热量限制与心血管老化的研究进展

热量限制(caloric restriction,CR)是指在不减少必需营养素摄入的情况下减少20%～40%的热量摄入. CR可通过由各种分子介导的氧化应激、炎症、程序性死亡、端粒体等机制,通过调节人及其他动物心血管老化的危险因素,进而减缓生理和病理状态下心血管老化进程.本文通过对CR与心血管老化研究进展的系统阐述,探寻人类预防心血管老化的解决之道.     

Is Sirt1 a miracle bullet for longevity?

The Sir2 (silent information regulator 2) family of nicotinamide adenine dinucleotide-dependent deacetylases has been implicated in the regulation of aging and longevity across a wide variety of organisms. Although controversial, Sir2 proteins have also been implicated as key mediators for the beneficial effects of caloric restriction (CR) on aging and longevity. In this issue, Bordone et al . report that transgenic mice in which the mammalian Sir2 ortholog Sirt1 is overexpressed mimic the physiological changes in response to CR. These findings have important implications for the development of CR mimetics and perhaps also for lifespan extension.     

The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women

Lifespan in rodents is prolonged by caloric restriction (CR) and by mutations affecting the somatotropic axis. It is not known if CR can alter the age‐associated decline in growth hormone (GH), insulin‐like growth factor (IGF)‐1 and GH secretion. To evaluate the effect of CR on GH secretory dynamics; forty‐three young (36.8 ± 1.0 years), overweight (BMI 27.8 ± 0.7) men (n = 20) and women (n = 23) were randomized into four groups; control = 100% of energy requirements; CR = 25% caloric restriction; CR + EX = 12.5% CR + 12.5% increase in energy expenditure by structured exercise; LCD = low calorie diet until 15% weight reduction followed by weight maintenance. At baseline and after 6 months, body composition (DXA), abdominal visceral fat (CT) 11 h GH secretion (blood sampling every 10 min for 11 h; 21:00–08:00 hours) and deconvolution analysis were measured. After 6 months, weight (control: ?1 ± 1%, CR: ?10 ± 1%, CR + EX: ?10 ± 1%, LCD: ?14 ± 1%), fat mass (control: ?2 ± 3%, CR: ?24 ± 3%, CR + EX: ?25 ± 3%, LCD: ?31 ± 2%) and visceral fat (control: ?2 ± 4%, CR: ?28 ± 4%, CR + EX: ?27 ± 3%, LCD: ?36 ± 2%) were significantly (P < 0.001) reduced in the three intervention groups compared to control. Mean 11 h GH concentrations were not changed in CR or control but increased in CR + EX (P < 0.0001) and LCD (P < 0.0001) because of increased secretory burst mass (CR + EX: 34 ± 13%, LCD: 27 ± 22%, P < 0.05) and amplitude (CR + EX: 34 ± 14%, LCD: 30 ± 20%, P < 0.05) but not to changes in secretory burst frequency or GH half‐life. Fasting ghrelin was significantly increased from baseline in all three intervention groups; however, total IGF‐1 concentrations were increased only in CR + EX (10 ± 7%, P < 0.05) and LCD (19 ± 4%, P < 0.001). A 25% CR diet for 6 months does not change GH, GH secretion or IGF‐1 in nonobese men and women.     

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

There is a connection between nutrient inputs, energy-sensing pathways, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as an energy sensor in regulating lifespan and mediating caloric restriction. These genes possess significant expression variation in natural populations, and our experimental genotypes span this level of natural activity variation. Our studies link the readout of energy state with the perturbation of the genes of central metabolism and demonstrate their effect on lifespan.     

Does caloric restriction extend life in wild mice?

To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.     

Modulation of white adipose tissue proteome by aging and calorie restriction

Aging is associated with an accrual of body fat, progressive development of insulin resistance and other obesity comorbidities that contribute to decrease life span. Caloric restriction (CR), which primarily affects energy stores in adipose tissue, is known to extend life span and retard the aging process in animal models. In this study, a proteomic approach combining 2‐DE and MS was used to identify proteins modulated by aging and CR in rat white adipose tissue proteome. Proteomic analysis revealed 133 differentially expressed spots, 57 of which were unambiguously identified by MS. Although CR opposed part of the age‐associated protein expression patterns, many effects of CR were on proteins unaltered by age, suggesting that the effects of CR on adipose tissue are only weakly related to those of aging. Particularly, CR and aging altered glucose, intermediate and lipid metabolism, with CR enhancing the expression of enzymes involved in oxalacetate and NADPH production, lipid biosynthesis and lipolysis. Consistently, insulin‐β and β3‐adrenergic receptors were also increased by CR, which denotes improved sensitivity to lipogenic/lipolytic stimuli. Other beneficial outcomes of CR were an improvement in oxidative stress, preventing the age‐associated decrease in several antioxidant enzymes. Proteins involved in cytoskeleton, iron storage, energy metabolism and several proteins with novel or unknown functions in adipose tissue were also modulated by age and/or CR. Such orchestrated changes in expression of multiple proteins provide insights into the mechanism underlying CR effects, ultimately allowing the discovery of new markers of aging and targets for the development of CR‐mimetics.     

Dietary restriction and aging, 2009

Dietary restriction (DR) is a robust nongenetic, nonpharmacological intervention that is known to increase active and healthy lifespan in a variety of species. Despite a variety of differences in the protocols and the way DR is carried out in different species, conserved relationships are emerging among multiple species. 2009 saw the field of DR mature with important mechanistic insights from multiple species. A report of lifespan extension in rapamycin‐treated mice suggested that the TOR pathway, a conserved mediator of DR in invertebrates, may also be critical to DR effects in mammals. 2009 also saw exciting discoveries related to DR in various organisms including yeast, worms, flies, mice, monkeys and humans. These studies complement each other and together aim to deliver the promise of postponing aging and age‐related diseases by revealing the underlying mechanisms of the protective effects of DR. Here, we summarize a few of the reports published in 2009 that we believe provide novel directions and an improved understanding of dietary restriction.