or maximum lifespan or promotes a more youthful physiology in humans at advanced ages is not yet known. However, available epidemiological evidence indicates that CR may already have contributed to an extension of average and maximum life span in one human population and appears to have lowered risk for age associated chronic diseases in other human populations. We review the human studies in the context of a special human population, older Okinawans, who appear to have undergone a mild form of prolonged CR for about half their adult lives.
Article
Potato phytonutrients include phenolic acids, flavonols, anthocyanins and carotenoids. Developmental effects on phytonutrient concentrations and gene expression was studied in white, yellow and purple potatoes. Purple potatoes contained the most total phenolics, which decreased during development (14 to 10 mg g-1), as did activity of phenylalanine ammonia lyase. The major phenolic, 5-chlorogenic acid (5CGA), decreased during development in all cultivars. Products of later branches of the phenylpropanoid pathway also decreased, including quercetin 3-O rutinoside, kaempferol 3-rutinoside and petunidin 3-(p-coumaroyl)-rutinoside-3-glucoside (from 6.4 to 4.0 mg g-1). Violaxanthin and lutein were the two most abundant carotenoids and decreased 30 to 70% in the yellow and white potatoes. Sucrose, which can regulate phenylpropanoid metabolism, decreased with development in all cultivars and was highest in purple potatoes. Total protein decreased by 15%-30% in two cultivars. Expression of most phenylpropanoid and carotenoid structural genes decreased during development. Immature potatoes like those used in this study are marketed as "baby potatoes," and the greater amounts of these dietarily desirable compounds may appeal to health-conscious consumers.
Article
This response letter addresses two points raised by le Bourg when discussing our previous paper entitled "Exploring the impact of climate on human longevity". First, the arguments explaining the accuracy of the numbers of centenarian in Okinawa are developed, and second the composition and healthfulness of the traditional Okinawan diet are described as well as the changes in dietary pattern and their impact on longevity.
Article
In the present study, a sulfated polysaccharide fucoidan extracted from Saccharina japonica was administered to normal and alloxan-diabetic rats/mice, and its effects on glycemia, insulin and serum lipid levels were evaluated. Fucoidan administered at 200 or 1200mg/kg body weight/day could significantly reduce the blood glucose level by 22% and 34%, respectively, in alloxan-induced diabetic rats. Serum insulin levels in diabetic mice were increased by the administration of fucoidan (P<0.05). The results of an oral glucose tolerance test (OGTT) revealed that fucoidan treatment had some effect on glucose disposal after 15 days of treatment. Furthermore, fucoidan altered plasma lipid levels by lowering cholesterol, triglyceride and plasma low-density lipoprotein concentrations, while elevating plasma high-density lipoprotein cholesterol at 100 or 300mg/kg body weight/day. The results suggested that fucoidan exhibited a considerable hypoglycemic effect, possibly by stimulating pancreatic release of insulin and/or by reducing insulin metabolism. Our results indicated that fucoidan could be developed as a potential oral hypoglycemic agents or functional food for the management of diabetes.
Article
Turmeric has been used commonly as a spice, food additive, and an herbal medicine worldwide. Known as a bioactive polyphenolic extract of Turmeric, curcumin has a broad range of health benefit properties for humans. Recently, active research on curcumin with respect to aging and related traits in model organisms has demonstrated that curcumin and its metabolite, tetrahydrocurcumin (THC), increase mean lifespan of at least three model organisms: nematode roundworm, fruit fly Drosophila, and mouse. Nematodes grown on media containing curcumin showed a significantly increased lifespan by reducing the production of reactive oxygen species. Genes osr-1, sek-1, mek-1, skn-1, unc-43, sir-2.1, and age-1 are required for curcumin-mediated lifespan extension. The lifespan extension of Drosophila by curcumin supplementation was associated with increased superoxide dismutase (SOD) activity, and decreased lipofuscin and malondialdehyde levels. Curcumin up-regulated expression of SOD genes and down-regulated expression of several age-related genes, such as dInR, ATTD, Def, CecB, and DptB. In addition, THC extended lifespan in Drosophila and inhibited the oxidative stress response by regulating FOXO and Sir2. Mice fed diets containing THC starting at the age of 13 months had significantly increased mean lifespan. In summary, the positive effects of curcumin on lifespan extension likely arise from beneficial regulation of common oxidative stress responses and age-related genes. Understanding the molecular mechanism(s) of curcumin action has provided base knowledge and rationale for future human clinical trials, and for nutritional intervention in aging and age-associated disorders in humans. © 2013 BioFactors, 2013.
Article
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.
Article
Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Article
Introduction: Mild stress-induced hormesis is becoming increasingly attractive as an ageing interventional strategy and is leading to the discovery of hormesis-inducing compounds called hormetins. Almost 50 years of modern biogerontolgical research has established a clear framework regarding the biological basis of ageing and longevity, and it is now generally accepted that ageing occurs in spite of the presence of complex pathways of maintenance, repair and defense, and there is no 'enemy within.' This viewpoint makes modulation of ageing different from the treatment of one or more age-related diseases. A promising strategy to slow down ageing and prevent or delay the onset of age-related diseases is that of mild stress-induced hormesis by using hormetins. Areas covered: The article presents the rationale and a strategy for discovering novel hormetins as potential drugs for ageing intervention by elucidating multiple stress responses of normal human cells. Furthermore, it discusses the first steps in identifying prospective hormetin drugs and provides a recent example of successful product development, based on the ideas of hormesis and by following the strategy described here. Expert opinion: As a biomedical issue, the biological process of ageing underlies several major diseases, and although the optimal treatment of every disease, irrespective of age, is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of ageing is the best approach for achieving healthy ageing and for extending the healthspan.
Article
The initial investigation of the nature of the proteins in the tuber of sweet potato (Ipomoea batatas Lam.) revealed a globulin-designated "ipomoein," which was reported by Jones and Gersdorff, (1931). Later, "ipomoein" was renamed "sporamin" and was found to be a major storage protein that accounted for over 80% of the total protein in the tuberous root. To date, sporamin has been studied by a series of biochemical and molecular approaches. The first purification of sporamin into two major fractions, A and B, was successfully completed in 1985. Several characteristics of the protein, such as the diversification of the nucleotide sequences in the gene family, the protein structure, the biological functions of storage, defense, inhibitory activity and ROS scavenging, were identified. In the past decade, sporamin was classified as a Kunitz-type trypsin inhibitor, and its insect-resistance capability has been examined in transgenic tobacco and cauliflower plants, indicating the multiple functions of this protein has evolved to facilitate the growth and development of sweet potato. Sporamin is constitutively expressed in the tuberous root and is not normally expressed in the stem or leaves. However, this protein is expressed systemically in response to wounding and other abiotic stresses. These dual expression patterns at the transcriptional level revealed that the complex regulatory mechanism of sporamin was modulated by environmental stresses. The versatile functions of sporamin make this storage protein a good research model to study molecular evolution, regulatory mechanisms and physiological functions in plants. This review summarizes and discusses recent approaches and future perspectives in agricultural biotechnology.
Article
Underlying the importance of research on the biology of aging is the fact that many nations face the demographic reality of a rapidly aging populace and the looming healthcare challenges that it brings. This reality is a result of aging itself being the most significant risk factor for a range of the most prevalent diseases, including many cancers, cardiovascular disease, and diabetes. Accordingly, interventions are sorely needed that would be able to delay or prevent diseases and disorders associated with the aging process and thereby increase the period of time that aging individuals are in good health (the health-span). Caloric restriction (CR) has emerged as a model of major interest as it is widely agreed that CR is the most potent environmental intervention that delays the onset of aging and extends life span in diverse experimental organisms. A better understanding of the mechanisms by which CR delays aging will reveal new insights into the aging process and the underlying causes of disease vulnerability with age. These novel insights will allow the development of novel treatments and preventive measures for age-associated diseases and disorders.
Article
During aging there is an increasing imbalance of energy intake and expenditure resulting in obesity, frailty, and metabolic disorders. For decades, research has shown that caloric restriction (CR) and exercise can postpone detrimental aspects of aging. These two interventions invoke a similar physiological signature involving pathways associated with stress responses and mitochondrial homeostasis. Nonetheless, CR is able to delay aging processes that result in an increase of both mean and maximum lifespan, whereas exercise primarily increases healthspan. Due to the strict dietary regime necessary to achieve the beneficial effects of CR, most studies to date have focused on rodents and non-human primates. As a consequence, there is vast interest in the development of compounds such as resveratrol, metformin and rapamycin that would activate the same metabolic- and stress-response pathways induced by these interventions without actually restricting caloric intake. Therefore the scope of this review is to (i) describe the benefits of CR and exercise in healthy individuals, (ii) discuss the role of these interventions in the diseased state, and (iii) examine some of the promising pharmacological alternatives such as CR- and exercise-mimetics.
Article
The importance of marine algae as sources of functional ingredients has been well recognized due to their valuable health beneficial effects. Therefore, isolation and investigation of novel bioactive ingredients with biological activities from marine algae have attracted great attention. Among functional ingredients identified from marine algae, fucoxanthin has received particular interest. Fucoxanthin has been attributed with extraordinary potential for protecting the organism against a wide range of diseases and has considerable potential and promising applications in human health. Fucoxanthin has been reported to exhibit various beneficial biological activities such as antioxidant, anticancer, anti-inflammatory, antiobesity, and neuroprotective activities. In this chapter, the currently available scientific literatures regarding the most significant activities of fucoxanthin are summarized.
Article
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Research has shown that the majority of the cardiometabolic alterations associated with an increased risk of CVD (e.g., insulin resistance/type 2 diabetes, abdominal obesity, dyslipidemia, hypertension, and inflammation) can be prevented, and even reversed, with the implementation of healthier diets and regular exercise. Data from animal and human studies indicate that more drastic interventions, i.e., calorie restriction with adequate nutrition (CR), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability). The purpose of this article is to review the current knowledge on the effects of CR on the aging of the cardiovascular system and CVD risk in rodents, monkeys, and humans. Taken together, research shows that CR has numerous beneficial effects on the aging cardiovascular system, some of which are likely related to reductions in inflammation and oxidative stress. In the vasculature, CR appears to protect against endothelial dysfunction and arterial stiffness and attenuates atherogenesis by improving several cardiometabolic risk factors. In the heart, CR attenuates age-related changes in the myocardium (i.e., CR protects against fibrosis, reduces cardiomyocyte apoptosis, prevents myosin isoform shifts, etc.) and preserves or improves left ventricular diastolic function. These effects, in combination with other benefits of CR, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans.
Article
Dietary restriction (DR: food restriction without malnutrition) is often considered as a nearly universal means to extend longevity in animal species and we could make the hypothesis that DR could increase longevity in humans. Some authors support the opinion that DR has already increased longevity in Okinawa inhabitants, and thus that DR can increase longevity in humans. The purpose of this article is to stress that no data on humans with a normal body mass index (neither overweight nor obese) indicate that DR can increase life span and health span, particularly because the results observed in Okinawa inhabitants can probably be considered as showing mainly deleterious effects of malnutrition rather than positive effects of DR. Since DR does not appear to increase human life span, studies testing for the effect of DR in humans should focus on the health effects of a mild DR in overweight and obese people, rather than in normal-weight people.
Article
Obesity and type 2 diabetes are pathologies with rapidly growing prevalence throughout the world. A few molecular targets offer the most hope for anti-obesity and anti-diabetic therapeutics. One of the keys to success will be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity and anti-diabetic effects of fucoxanthin, a characteristic carotenoid found in brown seaweeds, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of carotenoids for the expression of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups.