Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue‐specific regulation of glycine N‐methyltransferase (Gnmt), and that this regulation is required for full IIS‐mediated longevity. Furthermore, fat body‐specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmt‐dependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver‐specific IRS1 KO mice and is thus an evolutionarily conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue‐specific modulators of IIS‐mediated longevity may aid in developing future therapeutic treatments to ameliorate aging and prevent disease.     

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension,renoprotection, and muscle weakness in aged mice

Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H₂S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H₂S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.     

Dietary methionine requirement of pre‐adult blunt snout bream, (Megalobrama amblycephala Yih, 1955)

A nine‐week feeding trial was conducted to test the hypothesis that an adequate methionine diet might improve growth, feed utilization, body composition and physiology, and biochemical parameters in pre‐adult blunt snout bream Megalobrama amblycephala, whereas a methionine deficiency might have adverse effects on these parameters. Six isonitrogenous and isoenergetics semi‐purified diets (33.0% crude protein, 7.0% crude lipid) were formulated to contain graded methionine levels (0.39–1.54% of dry weight) at 0.25% increments replaced by equal proportions of glycine. Results show that the survival rate (SR) was not significantly affected by the dietary methionine level. Final weight (FW), feed efficiency ratios (FER), weight gain (WG), and specific growth rate (SGR) increased with increasing dietary methionine levels up to 1.00% and then showed a declining trend. Using quadratic regression analysis of FER and SGR, the dietary methionine requirement was estimated to be 0.74% (2.24% of dietary protein) and 0.76% of the diet (2.30% of dietary protein), respectively. Fish fed the 0.39% methionine diet showed significantly lower whole body protein content compared to those fed with 0.85, 1.00 and 1.24% methionine diets (P < 0.05). Whole body moisture, lipid, and ash contents in pre‐adult adult blunt snout bream were not significantly affected. The urea content in fish fed the 0.85% methionine diet was significantly higher than those of fish fed a 0.39, 0.56, 1.24, 1.54% methionine diet (P < 0.05), but not significantly different in fish fed the 1.00% methionine diet (P > 0.05). No significant differences were found in other indexes such as the hepatosomatic index (HSI), viscerosomatic index (VSI), condition factor (CF), albumin (ALB), total protein (TP), alanine aminotransferase (ALT), and spartate transaminase (AST) (P > 0.05). Most important, the optimal dietary methionine level of pre‐adult blunt snout bream should be 0.74–0.76% of the diet (2.24–2.30% of dietary protein).     

Acarbose, 17‐α‐estradiol,and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Four agents — acarbose (ACA), 17‐α‐estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB) — were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8–10% at three different doses, with P‐values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late‐life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.     

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S‐adenosylmethionine, which, after transferring its methyl group, is converted to S‐adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.     

Dietary glycine protects from chemotherapy-induced hepatotoxicity

Hepatotoxic side effects of neoadjuvant chemotherapy for colorectal liver metastases increase perioperative morbidity and mortality. Glycine protects liver from injury in various animal models. Thus, this study was designed to assess its effect on liver after chemotherapy. Sprague–Dawley rats (200–220 g) were fed a synthetic diet containing 5% glycine for 5 days. Subsequently, chemotherapy (FOLFIRI: irinotecan, folinic acid and fluorouracil, or FOLFOX: oxaliplatin, folinic acid and fluorouracil) was administered at standard doses. Transaminases, histology, immunohistochemistry and in vivo microscopy were used to index liver injury, to monitor intrahepatic microperfusion and activation of Kupffer cells. Glycine significantly decreased transaminases after chemotherapy to 25–50% of control values (p < 0.05). Microvesicular steatosis was significantly reduced from 18.5 ± 3.4 and 57.1 ± 8.6% in controls to 9.5 ± 1.8 and 37.7 ± 4.4% after FOLFIRI and FOLFOX, respectively. Furthermore, phagocytosis of latex beads was reduced by about 50%, while leukocyte adherence in central and midzonal subacinar zones decreased to 60–80% after glycine (p < 0.05). Glycine significantly reduced expression of inducible nitric oxide synthase after chemotherapy, while hepatic microcirculation was increased (p < 0.05). This study shows for the first time that glycine reduces chemotherapy-induced liver injury. The underlying mechanisms most likely include Kupffer cells and an improved intrahepatic microperfusion.     

The effects of dietary methionine and glycine on lead toxicity in choline-deficient chicks

A 2×2×2 factorial experiment was conducted to study the effects of dietary methionine, glycine, and lead (Pb) in cholinedeficient chicks. The variables were: adequate or deficient methionine; adequate or excess glycine; and 0 or 1000 ppm lead (as Pb acetate 3H₂O). Methionine stimulated growth when added to the methionine-deficient diets, but the response was greater when supplemental glycine was present. Addition of glycine to the glycine-adequate diets stimulated growth in the presence of adequate but not deficient methionine. The patterns of response to methionine were the same at both 0 and 1000 ppm dietary Pb. Added Pb depressed growth with all diets, but the depression was greater in methionine-deficient than in methionine-adequate diets. Hepatic nonprotein sulfhydryl (NPSH) and glutathione (GSH) concentrations were increased by both supplemental methionine and lead, and the effects were additive. Glycine levels did not significantly alter NPSH and GSH concentrations. Both methionine and glycine lowered Pb concentrations in kidney, and the effects were additive. The results are consistent with previous observations that added methionine ameliorates Pb-induced growth depression with choline-adequate diets, however, this effect is not as pronounced with choline-deficient diets. The results suggest (1) that glycine is limiting for growth in choline-deficient, methionine-adequate diets, and (2) that methionine and glycine may enhance Pb detoxification by different mechanisms.

Paper No. 10213 of the Journal Series of the NC Agricultural Research Service, Raleigh, NC 27695-7601. The use of trade names implies neither endorsement of the product named nor criticism of similar products not mentioned by the NCARS.     

Inducible knockdown of pregnancy‐associated plasma protein‐A gene expression in adult female mice extends life span

Pregnancy‐associated plasma protein‐A (PAPP‐A) knockout (KO) mice, generated through homologous recombination in embryonic stem cells, have a significantly increased lifespan compared to wild‐type littermates. However, it is unknown whether this longevity advantage would pertain to PAPP‐A gene deletion in adult animals. In the present study, we used tamoxifen (Tam)‐inducible Cre recombinase‐mediated excision of the floxed PAPP‐A (fPAPP‐A) gene in mice at 5 months of age. fPAPP‐A mice, which were either positive (pos) or negative (neg) for Tam‐Cre, received Tam treatment with quarterly boosters. Only female mice could be used with this experimental design. fPAPP‐A/neg and fPAPP‐A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain. We found that fPAPP‐A/pos mice had a significant extension of life span (P = 0.005). The median life span was increased by 21% for fPAPP‐A/pos compared to fPAPP‐A/neg mice. Analysis of mortality in life span quartiles indicated that the proportion of deaths of fPAPP‐A/pos mice were lower than fPAPP‐A/neg mice at young adult ages (P = 0.002 for 601–800 days) and higher than fPAPP‐A/neg mice at older ages (P = 0.004 for >1000 days). Thus, survival curves and age‐specific mortality indicate that female mice with knockdown of PAPP‐A gene expression as adults have an extended healthy life span.     

Influence of Dietary Conjugated Linoleic Acid and Fat Source on Body Fat and Apoptosis in Mice*

Objective: To determine whether altered dietary essential fatty acid (linoleic and arachidonic acid) concentrations alter sensitivity to conjugated linoleic acid (CLA)‐induced body fat loss or DNA fragmentation. Research Methods and Procedures: Mice were fed diets containing soy oil (control), coconut oil [essential fatty acid deficient (EFAD)], or fish oil (FO) for 42 days, and then diets were supplemented with a mixture of CLA isomers (0.5% of the diet) for 14 days. Body fat index, fat pad and liver weights, DNA fragmentation in adipose tissue, and fatty acid profiles of adipose tissue were determined. Results: The EFAD diet decreased (p < 0.05) linoleic and arachidonic acid in mouse adipose tissue but did not affect body fat. Dietary CLA caused a reduction (p < 0.05) in body fat. Mice fed the EFAD diet and then supplemented with CLA exhibited a greater reduction (p < 0.001) in body fat (20.21% vs. 6.94% in EFAD and EFAD + CLA‐fed mice, respectively) compared with mice fed soy oil. Dietary FO decreased linoleic acid and increased arachidonic acid in mouse adipose tissue. Mice fed FO or CLA were leaner (p < 0.05) than control mice. FO + CLA‐fed mice did not differ in body fat compared with FO‐fed mice. Adipose tissue apoptosis was increased (p < 0.001) in CLA‐supplemented mice and was not affected by fat source. Discussion: Reductions in linoleic acid concentration made mice more sensitive to CLA‐induced body fat loss only when arachidonic acid concentrations were also reduced. Dietary essential fatty acids did not affect CLA‐induced DNA fragmentation.     

Common genetic variants of the β2‐adrenergic receptor affect its translational efficiency and are associated with human longevity

β‐adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of β‐adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the β‐adrenergic signaling pathway are associated with human longevity. We performed a 10‐year follow‐up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long‐lived and 1028 geography‐matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r² = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni‐corrected P‐values in a combined analysis were 0.00053–0.010. Men with haplotype A‐C showed an increased probability to become centenarians (the frequency of A‐C in long‐lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17–1.88, P = 0.0007), in contrast to those with haplotype C‐G (the frequency of C‐G in long‐lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51–0.78, P = 0.000018). The permuted P‐values were 0.00005 and 0.0009, respectively. ADRB2 encodes the β2‐adrenergic receptor; the haplotype A‐C markedly reduced its translational efficiency compared with C‐G (P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of β2‐adrenergic receptors caused by genetic variants is inversely associated with human lifespan.     

Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma

Primary open‐angle glaucoma (POAG) is one of the most common causes for blindness worldwide. Although an elevated intraocular pressure (IOP) is the main risk factor, the exact pathology remained indistinguishable. Therefore, it is necessary to have appropriate models to investigate these mechanisms. Here, we analysed a transgenic glaucoma mouse model (βB1‐CTGF) to elucidate new possible mechanisms of the disease. Therefore, IOP was measured in βB1‐CTGF and wildtype mice at 5, 10 and 15 weeks of age. At 5 and 10 weeks, the IOP in both groups were comparable (P > 0.05). After 15 weeks, a significant elevated IOP was measured in βB1‐CTGF mice (P < 0.001). At 15 weeks, electroretinogram measurements were performed and both the a‐ and b‐wave amplitudes were significantly decreased in βB1‐CTGF retinae (both P < 0.01). Significantly fewer Brn‐3a⁺ retinal ganglion cells (RGCs) were observed in the βB1‐CTGF group on flatmounts (P = 0.02), cross‐sections (P < 0.001) and also via quantitative real‐time PCR (P = 0.02). Additionally, significantly more cleaved caspase 3⁺ RGCs were seen in the βB1‐CTGF group (P = 0.002). Furthermore, a decrease in recoverin⁺ cells was observable in the βB1‐CTGF animals (P = 0.004). Accordingly, a significant down‐regulation of Recoverin mRNA levels were noted (P < 0.001). Gfap expression, on the other hand, was higher in βB1‐CTGF retinae (P = 0.023). Additionally, more glutamine synthetase signal was noted (P = 0.04). Although no alterations were observed regarding photoreceptors via immunohistology, a significant decrease of Rhodopsin (P = 0.003) and Opsin mRNA (P = 0.03) was noted. We therefore assume that the βB1‐CTGF mouse could serve as an excellent model for better understanding the pathomechanisms in POAG.     

Knockout of receptor for advanced glycation end‐products attenuates age‐related renal lesions

Pro‐aging effects of endogenous advanced glycation end‐products (AGEs) have been reported, and there is increasing interest in the pro‐inflammatory and ‐fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill‐defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML‐enriched diet on renal aging. Two‐month‐old male, wild‐type (WT) and RAGE^?/? C57Bl/6 mice were fed a control or a CML‐enriched diet (200 μg CML/g_food) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE^?/? mice, with a predominantly tubular localization. The CML‐rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE^?/? mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A‐II (ApoA‐II) amyloidosis (p < 0.001). A positive linear correlation between sclerosis score and ApoA‐II amyloidosis score (r = 0.92) was observed. Compared with old WT mice, old RAGE^?/? mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE^?/? mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE^?/? mice, suggesting RAGE is an important receptor in so‐called inflamm‐aging.     

CpG‐related SNPs in the MS4A region have a dose‐dependent effect on risk of late–onset Alzheimer disease

CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome‐wide association study using a sliding‐window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome‐wide significant (p < 5 × 10^?8) associations were identified with 171 1.0 kb‐length windows spanning 932 kb in the APOE region (top p < 2.2 × 10^?308), five windows at BIN1 (top p = 1.3 × 10^?13), two windows at MS4A6A (top p = 2.7 × 10^?10), two windows near MS4A4A (top p = 6.4 × 10^?10), and one window at PICALM (p = 6.3 × 10^‐9). The total number of CGS‐derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10^?10), brain DNA methylation (p = 2.15 × 10^?10), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10^?4). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage‐derived genetic score to predict AD risk.     

Dietary inclusion of mealworm (Tenebrio molitor) meal as an alternative protein source in practical diets for juvenile rockfish (Sebastes schlegeli)

An 8‐week feeding trial was designed to evaluate the potential of yellow mealworm (Tenebrio molitor) as a locally available nutrient‐rich feedstuff for juvenile rockfish (Sebastes schlegeli). Experimental diets containing elevated levels of mealworm meal (WM) supplemented with synthetic methionine were formulated to be isonitrogenous, isolipidic and isoenergetic to a WM‐free fishmeal (FM) based control diet (designated as WM0, WM8, WM16, WM24 and WM32, respectively). To determine the necessity of dietary methionine supplementation at the highest inclusion of WM, a diet was prepared to contain 32% WM without methionine supplementation (WM32‐AA). Triplicate groups of rockfish juveniles (Mean ± S.E.; 3.11 ± 0.01 g) were fed one of the experimental diets to apparent satiation twice daily for 8 weeks. Fish growth performance in terms of weight gain and specific growth rate increased with increasing dietary inclusion of WM from 0 to 16% and then tended to decrease with further increase in dietary WM levels to 32%. Protein retention (PR) values followed the same trend as growth rates with the highest values found in fish offered WM16 diet. Although fish fed WM32‐AA diet showed significantly lower growth rate and PR values compared to those fed WM16 diet, their performance was still comparable to that of the WM‐free control group. Plasma triglyceride level was negatively affected by dietary WM inclusion and the lowest values were observed in the WM32‐AA group. Whole‐body and fillet proximate and essential amino acid compositions were not altered by dietary treatment and these values were comparable to those of the WM0 group. These findings suggested that WM might prove to be a promising alternative to FM in practical diets for juvenile rockfish and could be used at an inclusion level of up to 32% without having any adverse consequences for the health and performance of the fish. Although the diet containing 32% WM seemed to support a performance similar to that of the control diet, the recommended dietary inclusion level was no more than 16% of the diet dry matter.     

Dietary rapamycin supplementation reverses age‐related vascular dysfunction and oxidative stress,while modulating nutrient‐sensing,cell cycle,and senescence pathways

Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age‐related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age‐related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6–8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation (P < 0.01), and this was reversed after rapamycin treatment in old mice (P < 0.05). Aging was also associated with impaired endothelium‐dependent dilation (EDD) in the carotid artery (P < 0.05). Rapamycin improved EDD in old mice (P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice (P < 0.05), and rapamycin normalized these (P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated (P < 0.05), but not rapamycin‐treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse‐wave velocity (PWV) (P < 0.01), rapamycin treatment reduced aortic PWV (P < 0.05) and collagen content (P < 0.05) in old mice. Aortic adenosine monophosphate‐activated protein kinase (AMPK) phosphorylation and expression of the cell cycle‐related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 (P < 0.05), and this was ameliorated by rapamycin treatment (P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle.     

Calcium and Dairy Acceleration of Weight and Fat Loss during Energy Restriction in Obese Adults

Objective: Increasing 1, 25‐dihydroxyvitamin D in response to low‐calcium diets stimulates adipocyte Ca²⁺ influx and, as a consequence, stimulates lipogenesis, suppresses lipolysis, and increases lipid accumulation, whereas increasing dietary calcium inhibits these effects and markedly accelerates fat loss in mice subjected to caloric restriction. Our objective was to determine the effects of increasing dietary calcium in the face of caloric restriction in humans. Research Methods and Procedures: We performed a randomized, placebo‐controlled trial in 32 obese adults. Patients were maintained for 24 weeks on balanced deficit diets (500 kcal/d deficit) and randomized to a standard diet (400 to 500 mg of dietary calcium/d supplemented with placebo), a high‐calcium diet (standard diet supplemented with 800 mg of calcium/d), or high‐dairy diet (1200 to 1300 mg of dietary calcium/d supplemented with placebo). Results: Patients assigned to the standard diet lost 6.4 ± 2.5% of their body weight, which was increased by 26% (to 8.6 ± 1.1%) on the high‐calcium diet and 70% (to 10.9 ± 1.6% of body weight) on the high‐dairy diet (p < 0.01). Fat loss was similarly augmented by the high‐calcium and high‐dairy diets, by 38% and 64%, respectively (p < 0.01). Moreover, fat loss from the trunk region represented 19.0 ± 7.9% of total fat loss on the low‐calcium diet, and this fraction was increased to 50.1 ± 6.4% and 66.2 ± 3.0% on the high‐calcium and high‐dairy diets, respectively (p < 0.001). Discussion: Increasing dietary calcium significantly augmented weight and fat loss secondary to caloric restriction and increased the percentage of fat lost from the trunk region, whereas dairy products exerted a substantially greater effect.     

The role of lipid metabolism in aging,lifespan regulation,and age‐related disease

An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.     

Dietary folic acid (FA) requirement of a genetically improved Nile tilapia Oreochromis niloticus (Linnaeus, 1758)

The present study was conducted to determine the dietary folic acid (FA) requirement of genetically improved Nile tilapia, Oreochromis niloticus. Experimental diets were supplemented with 0.04, 0.22, 0.48, 0.96, 2.25, or 4.07 mg/kg FA, respectively, and fed to three replicate groups of 15 tilapia (mean initial weight = 60.23 ± 2.60 g; mean ± SD) for 12 weeks. Results showed that the weight gain rate increased linearly with increasing dietary FA from 0.04 to 0.40 mg/kg, then remained stable with higher supplementation. Similarly, hepatic FA concentration, red blood cell count (RBC), hemoglobin concentration (HB) and hematocrit (HCT) all markedly increased in fish fed with 4.07 mg/kg FA compared to those fed a control diet (p < .05). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities decreased with increasing dietary FA (p < .05). The FA requirement was estimated to be 0.4 mg/kg based on weight gain rate, and 0.7 mg/kg based on liver FA accumulation.