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1.  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
2.  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
3.  The Effects of Aging and Genotype on NMDA Receptor Expression in Growth Hormone Receptor Knockout (GHRKO) Mice 
Caloric restriction enhances N-methyl-D-aspartate (NMDA) receptor binding and upregulates messenger RNA expression of the GluN1 subunit during aging. Old growth hormone receptor knockout mice resemble old calorically restricted rodents in enhanced life span and brain function, as compared with aged controls. This study examined whether aged growth hormone receptor knockout mice also show enhanced expression of NMDA receptors. Six or 23- to 24-month-old male normal-sized control or dwarf growth hormone receptor knockout mice were assayed for NMDA-displaceable [3H]glutamate binding (autoradiography) and GluN1 subunit messenger RNA (in situ hybridization). There was slight sparing of NMDA receptor binding densities within aged medial prefrontal and motor cortices, similar to caloric restriction, but there were greater age-related declines in GluN1 messenger RNA in growth hormone receptor knockout versus control mice. These results suggest that some of the functional improvements in aged mice with altered growth hormone signaling may be due to enhancement of NMDA receptors, but not through the upregulation of messenger RNA for the GluN1 subunit.
doi:10.1093/gerona/glr024
PMCID: PMC3110907  PMID: 21459761
NMDA; GluN1; Laron mice; Prefrontal cortex; Hippocampus
4.  Aging, Neurogenesis, and Caloric Restriction in Different Model Organisms 
Aging and Disease  2013;4(4):221-232.
Brain aging is a multifactorial process that is occurring across multiple cognitive domains. A significant complaint that occurs in the elderly is a decrement in learning and memory ability. Both rodents and zebrafish exhibit a similar problem with memory during aging. The neurobiological changes that underlie this cognitive decline are complex and undoubtedly influenced by many factors. Alterations in the birth of new neurons and neuron turnover may contribute to age-related cognitive problems. Caloric restriction is the only non-genetic intervention that reliably increases life span and healthspan across multiple organisms although the molecular mechanisms are not well-understood. Recently the zebrafish has become a popular model organism for understanding the neurobiological consequences but to date very little work has been performed. Similarly, few studies have examined the effects of dietary restriction in zebrafish. Here we review the literature related to memory decline, neurogenesis, and caloric restriction across model organisms and suggest that zebrafish has the potential to be an important animal model for understanding the complex interactions between age, neurobiological changes in the brain, and dietary regimens or their mimetics as interventions.
PMCID: PMC3733585  PMID: 23936746
Dietary Restriction; Age; Zebrafish; Neuron Turnover; Synapses
5.  Beverage Consumption Patterns of a Low-Income Population 
Topics in clinical nutrition  2010;25(3):191-201.
High-energy-dense foods provide an inexpensive source of calories. Healthy Aging in Neighborhoods of Diversity across the Life Span study participants (n = 1987), low- to low-middle-income, urban African American and white adults, consumed between 17% and 20% of their daily energy intake from beverages. Of all beverages consumed, calorically sweetened beverages ranked second among African Americans and third among whites. Calorically-sweetened beverage consumption was not influenced by weight status. Increasing awareness of risks for adverse health outcomes associated with selected beverages may improve dietary choices.
PMCID: PMC2957908  PMID: 20976036
energy intake; obesity
6.  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
7.  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
8.  Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice 
Aging (Albany NY)  2010;2(12):945-958.
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. The chronic treatment of inbred 129/Sv mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but failed to influence the dynamics of body weight, decreased by 13.4% the mean life span of male mice and slightly increased the mean life span of female mice (by 4.4%). The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice, decreased by 3.5 times the incidence of malignant neoplasms in female mice while somewhat stimulated formation of benign vascular tumors in the latter.
PMCID: PMC3034183  PMID: 21164223
metformin; biomarkers of aging; life extension; carcinogenesis; mice
9.  Mitochondrial Longevity Pathways 
Biochimica et biophysica acta  2011;1813(4):634-644.
Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is also positively implicated in cellular stress defense mechanisms, and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age related decline in mitochondrial function and their impact on longevity.
doi:10.1016/j.bbamcr.2011.01.029
PMCID: PMC3071741  PMID: 21295080
Mitochondria; longevity; lifespan; ROS; oxidative damage; caloric restriction
10.  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
11.  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
12.  Effects of fructose-containing caloric sweeteners on resting energy expenditure and energy efficiency: a review of human trials 
Epidemiological studies indicate that the consumption of fructose-containing caloric sweeteners (FCCS: mainly sucrose and high-fructose corn syrup) is associated with obesity. The hypothesis that FCCS plays a causal role in the development of obesity however implies that they would impair energy balance to a larger extent than other nutrients, either by increasing food intake, or by decreasing energy expenditure. We therefore reviewed the literature comparing a) diet-induced thermogenesis (DIT) after ingestion of isocaloric FCCS vs glucose meals, and b) basal metabolic rate (BMR) or c) post-prandial energy expenditure after consuming a high FCCS diet for > 3 days vs basal,weight-maintenance low FCCS diet. Nine studies compared the effects of single isocaloric FCCS and glucose meals on DIT; of them, six studies reported that DIT was significantly higher with FCCS than with glucose, 2 reported a non-significant increase with FCCS, and one reported no difference. The higher DIT with fructose than glucose can be explained by the low energy efficiency associated with fructose metabolism. Five studies compared BMR after consumption of a high FCCS vs a low FCCS diet for > 3 days. Four studies reported no change after 4–7 day on a high FCCS diet, and only one study reported a 7% decrease after 12 week on a high FCCS diet. Three studies compared post-prandial EE after consumption of a high FCCS vs a low FCCS diet for > 3 days, and did not report any significant difference. One study compared 24-EE in subjects fed a weight-maintenance diet and hypercaloric diets with 50% excess energy as fructose, sucrose and glucose during 4 days: 24-EE was increased with all 3 hypercaloric diets, but there was no difference between fructose, sucrose and glucose. We conclude that fructose has lower energy efficiency than glucose. Based on available studies, there is presently no hint that dietary FCCS may decrease EE. Larger, well controlled studies are however needed to assess the longer term effects of FCCS on EE.
doi:10.1186/1743-7075-10-54
PMCID: PMC3751443  PMID: 23941499
Fructose; Sucrose; Energy expenditure; Thermogenesis; Basal metabolic rate; Energy efficiency; De novo lipogenesis; Gluconeogenesis; Human
13.  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
14.  Calories Do Not Explain Extension of Life Span by Dietary Restriction in Drosophila 
PLoS Biology  2005;3(7):e223.
Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.
Experimental evidence reveals that specific nutritional components, rather than reducing calorie intake per se, are responsible for extending lifespan via dietary restriction in Drosophila melanogaster.
doi:10.1371/journal.pbio.0030223
PMCID: PMC1140680  PMID: 16000018
15.  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
16.  Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age. 
Nucleic Acids Research  1997;25(5):974-982.
Mitochondrial DNA (mtDNA) rearrangements have been shown to accumulate with age in the post-mitotic tissues of a variety of animals and have been hypothesized to result in the age-related decline of mitochondrial bioenergetics leading to tissue and organ failure. Caloric restriction in rodents has been shown to extend life span supporting an association between bioenergetics and senescence. In the present study, we use full length mtDNA amplification by long-extension polymerase chain reaction (LX-PCR) to demonstrate that mice accumulate a wide variety of mtDNA rearrangements with age in post mitotic tissues. Similarly, using an alternative PCR strategy, we have found that 2-4 kb minicircles containing the origin of heavy-strand replication accumulate with age in heart but not brain. Analysis of mtDNA structure and conformation by Southern blots of unrestricted DNA resolved by field inversion gel electrophoresis have revealed that the brain mtDNAs of young animals contain the traditional linear, nicked, and supercoiled mtDNAs while old animals accumulate substantial levels of a slower migrating species we designate age-specific mtDNAs. In old caloric restricted animals, a wide variety of rearranged mtDNAs can be detected by LX-PCR in post mitotic tissues, but Southern blots of unrestricted DNA reveals a marked reduction in the levels of the age- specific mtDNA species. These observations confirm that mtDNA mutations accumulate with age in mice and suggest that caloric restriction impedes this progress.
PMCID: PMC146531  PMID: 9023106
17.  Effects of caloric restriction are species-specific 
Biogerontology  2006;7(3):157-160.
This article addresses two questions: (1) ‘can caloric restriction (CR) extend the life spans of all species of experimental animals’, and (2) ‘is CR likely to slow the human aging process and/or extend the human life span?’ The answer to the first question is clearly ‘no’, because CR decreases the life span of the housefly, Musca domestica, and fails to extend the life span of at least one mouse strain. The answer to the second question is unknown, because human CR has not yet been shown either to increase or curtail the human life span. However, recent efforts to develop insect models of CR have been unsuccessful and/or relatively uninformative, so any insights regarding the relationship between CR and human aging are more likely to arise from studies of established, mammalian models of CR.
doi:10.1007/s10522-006-9004-3
PMCID: PMC2835574  PMID: 16628489
Caloric restriction; Aging; Life span; Insect; Drosophila
18.  Counting Calories in Drosophila Diet Restriction 
Experimental gerontology  2006;42(3):247-251.
The extension of life span by diet restriction in Drosophila has been argued to occur without limiting calories. Here we directly measure the calories assimilated by flies when maintained on full- and restricted-diets. We find that caloric intake is reduced on all diets that extend life span. Flies on low-yeast diet are long-lived and consume about half the calories of flies on high yeast diets, regardless of the energetic content of the diet itself. Since caloric intake correlates with yeast concentration and thus with the intake of every metabolite in this dietary component, it is premature to conclude for Drosophila that calories do not explain extension of life span.
doi:10.1016/j.exger.2006.10.009
PMCID: PMC2606145  PMID: 17125951
diet restriction; calorie restriction; nutrition; aging; life span; Drosophila
19.  Effects of age and caloric restriction on mitochondrial protein oxidative damage in mice 
The hypothesis that life span extension by caloric restriction (CR) is contingent upon the attenuation of macromolecular oxidative damage was tested in two different strains of mice: the C57BL/6, whose life span is extended by CR, and the DBA/2, in which CR has relatively minor or no impact on longevity. Mice were fed ad libitum (AL) or restricted to 40% lesser food, starting at 4 months of age. Protein damage was measured as protein-linked adducts of 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) in skeletal muscle mitochondria at 6- and 23-months of age. Protein-HNE and -MDA content increased with age in C57BL/6 mice and CR significantly attenuated these augmentations. Metalloprotease 1, NADP-dependent mitochondrial malic enzyme (isoform 2) and citrate synthase were identified by mass spectroscopy to contain HNE/MDA adducts. DBA/2 mice exhibited little effect of age or CR on protein HNE/MDA content in skeletal muscle mitochondria. In contrast, protein-HNE levels in liver mitochondria showed a significant increase with age in AL-fed mice of both strains, and CR caused significant attenuation of this damage. Overall, results indicated that the age-related increase in protein oxidative damage and its abatement by CR are genotype- and tissue- specific, and not a universal phenomenon.
doi:10.1016/j.mad.2011.12.001
PMCID: PMC3268905  PMID: 22182424
HNE-protein conjugates; oxidative stress; protein oxidative damage; mitochondrial proteins; food restriction
20.  Metformin for aging and cancer prevention 
Aging (Albany NY)  2010;2(11):760-774.
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effect of caloric restriction is due to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both life span extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore metformin seems to decrease cancer risk in diabetic patients.
PMCID: PMC3006019  PMID: 21084729
metformin; biguanides; life span, aging; cancer prevention
21.  Could High Levels of Tissue Polypeptide Specific Antigen, a Marker of Apoptosis Detected in Nonalcoholic Steatohepatitis, Improve after Weight Loss? 
Disease markers  2009;26(2):55-63.
Background: Tissue Polypeptide Specific antigen has recently been proposed as diagnostic marker of apoptosis in NonAlcoholic SteatoHepatitis.
The aim of this study was to validate in patients suffering from NonAlcoholic SteatoHepatitis the clinical utility of this marker after different programs of weight reduction.
Methods: Overweight/obese patients with visceral adiposity and liver histology compatible were assigned to a Calorically-Restricted diet (n = 22), a Calorically-Restricted diet plus EXercise (n = 19) or No Healthy Life Style (control group, n = 21) for six months. The presence of Body-Weight loss was assessed by a Body Mass Index decrease of at least three points. Serum ALanine aminoTransferase, HOmeostasis Model Assessment method value and Tissue Polypeptide Specific antigen concentrations were determined at time 0, after 3 and 6 months in both the Intervention groups and in the controls’ one.
Results: In NonAlcoholic SteatoHepatitis patients who obtained Body-Weight reduction, a significant decrease of the serum Tissue Polypeptide Specific antigen values was showed with a clear linear trend across time, P = 0.0001.
Decrement of Tissue Polypeptide Specific antigen concentrations best differentiated the Body-Weight loss from the body-weight maintenance in respect to Tissue Polypeptide Specific antigen and HOmeostasis Model Assessment method values.
Conclusion: This study support the clinical utility of serum Tissue Polypeptide Specific antigen antigen levels in the follow-up of overweight/obese patients with NonAlcoholic SteatoHepatitis on weight reduction programs.
doi:10.3233/DMA-2009-0607
PMCID: PMC3833701  PMID: 19407360
TPS; NASH; Body-Weight loss
22.  THE DIHYDROLIPOAMIDE ACETYLTRANSFERASE IS A NOVEL METABOLIC LONGEVITY FACTOR AND IS REQUIRED FOR CALORIE RESTRICTION MEDIATED LIFE SPAN EXTENSION 
The Journal of biological chemistry  2007;282(9):6161-6171.
Calorie restriction (CR) extends life span in a wide variety of species. Recent studies suggest that an increase in mitochondrial metabolism mediates CR induced life span extension. Here we present evidence that Lat1 (dihydrolipoamide acetyltransferase), the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC), is a novel metabolic longevity factor in the CR pathway. Deleting the LAT1 gene abolishes life span extension induced by CR. Over-expressing Lat1 extends life span and this life span extension is not further increased by CR. Similar to CR, life span extension by Lat1 over-expression largely requires mitochondrial respiration indicating mitochondrial metabolism plays an important role in CR. Interestingly, Lat1 over-expression does not require the Sir2 family to extend life span, suggesting Lat1 mediates a branch of the CR pathway that functions in parallel to the Sir2 family. Lat1 is also a limiting longevity factor in non-dividing cells in that over expressing Lat1 extends cell survival during prolonged culture at stationary phase. Our studies suggest that Lat1 over-expression extends life span by increasing metabolic fitness of the cell. CR may therefore also extend life span and ameliorate age-associated diseases by increasing metabolic fitness through regulating central metabolic enzymes.
doi:10.1074/jbc.M607661200
PMCID: PMC2440684  PMID: 17200108
23.  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
24.  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
25.  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

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