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1.  Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans 
PLoS Medicine  2007;4(3):e76.
Background
Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood.
Methods and Findings
The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR.
Conclusions
The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.
Anthony Civitarese and colleagues observed an increase in mitochondrial DNA in muscle and a decrease in whole body oxygen consumption in healthy adults who underwent caloric restriction.
Editors' Summary
Background.
Life expectancy (the average life span) greatly increased during the 20th century in most countries, largely due to improved hygiene, nutrition, and health care. One possible approach to further increase human life span is “caloric restriction.” A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. This type of diet increases the life span of mice and delays the onset of age-related chronic diseases such as heart disease and stroke. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. People living in Okinawa, Japan, have a lower energy intake than the rest of the Japanese population and an extremely long life span. In addition, calorie-restricted diets beneficially affect several biomarkers of aging, including decreased insulin sensitivity (a precursor to diabetes). But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of “oxidative damage” in the body's proteins, fats, and DNA. Oxidants—in particular, chemicals called “free radicals”—are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria.
Why Was This Study Done?
Despite hints that caloric restriction might have similar effects in people as in rodents, there have been few well-controlled studies on the effect of good quality calorie-reduced diets in healthy people. It is also unknown whether an energy deficit produced by increasing physical activity while eating the same amount of food has the same effects as caloric restriction. Finally, it is unclear how caloric restriction alters mitochondrial function. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) organization is investigating the effect of caloric restriction interventions on physiology, body composition, and risk factors for age-related diseases. In this study, the researchers have tested the hypothesis that short-term caloric deficit (with or without exercise) increases the efficiency of mitochondria in human muscle.
What Did the Researchers Do and Find?
The researchers enrolled 36 healthy overweight but non-obese young people into their study. One-third of them received 100% of their energy requirements in their diet; the caloric restriction (CR) group had their calorie intake reduced by 25%; and the caloric restriction plus exercise (CREX) group had their calorie intake reduced by 12.5% and their energy expenditure increased by 12.5%. The researchers found that a 25% caloric deficit for six months, achieved by diet alone or by diet plus exercise, decreased 24-hour whole body energy expenditure (i.e., overall calories burned for body function), which suggests improved mitochondrial function. Their analysis of genes involved in mitochondria formation indicated that CR and CREX both increased the number of mitochondria in skeletal muscle. Both interventions also reduced the amount of DNA damage—a marker of oxidative stress—in the participants' muscles.
What Do These Findings Mean?
These results indicate that a short-term caloric deficit, whether achieved by diet or by diet plus exercise, induces the formation of “efficient mitochondria” in people just as in rodents. The induction of these efficient mitochondria in turn reduces oxidative damage in skeletal muscles. Consequently, this adaptive response to caloric restriction might have the potential to slow aging and increase longevity in humans as in other animals. However, this six-month study obviously provides no direct evidence for this, and, by analogy with studies in rodents, an increase in longevity might require lifelong caloric restriction. The results here suggest that even short-term caloric restriction can produce beneficial physiological changes, but more research is necessary before it becomes clear whether caloric restriction should be recommended to healthy individuals.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040076.
The CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) Web site contains information on the study and how to participate
American Federation for Aging Research includes information on aging with pages on the biology of aging and on caloric restriction
The Okinawa Centenarian Study is a population-based study on long-lived elderly people in Okinawa, Japan
US Government information on nutrition
MedlinePlus encyclopedia pages on diet and calories
The Calorie Restriction Society, a nonprofit organization that provides information on life span and caloric restriction
Wikipedia pages on calorie restriction and on mitochondria (note: Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040076
PMCID: PMC1808482  PMID: 17341128
2.  Caloric restriction as a mechanism mediating resistance to environmental disease. 
Environmental Health Perspectives  1998;106(Suppl 1):313-324.
It has been observed that susceptibility to many degenerative diseases increases concurrently with industrialization and rising living standards. Although epidemiologic studies suggest that specific environmental and dietary factors may be important, caloric intake alone (as reflected in body size) may account for much of the differential risk observed among diverse human populations. It has been suggested from animal studies that caloric intake may be the primary effector for many hormonal, metabolic, physiologic, and behavioral responses that coordinate reproductive strategy to apparent availability of food. When caloric intake is excessive, particularly at critical developmental stages, physiologic priorities are set for body growth and fecundity rather than for endurance and longevity. The converse occurs during periods of famine, thus increasing the probability that sufficient individuals survive to restore the population when conditions improve. Calorically restricted rodents have significantly longer reproductive and total life spans than their ad libitum-fed controls and exhibit a spectrum of biochemical and physiologic alterations that characterize their adaptation to reduced intake. These include reduced stature, hypercorticism in the absence of elevated adrenocorticotropic hormone levels, increased metabolic efficiency, decreased mitogenic response coupled with increased rates of apoptosis, reduced inflammatory response, induction of stress proteins and DNA repair enzymes, altered drug-metabolizing enzyme expression, and modified cell-mediated immune function. The overall profile of these changes is one of improved defense against environmental stress. This has been suggested as the mechanistic basis for the protective effects of low body weight on radiation and chemically induced cancers in experimental animals. It may also explain the significantly higher thresholds of acute toxicity observed when calorically restricted rodents are exposed to certain test compounds.
Images
PMCID: PMC1533299  PMID: 9539025
3.  Pro-Aging Effects of Glucose Signaling through a G Protein-Coupled Glucose Receptor in Fission Yeast 
PLoS Genetics  2009;5(3):e1000408.
Glucose is the preferred carbon and energy source in prokaryotes, unicellular eukaryotes, and metazoans. However, excess of glucose has been associated with several diseases, including diabetes and the less understood process of aging. On the contrary, limiting glucose (i.e., calorie restriction) slows aging and age-related diseases in most species. Understanding the mechanism by which glucose limits life span is therefore important for any attempt to control aging and age-related diseases. Here, we use the yeast Schizosaccharomyces pombe as a model to study the regulation of chronological life span by glucose. Growth of S. pombe at a reduced concentration of glucose increased life span and oxidative stress resistance as reported before for many other organisms. Surprisingly, loss of the Git3 glucose receptor, a G protein-coupled receptor, also increased life span in conditions where glucose consumption was not affected. These results suggest a role for glucose-signaling pathways in life span regulation. In agreement, constitutive activation of the Gα subunit acting downstream of Git3 accelerated aging in S. pombe and inhibited the effects of calorie restriction. A similar pro-aging effect of glucose was documented in mutants of hexokinase, which cannot metabolize glucose and, therefore, are exposed to constitutive glucose signaling. The pro-aging effect of glucose signaling on life span correlated with an increase in reactive oxygen species and a decrease in oxidative stress resistance and respiration rate. Likewise, the anti-aging effect of both calorie restriction and the Δgit3 mutation was accompanied by increased respiration and lower reactive oxygen species production. Altogether, our data suggest an important role for glucose signaling through the Git3/PKA pathway to regulate S. pombe life span.
Author Summary
Lowering caloric intake by limiting glucose (the preferred carbon and energy source) increases life span in various species. Excess glucose can have deleterious effects, but it is not clear whether this is due to the caloric contribution of glucose or to some other effect. Glucose sensed by the cells activates signaling pathways that, in yeast, favor the metabolic machinery that makes energy (glycolysis) and cell growth. The sensing of glucose also reduces stress resistance and the ability to live long. Does glucose provoke a pro-aging effect as a result of its metabolic activity or by activating signaling pathways? Here we addressed this question by studying the role of a glucose-signaling pathway in the life span of the fission yeast S. pombe. Genetic inactivation of the glucose-signaling pathway prolonged life span in this yeast, while its constitutive activation shortened it and blocked the longevity effects of calorie restriction. The pro-aging effects of glucose signaling correlated with a decrease in mitochondrial respiration and an increase in reactive oxygen species production. Moreover, a strain without glucose metabolism is still sensitive to detrimental effects of glucose due to signaling. Our work shows that glucose signaling through the glucose receptor GIT3 constitutes the main cause responsible for the pro-aging effects of glucose in fission yeast.
doi:10.1371/journal.pgen.1000408
PMCID: PMC2646135  PMID: 19266076
4.  Protein:carbohydrate ratios explain life span patterns found in Queensland fruit fly on diets varying in yeast:sugar ratios 
Age  2011;34(6):1361-1368.
Dietary restriction extends life span across a vast diversity of taxa, but significant challenges remain in elucidating the underlying mechanisms. Distinguishing between caloric and nutrient effects is an essential step. Recent studies with Drosophila and tephritid fruit flies have reported increased life span as dietary yeast-to-sugar ratios decreased and these effects have been attributed to changes in protein-to-carbohydrate (P:C) ratios of the diets rather than calories. However, yeast is a complex mix of macronutrients and micronutrients, and hence changes in yeast content of the diet necessarily alters other nutrients in lockstep. To explicitly test whether studies using yeast are justified in attributing results to diet protein content rather than correlated nutrients, we developed a chemically defined diet allowing manipulation of just the ratio of protein (free amino acids) to carbohydrate (sucrose) levels of diets while holding other nutrients constant. Mated, female Queensland fruit flies (Q-flies) were fed 1 of 18 diets varying in P:C ratios and diet concentration. Diet consumption, egg production, and life span were recorded for each fly. In close concordance with recent studies using yeast diets, flies had increased life span as P:C ratios decreased, and caloric restriction did not extend life span. Similarly, egg production was maximized on high P:C ratios, but lifetime egg production was maximized on intermediate P:C ratios, indicating a life history trade-off between life span and egg production rate. Finally, Q-flies adjusted their diet intake in response to P:C ratios and diet concentration. Our results substantiate recent claims that P:C ratios significantly modulate life span in flies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9308-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9308-3
PMCID: PMC3528373  PMID: 21904823
Bactrocera tryoni; Dietary restriction; Geometric framework; Holidic diet; Lifespan; Life history trade-off; Nutrition
5.  Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans 
Background
The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend life span by targeting pathways with a defined role in the aging process. On the environmental side, the molecular mechanisms responsible for the positive influence of interventions such as dietary restriction are being explored. The environment experienced by humans in modern societies already contains countless compounds that may influence longevity. Understanding the role played by common compounds that substantially affect the aging process will be critical for predicting and interpreting the outcome of introducing new interventions. Caffeine is the most widely used psychoactive drug worldwide. Prior studies in flies, worms, and mice indicate that caffeine may positively impact age-associated neurodegenerative pathology, such as that observed in Alzheimer’s disease.
Results
Here we report that caffeine is capable of extending life span and improving healthspan in Caenorhabditis elegans, a finding that is in agreement with a recently published screen looking for FDA-approved compounds capable of extending worm life span. Life span extension using caffeine displays epistatic interaction with two known longevity interventions: dietary restriction and reduced insulin signaling. Caffeine treatment also delays pathology in a nematode model of polyglutamine disease.
Conclusions
The identification of caffeine as a relevant factor in aging and healthspan in worms, combined with prior work in both humans and rodents linking caffeine consumption to reduced risk of age-associated disease, suggests that caffeine may target conserved longevity pathways. Further, it may be important to consider caffeine consumption when developing clinical interventions, particularly those designed to mimic dietary restriction or modulate insulin/IGF-1-like signaling. The positive impact of caffeine on a worm model of polyglutamine disease suggests that chronic caffeine consumption may generally enhance resistance to proteotoxic stress and may be relevant to assessing risk and developing treatments for human diseases like Alzheimer’s and Huntington’s disease. Future work addressing the relevant targets of caffeine in models of aging and healthspan will help to clarify the underlying mechanisms and potentially identify new molecular targets for disease intervention.
doi:10.1186/2046-2395-1-9
PMCID: PMC3922918  PMID: 24764514
Aging; Life span; Longevity; Healthspan; Worms; Caffeine; Proteotoxicity; Neurodegeneration
6.  Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast 
PLoS Genetics  2005;1(5):e69.
A model for replicative life span extension by calorie restriction (CR) in yeast has been proposed whereby reduced glucose in the growth medium leads to activation of the NAD+–dependent histone deacetylase Sir2. One mechanism proposed for this putative activation of Sir2 is that CR enhances the rate of respiration, in turn leading to altered levels of NAD+ or NADH, and ultimately resulting in enhanced Sir2 activity. An alternative mechanism has been proposed in which CR decreases levels of the Sir2 inhibitor nicotinamide through increased expression of the gene coding for nicotinamidase, PNC1. We have previously reported that life span extension by CR is not dependent on Sir2 in the long-lived BY4742 strain background. Here we have determined the requirement for respiration and the effect of nicotinamide levels on life span extension by CR. We find that CR confers robust life span extension in respiratory-deficient cells independent of strain background, and moreover, suppresses the premature mortality associated with loss of mitochondrial DNA in the short-lived PSY316 strain. Addition of nicotinamide to the medium dramatically shortens the life span of wild type cells, due to inhibition of Sir2. However, even in cells lacking both Sir2 and the replication fork block protein Fob1, nicotinamide partially prevents life span extension by CR. These findings (1) demonstrate that respiration is not required for the longevity benefits of CR in yeast, (2) show that nicotinamide inhibits life span extension by CR through a Sir2-independent mechanism, and (3) suggest that CR acts through a conserved, Sir2-independent mechanism in both PSY316 and BY4742.
Synopsis
Calorie restriction slows aging and increases life span in nearly every organism studied. The mechanism by which this occurs is one of the most important unanswered questions in biogerontology. One popular theory, based on work from the budding yeast Saccharomyces cerevisiae, proposes that calorie restriction works by causing a metabolic shift toward increased mitochondrial respiration, resulting in activation of a family of proteins known as Sirtuins. This study demonstrates that life span extension by calorie restriction does not require respiration and occurs even in cells completely lacking mitochondrial DNA. Interestingly, calorie restriction protects yeast cells against a severe longevity defect associated with absence of mitochondrial DNA, suggesting the possibility that the consequences of age-associated mitochondrial dysfunction might be alleviated or prevented by calorie restriction.
doi:10.1371/journal.pgen.0010069
PMCID: PMC1287956  PMID: 16311627
7.  Effect of long-term caloric restriction on oxygen consumption and body temperature in two different strains of mice 
Mechanisms of ageing and development  2007;128(10):539-545.
The hypothesis, that a decrease in metabolic rate mediates the life span prolonging effect of caloric restriction (CR), was tested using two strains of mice, one of which, C57BL/6, exhibits life span extension as a result of CR, while the other, DBA/2, shows little or no effect. Comparisons of the rate of resting oxygen consumption and body temperature were made between the strains after they were fed ad libitum (AL) or maintained under 40% CR, from 4 to 16 months of age. Ad libitum-fed mice of the two strains weighed the same when young and consumed similar amounts of food throughout the experiment; however, the C57BL/6 mice weighed 25% more than DBA/2 mice at 15 months of age. The rate of oxygen consumption was normalized as per gram body weight, lean body mass or organ weight as well as per animal. The body temperature and the rate of oxygen consumption, expressed according to all of the four criteria, were decreased in the DBA/2 mice following CR. The C57BL/6 mice also showed a CR-related decrease in body temperature and in the rate of oxygen consumption per animal and when normalized according to lean body mass or organ weight. The results of this study indicate that CR indeed lowers the rate of metabolism; however, this effect by CR does not necessarily entail the prolongation of the life span of mice.
doi:10.1016/j.mad.2007.07.005
PMCID: PMC2048713  PMID: 17822741
caloric restriction; metabolic rate; aging; life span; energy balance; obesity; inbred mice; C57BL/6; DBA/2
8.  Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans 
Background
Dietary restriction (DR) increases life span and delays age-associated disease in many organisms. The mechanism by which DR enhances longevity is not well understood.
Results
Using bacterial food deprivation as a means of DR in C. elegans, we show that transient DR confers long-term benefits including stress resistance and increased longevity. Consistent with studies in the fruit fly and in mice, we demonstrate that DR also enhances survival when initiated late in life. DR by bacterial food deprivation significantly increases life span in worms when initiated as late as 24 days of adulthood, an age at which greater than 50% of the cohort have died. These survival benefits are, at least partially, independent of food consumption, as control fed animals are no longer consuming bacterial food at this advanced age. Animals separated from the bacterial lawn by a barrier of solid agar have a life span intermediate between control fed and food restricted animals. Thus, we find that life span extension from bacterial deprivation can be partially suppressed by a diffusible component of the bacterial food source, suggesting a calorie-independent mechanism for life span extension by dietary restriction.
Conclusion
Based on these findings, we propose that dietary restriction by bacterial deprivation increases longevity in C. elegans by a combination of reduced food consumption and decreased food sensing.
doi:10.1186/1471-213X-8-49
PMCID: PMC2408926  PMID: 18457595
9.  Quantitative and Molecular Genetic Analyses of Mutations Increasing Drosophila Life Span 
PLoS Genetics  2010;6(7):e1001037.
Understanding the genetic and environmental factors that affect variation in life span and senescence is of major interest for human health and evolutionary biology. Multiple mechanisms affect longevity, many of which are conserved across species, but the genetic networks underlying each mechanism and cross-talk between networks are unknown. We report the results of a screen for mutations affecting Drosophila life span. One third of the 1,332 homozygous P–element insertion lines assessed had quantitative effects on life span; mutations reducing life span were twice as common as mutations increasing life span. We confirmed 58 mutations with increased longevity, only one of which is in a gene previously associated with life span. The effects of the mutations increasing life span were highly sex-specific, with a trend towards opposite effects in males and females. Mutations in the same gene were associated with both increased and decreased life span, depending on the location and orientation of the P–element insertion, and genetic background. We observed substantial—and sex-specific—epistasis among a sample of ten mutations with increased life span. All mutations increasing life span had at least one deleterious pleiotropic effect on stress resistance or general health, with different patterns of pleiotropy for males and females. Whole-genome transcript profiles of seven of the mutant lines and the wild type revealed 4,488 differentially expressed transcripts, 553 of which were common to four or more of the mutant lines, which include genes previously associated with life span and novel genes implicated by this study. Therefore longevity has a large mutational target size; genes affecting life span have variable allelic effects; alleles affecting life span exhibit antagonistic pleiotropy and form epistatic networks; and sex-specific mutational effects are ubiquitous. Comparison of transcript profiles of long-lived mutations and the control line reveals a transcriptional signature of increased life span.
Author Summary
Recent advances in medical science as well as vastly improved living conditions have resulted in a steady increase in human life span, with a concomitant increase in health issues associated with aging. In addition, understanding life history evolution requires that we know why organisms age and why there is variation in aging and senescence. To identify genes involved in aging, we assessed longevity in a collection of over 1,300 Drosophila lines homozygous for a single P transposable element mutation. We found 58 mutations in novel loci that increase life span by up to 33%. Most mutations had different effects on male and female life span, and for some the effects were opposite between the sexes. Effects of these mutations on starvation resistance, chill coma recovery, and climbing ability varied, but all had a deleterious effect on at least one other trait. A sample of ten mutations with increased life span formed genetic interaction networks, but the genetic interactions were different, and sometimes in opposite directions, in males and females. Transcript profiles of seven long-lived mutations and the control line reveal a core transcriptional signature of increased life span involving novel candidate genes for future analysis.
doi:10.1371/journal.pgen.1001037
PMCID: PMC2912381  PMID: 20686706
10.  Thermoregulatory, cardiovascular, and metabolic responses to mild caloric restriction in the Brown Norway rat 
Physiological Reports  2013;1(2):e00016.
Caloric restriction (CR) has been demonstrated to prolong the life span of a variety of species. CR-induced reduction in core temperature (Tc) is considered a key mechanism responsible for prolonging life span in rodents; however, little is known about the regulation of CR-induced hypothermia as a function of the circadian cycle. We assessed how mild CR that resulted in a 10% reduction in body weight affected the 24 h patterns of Tc as well as heart rate (HR) and motor activity (MA) of the Brown Norway rat. Telemetered rats were allowed to feed for 20 weeks ad libitum (AL) or given a CR diet. Tc, HR, and MA of CR rats exhibited nocturnal reductions and diurnal elevations, opposite to that of AL rats. The effects of CR appeared to peak at ∼4 weeks. Metabolic rate (MR) and respiratory exchange ratio (RER) were measured overnight after 18 weeks of CR. MR and RER were elevated markedly at the time of feeding in CR rats and then declined during the night. We found that the pattern of Tc was altered with CR, characterized by elimination of high nocturnal Tc's typically observed in AL animals. In terms of mechanisms to prolong life span in CR animals, we suggest that the shift in the pattern of Tc during CR (i.e., elimination of high Tc's) may be as critical as the overall mean reduction in Tc. Future studies should address how the time of feeding may affect the thermoregulatory response in calorically restricted rats.
doi:10.1002/phy2.16
PMCID: PMC3831912  PMID: 24303105
Caloric restriction; longevity; metabolic rate; radiotelemetry; thermoregulation
11.  Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9 
PLoS Genetics  2008;4(1):e13.
Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.
Author Summary
Reduction in calorie intake is a well-established intervention that extends the life span of a variety of biological model organisms studied. Calorie restriction also delays and attenuates age-related changes in primates, although its longevity-promoting effect has not been demonstrated. Here, we utilized a single cell organism, baker's yeast, to examine the role of evolutionarily conserved genes in life span regulation and their involvement in calorie restriction. The yeast mutants lacking Ras2, Tor1, or Sch9 are long-lived. The anti-aging effect observed in these mutants depends on the protein Rim15 and several key regulators of gene expression that are essential in inducing cellular protection under stress. The beneficial effects of calorie restriction are much smaller in yeast that are missing these proteins, indicating their essential role in promoting longevity. Our study also showed that by combining the genetic manipulation and calorie restriction intervention, yeast can reach a life span ten times that of those grown under standard conditions. This extreme longevity requires Rim15 and also depends on other yet-to-be identified mechanisms. Our findings provided new leads that may help to elucidate the mechanisms underlying the anti-aging effect of calorie restriction in mammals.
doi:10.1371/journal.pgen.0040013
PMCID: PMC2213705  PMID: 18225956
12.  Bariatric Surgery 
Executive Summary
Objective
To conduct an evidence-based analysis of the effectiveness and cost-effectiveness of bariatric surgery.
Background
Obesity is defined as a body mass index (BMI) of at last 30 kg/m2.1 Morbid obesity is defined as a BMI of at least 40 kg/m2 or at least 35 kg/m2 with comorbid conditions. Comorbid conditions associated with obesity include diabetes, hypertension, dyslipidemias, obstructive sleep apnea, weight-related arthropathies, and stress urinary incontinence. It is also associated with depression, and cancers of the breast, uterus, prostate, and colon, and is an independent risk factor for cardiovascular disease.
Obesity is also associated with higher all-cause mortality at any age, even after adjusting for potential confounding factors like smoking. A person with a BMI of 30 kg/m2 has about a 50% higher risk of dying than does someone with a healthy BMI. The risk more than doubles at a BMI of 35 kg/m2. An expert estimated that about 160,000 people are morbidly obese in Ontario. In the United States, the prevalence of morbid obesity is 4.7% (1999–2000).
In Ontario, the 2004 Chief Medical Officer of Health Report said that in 2003, almost one-half of Ontario adults were overweight (BMI 25–29.9 kg/m2) or obese (BMI ≥ 30 kg/m2). About 57% of Ontario men and 42% of Ontario women were overweight or obese. The proportion of the population that was overweight or obese increased gradually from 44% in 1990 to 49% in 2000, and it appears to have stabilized at 49% in 2003. The report also noted that the tendency to be overweight and obese increases with age up to 64 years. BMI should be used cautiously for people aged 65 years and older, because the “normal” range may begin at slightly above 18.5 kg/m2 and extend into the “overweight” range.
The Chief Medical Officer of Health cautioned that these data may underestimate the true extent of the problem, because they were based on self reports, and people tend to over-report their height and under-report their weight. The actual number of Ontario adults who are overweight or obese may be higher.
Diet, exercise, and behavioural therapy are used to help people lose weight. The goals of behavioural therapy are to identify, monitor, and alter behaviour that does not help weight loss. Techniques include self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, cognitive restructuring, contingency management, and identifying and using social support. Relapse, when people resume old, unhealthy behaviour and then regain the weight, can be problematic.
Drugs (including gastrointestinal lipase inhibitors, serotonin norepinephrine reuptake inhibitors, and appetite suppressants) may be used if behavioural interventions fail. However, estimates of efficacy may be confounded by high rates of noncompliance, in part owing to the side effects of the drugs. In addition, the drugs have not been approved for indefinite use, despite the chronic nature of obesity.
The Technology
Morbidly obese people may be eligible for bariatric surgery. Bariatric surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management, such as diet, increased physical activity, behavioural modification, and drugs.
There are various bariatric surgical procedures and several different variations for each of these procedures. The surgical interventions can be divided into 2 general types: malabsorptive (bypassing parts of the gastrointestinal tract to limit the absorption of food), and restrictive (decreasing the size of the stomach so that the patient is satiated with less food). All of these may be performed as either open surgery or laparoscopically. An example of a malabsorptive technique is Roux-en-Y gastric bypass (RYGB). Examples of restrictive techniques are vertical banded gastroplasty (VBG) and adjustable gastric banding (AGB).
The Ontario Health Insurance Plan (OHIP) Schedule of Benefits for Physician Services includes fee code “S120 gastric bypass or partition, for morbid obesity” as an insured service. The term gastric bypass is a general term that encompasses a variety of surgical methods, all of which involve reconfiguring the digestive system. The term gastric bypass does not include AGB. The number of gastric bypass procedures funded and done in Ontario, and funded as actual out-of-country approvals,2 is shown below.
Number of Gastric Bypass Procedures by Fiscal Year: Ontario and Actual Out-of-Country (OOC) Approvals
Data from Provider Services, MOHLTC
Courtesy of Provider Services, Ministry of Health and Long Term Care
Review Strategy
The Medical Advisory Secretariat reviewed the literature to assess the effectiveness, safety, and cost-effectiveness of bariatric surgery to treat morbid obesity. It used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases. The interventions of interest were bariatric surgery and, for the controls, either optimal conventional management or another type of bariatric procedure. The outcomes of interest were improvement in comorbid conditions (e.g., diabetes, hypertension); short- and long-term weight loss; quality of life; adverse effects; and economic analysis data. The databases yielded 15 international health technology assessments or systematic reviews on bariatric surgery.
Subsequently, the Medical Advisory Secretariat searched MEDLINE and EMBASE from April 2004 to December 2004, after the search cut-off date of April, 2004, for the most recent systematic reviews on bariatric surgery. Ten studies met the inclusion criteria. One of those 10 was the Swedish Obese Subjects study, which started as a registry and intervention study, and then published findings on people who had been enrolled for at least 2 years or at least 10 years. In addition to the literature review of economic analysis data, the Medical Advisory Secretariat also did an Ontario-based economic analysis.
Summary of Findings
Bariatric surgery generally is effective for sustained weight loss of about 16% for people with BMIs of at least 40 kg/m2 or at least 35 kg/m2 with comorbid conditions (including diabetes, high lipid levels, and hypertension). It also is effective at resolving the associated comorbid conditions. This conclusion is largely based on level 3a evidence from the prospectively designed Swedish Obese Subjects study, which recently published 10-year outcomes for patients who had bariatric surgery compared with patients who received nonsurgical treatment. (1)
Regarding specific procedures, there is evidence that malabsorptive techniques are better than other banding techniques for weight loss and resolution of comorbid illnesses. However, there are no published prospective, long-term, direct comparisons of these techniques available.
Surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management, such as diet, increased physical activity, behavioural modification, and drugs. In the absence of direct comparisons of active nonsurgical intervention via caloric restriction with bariatric techniques, the following observations are made:
A recent systematic review examining the efficacy of major commercial and organized self-help weight loss programs in the United States concluded that the evidence to support the use of such programs was suboptimal, except for one trial on Weight Watchers. Furthermore, the programs were associated with high costs, attrition rates, and probability of regaining at least 50% of the lost weight in 1 to 2 years. (2)
A recent randomized controlled trial reported 1-year outcomes comparing weight loss and metabolic changes in severely obese patients assigned to either a low-carbohydrate diet or a conventional weight loss diet. At 1 year, weight loss was similar for patients in each group (mean, 2–5 kg). There was a favourable effect on triglyceride levels and glycemic control in the low-carbohydrate diet group. (3)
A decision-analysis model showed bariatric surgery results in increased life expectancy in morbidly obese patients when compared to diet and exercise. (4)
A cost-effectiveness model showed bariatric surgery is cost-effective relative to nonsurgical management. (5)
Extrapolating from 2003 data from the United States, Ontario would likely need to do 3,500 bariatric surgeries per year. It currently does 508 per year, including out-of-country surgeries.
PMCID: PMC3382415  PMID: 23074460
13.  Tor1/Sch9-Regulated Carbon Source Substitution Is as Effective as Calorie Restriction in Life Span Extension 
PLoS Genetics  2009;5(5):e1000467.
The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Δ, tor1Δ, and ras2Δ mutants, was sufficient to reverse chronological life span extension in sch9Δ mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.
Author Summary
Studies using model organisms have pointed to the existence of evolutionarily conserved genes and signaling pathways that regulates life span. Changes in the activity of these genes/pathways have also been implicated in mediating the beneficial effect of calorie restriction, a well-recognized intervention that extends the life span from yeast to mammals. We investigated the global gene expression changes and identified genes involved in the metabolism of various kinds of carbon sources that are associated with longevity in the single cell organism, the baker's yeast. Although glucose and ethanol are common carbon sources for growth, they also have detrimental pro-aging effects in yeast. Long-lived yeast mutants actively utilize available glucose and ethanol and produce glycerol, which does not adversely affect the yeast life span extension. Our finding suggest that this “carbon source substitution” observed in long-lived yeast creates an environment mimicking calorie restriction, which together with the direct regulation of stress resistance systems optimizes life span extension. Findings using these simple genetic models will help to elucidate fundamental longevity regulatory mechanisms and identify similar pathways in mammals.
doi:10.1371/journal.pgen.1000467
PMCID: PMC2669710  PMID: 19424415
14.  Life-Span Extension by Caloric Restriction Is Determined by Type and Level of Food Reduction and by Reproductive Mode in Brachionus manjavacas (Rotifera) 
We measured life span and fecundity of three reproductive modes in a clone of the monogonont rotifer Brachionus manjavacas subjected to chronic caloric restriction (CCR) over a range of food concentrations or to intermittent fasting (IF). IF increased life span 50%–70% for all three modes, whereas CCR increased life span of asexual females derived from sexually or asexually produced eggs, but not that of sexual females. The main effect of CR on both asexual modes was to delay death at young ages, rather than to prevent death at middle ages or to greatly extend maximum life span; in contrast CR in sexual females greatly increased the life span of a few long-lived individuals. Lifetime fecundity did not decrease with CCR, suggesting a lack of resource allocation trade-off between somatic maintenance and reproduction. Multiple outcomes for a clonal lineage indicate that different responses are established through epigenetic programming, whereas differences in life-span allocations suggest that multiple genetic mechanisms mediate life-span extension.
doi:10.1093/gerona/gls170
PMCID: PMC3693672  PMID: 22904096
Caloric restriction; Life span extension; Aging; Resource allocation; Rotifer
15.  How Much Should We Weigh for a Long and Healthy Life Span? The Need to Reconcile Caloric Restriction versus Longevity with Body Mass Index versus Mortality Data 
Total caloric restriction (CR) without malnutrition is a well-established experimental approach to extend life span in laboratory animals. Although CR in humans is capable of shifting several endocrinological parameters, it is not clear where the minimum inflection point of the U-shaped curve linking body mass index (BMI) with all-cause mortality lies. The exact trend of this curve, when used for planning preventive strategies for public health is of extreme importance. Normal BMI ranges from 18.5 to 24.9; many epidemiological studies show an inverse relationship between mortality and BMI inside the normal BMI range. Other studies show that the lowest mortality in the entire range of BMI is obtained in the overweight range (25–29.9). Reconciling the extension of life span in laboratory animals by experimental CR with the BMI–mortality curve of human epidemiology is not trivial. In fact, one interpretation is that the CR data are identifying a known: “excess fat is deleterious for health”; although a second interpretation may be that: “additional leanness from a normal body weight may add health and life span delaying the process of aging.” This short review hope to start a discussion aimed at finding the widest consensus on which weight range should be considered the “healthiest” for our species, contributing in this way to the picture of what is the correct life style for a long and healthy life span.
doi:10.3389/fendo.2014.00121
PMCID: PMC4115619  PMID: 25126085
longevity; life span; caloric restriction; dietary restriction; body weight; body mass index; mortality; obesity paradox
16.  Comparison of metabolic rate and oxidative stress between two different strains of mice with varying response to caloric restriction 
Experimental gerontology  2008;43(8):757-763.
Metabolic rate and parameters associated with oxidative stress were compared in two strains of mice, one of which, C57BL/6, exhibits an extension of life span in response to caloric restriction while the other, DBA/2, shows no such effect. Metabolic rate was higher in the DBA/2 than in the C57BL/6 mice, when measured at 5–6 months of age as in vivo and in vitro rates of oxygen consumption or body temperature. There were no remarkable inter-strain differences in activities of the antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase or in the rates of mitochondrial superoxide anion radical generation in heart or skeletal muscles. Comparison of glutathione redox state in the heart and skeletal muscles at 3 and 20 months of age indicated that the amount of glutathione (GSH) and the GSH:GSSG (glutathione disulfide) ratio were relatively higher in the young DBA/2 mice, but there were no inter-strain differences in the older mice. The age-related elevation in the level of oxidative stress reflected by GSH:GSSG ratio was greater in the C57BL/6 than DBA/2 mice. The energy balance, indicated by the gain/loss in body weight per unit of food consumed, is higher in C57BL/6 than DBA/2 mice. It is hypothesized that the genotype-specific extension of life span by caloric restriction may involve modulation of oxidative stress produced as a result of an interplay between metabolic rate and energy balance during aging.
doi:10.1016/j.exger.2008.04.016
PMCID: PMC2579783  PMID: 18541398
17.  The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations 
The average life-span of the population of industrialized countries has improved enormously over the last decades. Despite evidence pointing to the role of food intake in modulating life-span, exceptional longevity is still considered primarily an inheritable trait, as pointed out by the description of families with centenarian clusters and by the elevated relative probability of siblings of centenarians to become centenarians themselves. However, rather than being two separate concepts, the genetic origin of exceptional longevity and the more recently observed environment-driven increase in the average age of the population could possibly be explained by the same genetic variants and environmentally modulated mechanisms (caloric restriction, specific nutrients). In support of this hypothesis, polymorphisms selected for in the centenarian population as a consequence of demographic pressure have been found to modulate cellular signals controlled also by caloric restriction. Here, we give an overview of the recent findings in the field of the genetics of human exceptional longevity, of how some of the identified polymorphisms modulate signals also influenced by food intake and caloric restriction, of what in our view have been the limitations of the approaches used over the past years to study genetics (sib-pair-, candidate gene association-, and genome-wide association-studies), and briefly of the limitations and the potential of the new, high-throughput, next-generation sequencing techniques applied to exceptional longevity.
doi:10.1186/1742-4933-9-7
PMCID: PMC3407776  PMID: 22524405
Aging; Centenarians; Longevity
18.  Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age 
Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the first 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also significantly increases longevity. Furthermore, mice exposed to a CR diet show changes in liver messenger RNA patterns, in phosphorylation of Erk, Jnk2, and p38 kinases, and in phosphorylation of mammalian target of rapamycin and its substrate 4EBP1, HE-binding protein 1 that are not observed in liver from age-matched Meth-R mice. These results introduce new protocols that can increase maximal life span and suggest that the spectrum of metabolic changes induced by low-calorie and low-methionine diets may differ in instructive ways.
doi:10.1093/gerona/glp051
PMCID: PMC2691799  PMID: 19414512
Methionine; Litter size; Caloric restriction; TOR; ERK
19.  Dietary and lifestyle predictors of age at natural menopause and reproductive span in the Shanghai Women's Health Study 
Menopause (New York, N.Y.)  2008;15(5):924-933.
Objectives:
Modifiable factors predicting the onset of menopause, a transition with important implications for women's health, have not been fully characterized. We evaluated the impact of dietary, lifestyle and reproductive factors on age at natural menopause and reproductive span in Chinese women.
Design:
Study participants were Chinese women aged 40–70 who experienced natural menopause and participated in a population-based, prospective study, the Shanghai Women's Health Study (n=33,054). Dietary intakes at the baseline survey were assessed by food-frequency questionnaire. Regression (β) coefficients, calculated by multivariable linear regression, were used to estimate the effects of dietary, lifestyle, and reproductive patterns on age at menopause and the number of reproductive years, adjusting for potential confounding factors.
Results:
Early menarche, younger age at first-live birth, older age at last live-birth, longer duration of breastfeeding, and higher parity were associated with longer reproductive years (Ptrend<0.01 for all). Higher body-mass index at age 20, mid-life weight gain, and leisure-time physical activity during adolescence and adulthood predicted later menopause and longer reproductive span (Ptrend<0.01 for all). Total intakes of calories, fruits, protein, and possibly carbohydrates were positively associated with later menopause (Ptrend <0.05 for all) and longer reproductive span [Ptrend <0.05, except for carbohydrates (Ptrend =0.06)], and long-term tea consumption predicted longer reproductive span (Ptrend =0.03). Vegetable, fat, soy, and fiber intakes did not significantly affect reproductive span or age at menopause. Smoking was inversely related to both age at menopause and reproductive span (Ptrend <0.01).
Conclusions:
In addition to reproductive factors, intakes of fruit, protein, smoking, and tea consumption, lifetime patterns of physical activity, and weight gain influenced the onset of menopause and/or reproductive span in Chinese women.
doi:10.1097/gme.0b013e3181786adc
PMCID: PMC2615483  PMID: 18600186
Age at onset of menopause; Dietary intake; Physical activity; Reproductive span; Smoking; Tea; Weight gain
20.  Conjectures on some curious connections among social status, calorie restriction, hunger, fatness, and longevity 
Many animal and human studies show counterintuitive effects of environmental influences on energy balance and life span. Relatively low social and/or economic status seems to be associated with and produce greater adiposity, and reduced provision (e.g., caloric restriction) of food produces greater longevity. We suggest that a unifying factor may be perceptions of the environment as “energetically insecure” and inhospitable to reproduction, which may in turn provoke adiposity-increasing and longevity-extending mechanisms. We elaborate on two main aspects of resources (or the perceptions thereof) on body weight and longevity. We first discuss the effects of social dominance on body weight regulation in human and animal models. Second, we examine models of the interactions between caloric restriction, body composition, and longevity. Finally, we put forth a relational model of the influences of differing environmental cues on body composition and longevity.
doi:10.1111/j.1749-6632.2012.06672.x
PMCID: PMC3464393  PMID: 22834696
hunger; fatness; caloric restriction; social status; longevity
21.  Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice 
eLife  2013;2:e01098.
We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.
DOI: http://dx.doi.org/10.7554/eLife.01098.001
eLife digest
There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer.
Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan.
Now, Sun et al. have studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin.
Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. However, Sun et al. found that caloric restriction further increased the lifespans of their GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling.
The results of this study are an important step forward for understanding how growth hormone signaling and caloric restriction regulate aging, both individually and in combination. The GHRH knockout mice are likely to become an important model system for studying these processes and for understanding the complex interactions between diet and hormonal pathways.
DOI: http://dx.doi.org/10.7554/eLife.01098.002
doi:10.7554/eLife.01098
PMCID: PMC3810783  PMID: 24175087
mice; aging; caloric restriction; growth hormone; Mouse
22.  Metformin Supplementation and Life Span in Fischer-344 Rats 
Calorie restriction (CR) has been known for more than 70 years to extend life span and delay disease in rodent models. Metformin administration in rodent disease models has been shown to delay cancer incidence and progression, reduce cardiovascular disease and extend life span. To more directly test the potential of metformin supplementation (300 mg/kg/day) as a CR mimetic, life-span studies were performed in Fischer-344 rats and compared with ad libitum feeding and CR (30%). The CR group had significantly reduced food intake and body weight throughout the study. Body weight was significantly reduced in the metformin group compared with control during the middle of the study, despite similar weekly food intake. Although CR significantly extended early life span (25th quantile), metformin supplementation did not significantly increase life span at any quantile (25th, 50th, 75th, or 90th), overall or maximum life span (p > .05) compared with control.
doi:10.1093/gerona/glq033
PMCID: PMC2854888  PMID: 20304770
Calorie restriction; Metformin; Mimetic; Life span; Aging
23.  Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews 
PLoS Medicine  2013;10(12):e1001578.
Maira Bes-Rastrollo and colleagues examine whether financial conflicts of interest are likely to bias conclusions from systematic reviews that investigate the relationship between sugar-sweetened beverages and weight gain or obesity.
Please see later in the article for the Editors' Summary
Background
Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity.
Methods and Findings
We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest.
We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3–19.3).
An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity.
Conclusions
Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In our daily lives, we frequently rely on the results of scientific research to make decisions about our health. If we are healthy, we may seek out scientific advice about how much exercise to do to reduce our risk of a heart attack, and we may follow dietary advice issued by public health bodies to help us maintain a healthy weight. If we are ill, we expect our treatment to be based on the results of clinical trials and other studies. We assume that the scientific research that underlies our decisions about health-related issues is unbiased and accurate. However, there is increasing evidence that the conclusions of industry-sponsored scientific research are sometimes biased. So, for example, reports of drug trials sponsored by pharmaceutical companies sometimes emphasize the positive results of trials and “hide” unwanted side effects deep within the report or omit them altogether.
Why Was This Study Done?
Although the effects of company sponsors on the conclusions of pharmaceutical research have been extensively examined, little is known about the effects of industry sponsorship on nutrition research, even though large commercial entities are increasingly involved in global food and drink production. It is important to know whether the scientific evidence about nutrition is free of bias because biased information might negatively affect the health of entire populations. Moreover, scientific evidence from nutrition research underlies the formulation of governmental dietary guidelines and food-related public health interventions. In this systematic review, the researchers investigate whether the disclosure of potential financial conflicts of interest (for example, research funding by a beverage company) has influenced the results of systematic reviews undertaken to examine the association between the consumption of highly lucrative sugar-sweetened beverages (SSBs) and weight gain or obesity. Systematic reviews identify all the research on a given topic using predefined criteria. In an ideal world, systematic reviews provide access to all the available evidence on specific exposure–disease associations, but publication bias related to authors' conflicts of interest may affect the reliability of the conclusions of such studies.
What Did the Researchers Do and Find?
The researchers identified 18 conclusions from 17 systematic reviews that had investigated the association between SSB consumption and weight gain or obesity. In six of these reviews, a financial conflict of interest with a food industry was disclosed. Among the reviews that reported having no conflict of interest, 83.3% of the conclusions were that SSB consumption could be a potential risk factor for weight gain. By contrast, the same percentage of reviews in which a potential financial conflict of interest was disclosed concluded that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain, or reported contradictory results and did not state any definitive conclusion about the association between SSB consumption and weight gain. Reviews in which a potential conflict of interest was disclosed were five times more likely to present a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no financial conflict of interest.
What Do These Findings Mean?
These findings indicate that systematic reviews that reported financial conflicts of interest or sponsorship from food or drink companies were more likely to reach a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no conflicts of interest. A major limitation of this study is that it cannot assess which interpretation of the available evidence is truly accurate. For example, the scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings. However, the interests of the food industry (increased sales of their products) are very different from those of most researchers (the honest pursuit of knowledge), and recent randomized trials support a positive association between SSB consumption and overweight/obesity. Thus, these findings draw attention to possible inaccuracies in scientific evidence from research funded by the food and drink industry. They do not imply that industry sponsorship of nutrition research should be avoided entirely. Rather, as in other research areas, clear guidelines and principles (for example, sponsors should sign contracts that state that they will not be involved in the interpretation of results) need to be established to avoid dangerous conflicts of interest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001578.
The Research Ethics Program at the University of California, San Diego provides an overview of conflicts of interest for researchers and details of US regulations and guidelines
The PLOS Medicine series on Big Food examines the activities and influence of the food industry in global health
A PLOS Medicine Research Article by Basu et al. uses mathematical modeling to investigate whether SSB taxation would avert obesity and diabetes in India
A 2012 policy brief from the Yale Rudd Center for Food Policy and Obesity discusses current evidence regarding SSB taxes
The US National Institutes of Health has regulations on financial conflicts of interest for institutions applying to receive funding
Wikipedia has pages on conflict of interest, reporting bias, systematic review, and SSBs (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001578
PMCID: PMC3876974  PMID: 24391479
24.  Mitochondrial function as a determinant of life span 
Pflugers Archiv   2009;459(2):277-289.
Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.
doi:10.1007/s00424-009-0724-5
PMCID: PMC2801852  PMID: 19756719
Mitochondria; Obesity; Aging; Cellular response; Cell death
25.  Studies of aging in ames dwarf mice: Effects of caloric restriction 
Ames dwarf mice, which are small and deficient in growth homone (GH), prolactin (PRL), and thyroid stimulating hormone (TSH) live much longer (1–1.25 years) than their normal siblings. It was of interest to examine the response of these animals to caloric restriction (CR) because of the possibility that dwarf mice are voluntarily caloric restricted. We are testing the hypothesis that this possible natural caloric restriction will negate any benefits of an imposed CR on lifespan.
Male and female Ames dwarf mice and their normal counterparts have been fed ad libitum (AL) or a 30% CR diet for 25–29 months. Animals were monitored daily and weighed weekly. At 12–15 months of age, CR mice weighed significantly less than their AL fed counterparts (normal females: −42%, normal males: −23%, dwarf females: −18.8%, and dwarf males: −22.2%). Only in dwarf females has this significant difference disappeared with age. At one year of age, a comparison of daily food consumption revealed that female dwarf mice consume significantly more food per gram body weight than normal females and a similar tendency is evident for males. Although they received 30% less food, CR mice ate the same amount as AL mice per gram body weight.
On measures of total locomotor activity, CR mice were significantly more active than their AL-fed counterparts. On an inhibitory avoidance learning task, 18–21 month old dwarf mice exhibited significantly better retention than their age-and diet-matched normal counterparts. Histopathological analysis in aging dwarf versus normal mice suggested that the incidence of tumors does not differ between the two groups but tumors appear to develop later in dwarf than in normal mice.
After 2.25 years on the study 27% of AL normals, 52% of CR normals, 74% of AL dwarfs, and 87% of CR dwarfs are still alive. We conclude that Ames dwarfs are not CR mimetics although they share many characteristics. It remains to be determined whether CR will delay aging and cause a further life extension in Ames dwarf mice.
doi:10.1007/s11357-000-0002-0
PMCID: PMC3455356  PMID: 23604794

Results 1-25 (1310640)