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Caloric restriction and skin aging

caloric restriction and skin aging

Resveratrol not only induces SIRT1 activation to modulate insulin signaling, agkng also extends xging and prevents age-related diseases caloric restriction and skin aging part by regulating NF-κB signaling and MAPK Bhullar and Hubbard, Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.

Caloric restriction and skin aging -

Curcumin, as a CRM, has been found to have various biological activities such as antioxidant, anti-inflammatory, anti-rheumatic, anti-cancer, and anti-neurodegenerative activities, and can treat a variety of chronic diseases.

Some studies have shown that curcumin is metabolically protective by regulating DNA methylation and histone acetylation. For example, In a rat model of non-alcoholic fatty liver disease NAFLD , curcumin treatment significantly reversed DNA methylation levels, increased expression of peroxisome proliferator activated receptor alpha PPAR -α and protein, and improved lipid accumulation in the model Li et al.

Curcumin is effective in the treatment of myocardial infarction by inhibiting pHAT activity and downstream GATA4, NF-κB, and TGF-β-Smad signaling pathways, resulting in decreased expression of cardiac hypertrophy genes Li et al. In addition to HAT inhibition, curcumin also improved vascular structure by inhibiting the expression of HDAC1, thereby promoting tissue inhibitor of metalloproteinase-1 TIMP1 transcriptional activation and inhibiting the expression of MMP-2 and TGFβ Hu et al.

These data suggest that curcumin is a class of chemicals with potential life-prolonging and aging-related disease prevention effects.

Although a large number of experiments have shown that curcumin has anti-aging effects and also has the effect of treating aging-related diseases, clinical experimental data on curcumin are still very limited, and data and validation of long-term responses are lacking.

In addition, curcumin has low solubility, rapid metabolism, and is difficult to reach effective concentrations in the human body, which is also an urgent problem to be solved. In addition to the above two compounds, quercetin is also one of the well-studied natural polyphenols.

Quercetin can inhibit oxidative damage induced by oxidized LDLoxldl in endothelial cells by activating SIRT1 and regulating AMPK signaling Hung et al.

Fisetin has anti-inflammatory, neuroprotective, anticancer, and antidiabetic effects, and its regulatory effects on oxidative stress during aging are unknown. In rats, oral administration of phenastine for 6 weeks suppressed aging-induced increases in reactive oxygen species, erythrocyte apoptosis, lipid peroxidation, and protein oxidation levels Naeimi and Alizadeh, ; Singh et al.

Therefore, a diet rich in fesoterone may be a potential anti-aging intervention strategy. DMC may therefore act synergistically with other CR mimetics against mTOR. Anthocyanin-rich blueberry extract can reduce HAT activity, reduce TNFα signaling and pro-inflammatory gene expression in the liver, regulate gene expression, block liver fibrosis, and protect liver function in aging mice by increasing histone H3 acetylation at lysine residues on histones K9, K14, and K18 Wei et al.

Anthocyanins therefore modulate HDAC and HAT activity to suppress inflammation-related diseases. Rapamycin is a major inhibitor of the mTOR signaling pathway. Rapamycin not only increases life span, but also improves quality of life and health.

Studies have shown that rapamycin treatment can prolong the life span of invertebrates and mice, slow down or even reverse a variety of age-related changes in mice including arterial function changes, cardiomegaly, periodontitis, immunosenescence, and cognitive decline Li et al.

Interestingly, Anisimov et al. reported a greater increase in mean lifespan in females treated with rapamycin Anisimov et al. These results suggest that prolonging human healthy lifespan by rapamycin is a feasible strategy, however, unfortunately, rapamycin is also able to inhibit TORC2 in multiple tissues including liver, adipose tissue, and skeletal muscle Lamming LY et al.

So long-term use of rapamycin produces many side effects, including increased risk of cataracts, viral and fungal infections, and joint pain, which limit its use to delay aging in healthy individuals.

In addition, the dosage is also a problem, and humans usually take rapamycin at doses of 2—5 mg per day, while laboratory mice take doses as high as 2.

Thus, the use of safer, but possibly weaker, indirect mTORC1 inhibitors, such as metformin and resveratrol, may prove useful. However, some researchers believe that rapamycin may not be a true CRM, and the combination of dietary restriction and rapamycin may work better than either alone Strong et al.

Metformin is a biguanide antidiabetic agent. It has been shown that metformin, in addition to its proven efficacy as a hypoglycemic agent, can exert multiple anti-aging effects at the cellular and tissue levels is also a traditional CRM Barzilai et al.

Studies have shown that people with type 2 diabetes taking metformin have longer survival than people who are not diabetic and do not take the drug Bannister et al. Metformin also reduces the incidence of cardiovascular disease, increases cognitive function, and improves age-related dysfunction Solymar et al.

The mechanisms by which metformin may exert its anti-aging effects have been investigated Wyss-Coray, : inhibition of mitochondrial electron respiratory chain complex 1, reduction of ROS production and inhibition of JNK signaling McHugh and Gil, ; activation of AMPK signaling pathway, inhibition of mTOR Fontana et al.

Metformin favorably impacts metabolic and cellular processes, all of which impact cell proliferation, senescence, stress defense, autophagy, protein synthesis, and inflammation that are strongly age-related. Metformin can also affect epigenome and gene expression to influence aging. For example, metformin induced HAT1 phosphorylation and increased its activity in a mouse embryonic fibroblast model Marin et al.

HDACs can deacetylate histones, various transcription factors, and regulatory proteins, thereby directly or indirectly affecting glucose metabolism. Following metformin treatment, HDAC4, 5, and 7 activity in rat liver was inhibited, followed by an increase in global H3 acetylation levels Khan and Jena, Similarly, metformin can improve ovarian reserve and delay the aging process in mice by inducing SIRT1 expression and reducing oxidative damage Xian Qin et al.

However, metformin may also produce undesirable side effects, and exposure to metformin has been reported to be time- and dose-dependent, with chronic use resulting in adverse events such as increased cognitive impairment and vitamin B12 deficiency in patients with type 2 diabetes and increased lactate levels in mice and humans de Jager et al.

In general, metformin decreased the activity of most HATS, HDACs, and DNMT and increased the activity of HAT1 and SIRT1 through AMPK-mediated phosphorylation. But it is difficult to generalize the effect of metformin on epigenome and gene expression. Aspirin, a non-steroidal anti-inflammatory drug, is also considered a mimetic of CR.

Aspirin has been shown to extend median lifespan in nematodes, flies, and mice. The effect of aspirin on the epigenome may also serve as a potential mechanism.

Data suggests that aspirin can reverse tumor suppressor gene hypermethylation in cancer tissue, affect deacetylase activity, and may also downregulate miRNAs with oncogenic-like function or upregulate miRNAs with tumor suppressor-like function. In particular, DNA methylation alterations, are considered to be one of the most common molecular alterations in human tumors.

Studies have shown that aspirin can inhibit DNA methylation and epigenetic aging in healthy colon over time, thereby reducing the risk of cancer Noreen et al. In contrast, in the ASPREE a randomized double-blind placebo-controlled trial trial, daily low-dose aspirin in older adults without known disease did not reduce cardiovascular disease-related mortality and increased bleeding and all-cause mortality McNeil et al.

In addition, long-term use of aspirin may cause side effects such as stomach bleeding and brain bleeding, and the older the age, the greater the possibility of internal bleeding, and it is recommended that the doctor should agree before taking it.

Among the available dietary anti-aging interventions, in addition to CR, different forms of IF have gained scientific and public interest because of their broad health-promoting properties.

IF includes different rhythmic or recurrent rhythmic fasting regimens, such as alternate-day fasting, periodic fasting, and time-limited eating.

Although there are fewer reports on IF than CR, recent studies clearly show that IF also extends the lifespan of vertebrate and invertebrate model organisms Honjoh et al. In fact, CR and IF also lead to common metabolic and physiological changes in multiple tissues and organs Francesco et al.

For example, ketone bodies, increased insulin sensitivity, and decreased IGF A study showed that caloric restriction and intermittent fasting both reduced body weight and glycosylated hemoglobin levels in obese diabetic patients at risk for cardiovascular disease.

Both regimens reduce overall inflammatory response and oxidative stress and also elicit similar behavioral changes, such as increases in hunger response and cognitive response Francesco et al.

Therefore, it is generally accepted that common molecular mechanisms may mediate the process of lifespan extension by CR and IF. However, there are also independent mechanisms between CR and IF.

A major difference is that IF may extend lifespan without reducing calorie intake overall by exploiting molecular pathways in response to fasting Anson et al.

However, a comprehensive understanding of the mechanisms by which IF extends lifespan remains lacking. So far, it has not been possible to determine whether the effects observed with CR alone and fasting can be seen as completely independent of each other.

At the same time, whether IF may have a better effect than CR has been highly debated. CR reduces oxidative stress and increases lifespan in many species. Limiting essential amino acid intake is a critical medium for the life-prolonging effects of CR, including limiting methionine intake Gallinetti et al.

Methionine is an essential amino acid for normal growth and development of the human body and is involved in protein synthesis, functional regulation, and DNA methylation Levine et al.

In humans, methionine can be obtained from food or gastrointestinal microorganisms. MR has been shown to prolong the healthy lifespan of different model organisms Richie et al. The life-extension effect of MR has been attributed to many different mechanisms. A critical component of the beneficial effects of MR on cell survival and longevity is activation of autophagy.

The autophagic process depends on the proteolytic activity of vacuoles, which is determined by vacuolar acidification Nakamura et al. Ruckenstuhl et al. found that MR prolonged yeast lifespan in an autophagy-dependent manner. Single deletion of several core autophagy factors Atg5, Atg7, or Atg8 could completely abolish the longevity ability of MR.

MR enhances vacuum acidity, a phenotype that essentially requires autophagy Ruckenstuhl et al. Sutter et al. also showed that methionine regulates mTORC1 signaling pathway and autophagy by regulating the methylation status of phosphatase 2A PP2A in yeast Sutter Benjamin et al.

SIRT1 can also affect autophagy. The effect of MR on SIRT1 may be related to age. Fibroblast growth factor FGF is one of the most important growth factors and plays an important role in the pathogenesis of metabolic diseases such as obesity and diabetes Xu et al.

In obese mice, MR. SIRT1 activates PPARα and PGC-1α in mice and then stimulates FGF synthesis and fatty acid oxidation Purushotham et al. But the increase of FGF was not associated with SIRT1 expression in Lee et al.

Lees et al. Thus, MR-induced synthesis of FGF is only some of them SIRT1-dependent. These imply the potential value of dietary MR in preventing diabetes.

In addition, FGF also inhibited the IGF-1 pathway in mice, but had no effect on hepatic IGF-1 production in 2-month-old mice Lees et al. MR can reduce cancer morbidity and mortality.

In a subsequent study published in , cancer cells and normal cells were cultured in culture medium, and the growth of malignant cells was significantly impaired in methionine-free culture medium, while the growth of normal cells did not change.

Thus, MR has the ability to alter cancer cells while maintaining normal, healthy cells Cavuoto and Fenech, Similarly, MR suppressed prostate cancer development in mouse models of prostate cancer, particularly in the anterior and dorsal lobes where prostate cancer was most severe Sinha et al.

In a nude mouse model inoculated with MCF10AT1 breast cancer cells, MR0. Recently, the effects of nutrients on gene expression have aroused high concern among scientists around the world.

Epigenetic alterations have been suggested as a potential mechanism for metabolic phenotype switching in methionine restriction.

However, the effect of DNA and histone modifications on the beneficial effects of methionine restriction is unknown. Studies in adult mice have shown that MR. Methionine restriction can also alter histone methylation and acetylation in humans Mentch et al. Several miRNAs are also involved in nutrient sensing and regulatory signaling pathways, and they also change when performing MR.

For example, limiting methionine. However, there is no clear evidence on the role of miRNAs in the life-prolonging effects of methionine-restricted diets. Prolonging health or longevity is beneficial at both the individual and social levels. However, so far, only a few experimental settings have been shown to extend mammalian lifespan.

Autophagy and epigenetic modification are multigene regulatory processes that play an important role in regulating aging as well as aging-related diseases.

Autophagy, such as a double-edged sword, can maintain cell survival and delay aging, but excessive autophagy can lead to cell death and promote aging.

Therefore, how to precisely regulate and activate autophagy while clarifying the interaction between autophagy and epigenetic modifications may contribute to the proposal of anti-aging methods.

Epigenetic modification, unlike DNA mutations, is a reversible regulation. This suggests that epigenetic modification is expected to be a potential therapeutic strategy against aging and its aging-related diseases. Further understanding of the role of epigenetics in human aging and longevity requires a deeper understanding of the influence of the external environment on epigenetics, such as the mechanism of epigenetics in CR-mediated longevity regulation.

In recent years, although autophagy and epigenetic modifications induced by CR have been experimentally confirmed in delaying aging and preventing some age-related degenerative diseases, the degree, time limit, food composition and study subjects of CR are different, which may have an impact on its biological effects.

In humans, the effects of nutritional interventions are related to factors such as specific populations, modes of intervention, and genetics. We also need a deeper understanding of epigenetic mechanisms in the regulation of energy restriction-mediated longevity. In preclinical studies, fasting and CR have been shown to prolong life and health, induce autophagy, and improve symptoms of various diseases.

However, the transition to the clinic has been slow, and hunger, compliance, and health during fasting are also issues to consider. Importantly, long-term and follow-up trials are needed to assess their long-term efficacy and safety.

In mice, for example, chronic CR increases susceptibility to infection, particularly of viral nature. In contrast, restriction of a specific amino acid, namely methionine, has also been shown to greatly enhance autophagy and prolong mammalian lifespan, with the advantage of having good applicability.

For practical applications, it may not be so important which dietary intervention produces a better effect, but what dietary intervention the patient is personally suitable and willing to follow. There are now some clinical data demonstrating that CR prolongs life expectancy in individuals by reducing the risk of aging-related diseases, but may adversely affect certain groups, and optimal intake and duration of long-term CR, receptor sensitivity, and degree of activation of post-receptor pathways remain to be determined in further studies.

CR may have a much smaller benefit on human lifespan than animals and may be more useful than prolonging lifespan in reducing functional decline and preventing chronic diseases.

In addition, because the study of long-term high-intensity CR in humans is very limited, CR drugs and compounds that can replace CR have also received attention in recent years, such as metformin and rapamycin, but they will also produce inevitable toxic side effects.

Identifying new, secure CRMs will therefore be important. At present, CRM is only a drug used alone, and whether multiple CRMs can be used in combination, or interact with other anti-aging interventions such as exercise to exert more prominent therapeutic effects remains to be explored.

JZ, JS, and XW drafted and revised the paper. WK, CH, and YP revised the paper. All authors contributed to the article and approved the submitted version. This research was funded by Science and Shandong Provincial Natural Science Foundation [ZRLH], the Innovation Project of Shandong Academy of Medical Sciences and Academic promotion programme of Shandong First Medical University [No.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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and C. collected the survival data, performed the analyses and wrote the manuscript. and M. helped complete the analysis of the normal survival data for C. and J. helped collect the survival data for Drosophila.

and Q. reviewed the manuscript. and X. designed the experiment and are the corresponding authors for this study. All authors read and approved the final manuscript. Correspondence to Xiaowo Wang or Zhao Wang.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Liang, Y. Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of survival curves.

Sci Rep 8 , Download citation. Received : 05 January Accepted : 22 March Published : 10 April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

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Abstract Despite technological advances, the survival records from longevity experiments remain the most indispensable tool in ageing-related research. Introduction Research on the biology of ageing has been conducted for centuries. Results Changes in the size and shape of survival curves represent different anti-ageing effect patterns We obtained survival data from graphs 11 , 12 extracted from the retrieved literature by using Gompertz model to fit the survival curve with the maximum-likelihood estimation MLE Figure 1.

Full size image. Figure 2. Figure 3. Figure 4. Discussion It is widely accepted that CR, medications and genetic manipulations extend lifespan in a diversity of species ranging from yeast to primates. Figure 5. Methods Data collection Survival data from lifespan experiments were extracted from the literature.

Model fitting for the survival curves The survival curves in the various papers were generated from different numbers of samples and time intervals, preventing a direct comparison of the raw curves.

Feature selection Because many factors affect survival, considerable variation was observed even between the survival curves for the normal control samples from the different papers, hindering a direct comparison of the curves for different treatments from different papers.

Curve comparison method We used case-control plots of C. Gene set enrichment and gene ontology GO analysis As those lifespan strategies that have a longer extension and a parallel pattern seem to be better strategies, we analysed the biological functions of the genes in the regions affected by such strategies by GO analysis using DAVID 27 , 28 , Significance analysis We used two-sample KS tests to determine if two subgroups had different anti-ageing patterns and applied this test to the different features studied 47 , References Fontana, L.

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Article MathSciNet MATH Google Scholar Marsaglia, G. Google Scholar Download references. Author information Author notes Yaru Liang and Chang Liu contributed equally to this work. View author publications.

Ethics declarations Competing Interests The authors declare no competing interests. Additional information Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material. Supplementary Information. Supplementary Data S1. Supplementary Data S2.

Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4. About this article. Cite this article Liang, Y. Copy to clipboard. This article is cited by Sequential host-bacteria and bacteria-bacteria interactions determine the microbiome establishment of Nematostella vectensis H.

Domin J. Zimmermann S. Fraune Microbiome Sis2 regulates yeast replicative lifespan in a dose-dependent manner Tolga T.

Aging caloric restriction and skin aging the subject of many studies, Avocado Spring Rolls the discovery of many caloric restriction and skin aging. Epigenetic influences numerous xnd processes restricyion regulating gene expression and also plays a crucial role Youthful glow aging regulation. Increasing data suggests that caloric restriction and skin aging changes can ekin epigenetic marks associated zging aging. Caloric restrction CR is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging. caloric restriction and skin aging

Caloric restriction and skin aging -

They were also provided behavioral counseling about diet over the first 24 weeks. The participants who weren't in the calorie-restricted group weren't told how much they should eat and did not get any counseling. To measure the rate of aging, the researchers used an algorithm to see how certain DNA biomarkers in the blood changed over time.

The algorithm was based on previously acquired data from about 1, people who were followed for 20 years to see how rapidly their organ functioning — including the heart, liver, kidney and lungs — declined as they grew older, Belsky said. Participants in the study were not followed up with after the two-year intervention.

A separate study, also funded by the agency, is planning to look at the effects of a calorie-restricted diet after 10 years, he added. Still, Hadley said, the new study reinforces findings from previous research that some calorie restriction can promote health benefits, including living longer and healthier lives.

Researchers still don't know exactly why cutting calories appears to slow the aging process, though there is evidence that calorie restriction prompts changes at the cellular level, Belsky said.

There are resource stresses in the environment. We need to make sure that we are using all of the resources available to us most efficiently. Pankaj Kapahi, a researcher at the Buck Institute for Research on Aging, said that along with calorie restriction, exercise and eating a balanced diet are also important factors to consider for aging.

He was not involved in the research. Kapahi added that the study's findings do not mean people should starve themselves, saying that could lead to malnutrition and poor mental health.

Valter Longo, a biochemist and director of the Longevity Institute at the University of Southern California, said that limiting calories for extended periods of time can be harmful. Studies in animals, for example, have shown that long-term calorie restriction was found to be associated with a risk of reduced muscle strength, slower metabolism and an impaired immune system, said Longo, who was not involved in the study.

Hadley cautioned against overinterpreting the results, saying calorie restriction may not be for everyone, including those with multiple underlying conditions. He advised speaking with a doctor before undergoing a calorie-restricted diet.

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

IE 11 is not supported. HF mice had ad libitum access to a high-calorie diet. HF mice gained weight, whereas HDR mice, despite being on a high-calorie diet, were indistinguishable from NF controls. Energy expenditure was also measured in month-old mice using a comprehensive laboratory animal monitoring system.

For the reason that the body sizes of mice varied individually, we compared the metabolic rates by normalizing the data with the body weight of each mouse. Calorie-restricted mice manifested circadian rhythms in the oxygen consumption, systemic respiratory exchange ratio, and heat production Figure 1F , 1H.

Food quantity restriction alone had no significant effect as compared with NF mice. Additionally, calorie restriction increased physical activity during the light cycle in the LF group and decreased body temperature in LF and NDR groups at the age of 15 months Supplementary Figure 1.

Small animal magnetic resonance imaging MRI was used to determine the body composition of mice of all ages. Variations in fat mass explained the change in overall body weight, while lean mass was identical for all the experimental groups Figure 2A — 2C. In comparison with ad libitum-fed high-calorie or normal-calorie diets HF or NF , calorie restriction reduced the levels of fat mass, whereas food intake seemed to have no effect on fat mass Figure 2C and Supplementary Figure 2.

These results indicated that calorie plays a decisive role in body fat reduction by calorie restriction. histological analyses of adipose tissue showed that calorie restriction resulted in a significant reduction in overall fat content. Further, large unilocular fat droplets significantly accumulated in brown adipose tissue BAT of HF mice, which were nearly absent in LF and NDR mice Figure 2E.

Besides, serum leptin levels were positively correlated with total body fat content. As predicted, serum leptin levels were lower in all calorie-restricted mice comparing to NF mice Figure 2F.

Figure 2. Effects of calories and food quantity on the lifespan and energy state. A T 1 -weighted MRI images of mice, where the highlighted part represents body fat.

B Body composition of mice in each dietary group at different ages, and the corresponding C fat mass as a percentage of total body weight. In mice with diet-induced, fat accumulation in adipose tissue is associated with severer inflammation [ 26 ].

Besides, mRNA levels of TNFα and IL1β in eWAT and BAT indicated reduced inflammation in the adipose tissue of calorie-restricted mice Supplementary Figure 3A , 3B.

Expressions of Pgc1α and Ucp1 were upregulated in calorie-restricted mice Supplementary Figure 3C , 3D. Our results showed that calories are a key determinant of obesity, and restriction of food quantity alone could hardly resist obesity.

Aging is related to an attenuation of locomotor and cognitive function Figure 3A — 3D [ 27 ]. Interventions LF and NDR improved locomotor activity and performance on a rotarod test, which did not correlate with body weight Figure 3A , 3B.

It is presently unclear how far the healthspan effects of calorie restriction e. Thus, it is critical to determine whether the extended lifespan is associated with increases or deficits of cognitive capacity, therefore, we carried out a Morris water maze test at 6, 15, and 24 months of age Figure 3C , 3D.

There was an age-dependent impairment in learning and memory that was attenuated by calorie restriction, as measured by the latency to reach a platform. Short-term memory and context-dependent memory were investigated in the novel-object recognition tasks [ 28 , 29 ].

LF and NDR mice showed higher recognition indexes compared to controls Figure 3D. The mice spent more time exploring new objects, whereas no change in the total exploration time, indicating improvements in short-term cognitive performance, but not in general activity.

CREB is an effector of neurotrophic factors that accounting for several neurodegenerative diseases associated with aging and brain responses to calorie restriction.

The CREB-SIRT1 axis is an important component of the nutrient-sensitive molecular network associating calorie intake and energy metabolism with brain health [ 30 ], so we assessed the total amount and phosphorylation of the CREB and the expression of SIRT1, which is known to be a direct transcriptional target of CREB [ 31 ].

The expression of CREB was not modified by our dietary regimens; however, the phosphorylation of CREB on Serine increased in the hippocampi of the LF group Figure 3E , which suggested that the memory improvement was related to the activation of the CREB-SIRT1 axis.

Figure 3. Aging-sensitive markers, physical activity, and glucose tolerance of mice. B Latency to fall from a rotarod indicated the motor coordination of mice.

C The results of the Morris water maze test for the mice under different dietary regimens. D The recognition index in the novel-object recognition test. E Representative immunoblots and densitometric quantification of the immunoblots for phosphor-SerCREB pCREB in the mouse liver.

H GTTs in the different experimental groups and the corresponding I areas under the curve AUC. Five mice per group were analyzed. Because calorie restriction attenuated fat accumulation and adipose inflammation, we next investigated whether it can protect from obesity-related insulin resistance and type II diabetes.

We found that the levels of fasting glucose were higher in the HF groups compared with controls, but neither calorie restriction nor quantity restriction affected fasting glucose levels Figure 3F. Compared with the regimen NF, fasting serum insulin contents were slightly lower by regimens LF and NDR Figure 3G.

The glucose tolerance test GTT showed improved glucose-tolerant of all the mice subjected to calorie or quantity restriction than that of NF group Figure 3H , 3I. Besides, solely calorie restriction alone improved glucose tolerance, and this effect was similar to that of the simultaneous quantity and calorie restriction.

Our results indicated that calories are the critical factor of all dietary restriction paradigms, whereas the effect of food quantity was not proved. Compared to the normal diet ad libitum regimen NF , calorie restriction alone LF group resulted in a lower weight; similar results were obtained in the NDR group.

Nonetheless, the effect of quantity restriction alone was not remarkable Figure 1C. The excessive increase in adiposity induced hepatic steatosis. In order to identify the pathological state and hepatic steatosis of mice in the five groups, we chose the Brunt Scoring System under blinded conditions.

We found that hepatic steatosis was obviously reduced in LF mice in contrast with NF and HF mice Figures 4A , Supplementary Figure 4A , 4B. Moreover, hepatic steatosis and injury markers including total cholesterol, triglycerides, aspartate aminotransferase [AST], and alanine aminotransferase [ALT] were obviously improved in LF mice Figure 4B.

Additionally, quantitative analysis of electron microscopy images showed no significant decrease in intracellular fat deposits, mitochondrial density, or endoplasmic reticulum in the livers of LF mice compared to the NF mice Figure 4C , 4D. Figure 4. Liver functions affected by the dietary interventions.

Original magnification: 20×. Steatohepatitis was scored by a histopathologist who was blinded to the source condition of each sample by a semiquantitative method derived from a published procedure [ 32 ]. B Liver function was assessed via the serum concentrations of triglycerides, cholesterol, ALT, and AST.

C Transmission electron microscopy images of the liver in different experimental groups. Representative images at a magnification of 10,× are shown.

D Mitochondrial density and size. Quantification of mitochondrial size was performed on five mice from each group.

Significantly higher numbers of dilated glomeruli and greater swelling of the renal tubule epithelium were noted in the HF and NF mice during aging; these parameters are well-known hallmarks of aging Supplementary Figure 5A.

Calorie restriction alone and, separately, quantity restriction alone alleviated the kidney fat lesions. Serum creatinine and urea nitrogen did not manifest significant differences at 6 and 15 months of age. However, compared with the NF mice at 24 months of age, serum creatinine levels in the LF, HDR, and NDR mice all significantly decreased, indicating protection from renal injury Supplementary Figure 5B , 5C.

Kidneys are the most important excretion organs of the body, and the main functions of kidneys are to filter the liquid forming urine, to excrete metabolic waste, and to regulate the balance of electrolytes and acid-base balance in the body.

Our results revealed protective effects of the restrictions on calories and on food quantity against renal injury and inflammation.

Because calorie restriction is known to activate AMPK and SIRT1 or inhibit the mTOR pathway, we quantified the relevant signaling including the ratio of phosphorylated S6K compared to total S6K in the livers of the four groups of mice and found that the fold change of SIRT1 was most strongly related to the maximum lifespan Figure 5A , 5B , suggesting that SIRT1 is the key protein for the lifespan extension by calorie restriction.

Figure 5. Quantitative analysis of the expression of proteins related to classic pathways of calorie restriction. B Immunohistochemical analysis of SIRT1 and Ac-NFĸB expression in the liver. Nevertheless, the lifespan extension by calorie restriction is related to complex pathways and processes.

To investigate the molecular mechanisms underlying physiological and lifespan distinctions in five dietary interventions, we determined the hepatic transcriptome of 3 mice in each group at 62 weeks of age by means of whole-genome microarray analysis.

Via this selection criterion, we found the genes whose expression showed the highest positive and negative correlations with the lifespan. Gene Ontology GO and KEGG pathway analyses suggested that these genes are related to various biological processes, including upregulated biosynthesis and metabolism of the fatty acid, biosynthesis of unsaturated fatty acids and amino acids including arginine Figure 6A , 6C.

Several other enriched pathways included carbon metabolism, glyoxylate and dicarboxylate metabolism, glycerophospholipid metabolism, and glycine, serine, and threonine metabolism Figure 6B , 6D.

In addition, a protein-protein interaction network was conducted to recognize core regulatory genes by means of microarray expression profiles. Reverse-transcription quantitative PCR confirmed that the expression of genes involved in fatty acid biosynthesis and metabolism, such as Ppp1r3g , Fabp5 , Fasn , and Fos , significantly positively correlated with the lifespan Figure 6E.

The expression of genes related to carbon metabolism, including Gbp5 , significantly inversely correlated with the lifespan Figure 6F. Figure 6. Midlife liver gene expression correlations with lifespan are predictive of aging regulators.

A GO analysis of target genes with expression levels that are most positively correlated with the lifespan. B GO analysis of target genes with expression levels that are most negatively correlated with the lifespan. C Gene network modules depicting the pathways and genes that are most positively correlated with the lifespan.

D Gene network modules showing the pathways and genes that are most negatively correlated with the lifespan. E mRNA expression of genes that are significantly positively correlated with the lifespan.

F mRNA expression of genes that are significantly negatively correlated with the lifespan. In this research, we clarified that dietary interventions resulted in accordant alterations in aging-associated physiological and physical characteristics.

Food quantity restriction alone did not yield a significant improvement in aging-related parameters, including body weight, inflammation, hepatic steatosis, and behavior test results. However, food quantity restriction seemed to attenuate the lifespan extension by calorie restriction.

Simultaneously restriction of the food quantity and calories NDR group extended the healthspan, without a significant influence on the lifespan. That is to say, in mice, the health and survival outcomes in response to calorie restriction are different to a certain extent.

Mice under these dietary regimens may consume more energy to sustain their healthspan, thus shortening their lifespan. We tried to keep the total calories the same when adjusting the food quantity. Inevitably, we had to use diets with different compositions, such as corn sugar, soy oil, or lard oil, which leads to two variables in the diets including composition and quantity, when the total calories are the same.

If the quantity is reduced, the fat has to be increased to keep the same calories and vice versa. However, it was reported that daily calorie intake per se was identified as a determinant factor of the lifespan, and the source of calories carbohydrates, fat, or protein was considered irrelevant [ 11 ].

The proportion of fat soy oil in the diet of NDR group is higher, and as we know, soy oil contains large quantities of saturated fatty acids which is good for health. The shorter lifespan extension of NDR compared to LF still proved that quantity restriction probably attenuated lifespan extension of calorie restriction.

The effects of calorie restriction are age-dependent. The effects of different dietary regimens on aging-related characteristics varied widely among different ages throughout the lifespan.

For example, the data on learning abilities and memory of mice under different regimens are quite contradictory among different age groups, that is to say, calorie restriction did not improve learning and memory in 6- and month-old mice but it significantly improved that of month-old mice.

In the novel object recognition task, only young-aged calorie-restricted mice significantly spent more time exploring new objects, without significant differences from the control at the middle age and old age.

This difference may perhaps be due to the difference in sensitivity between the Morris water maze and novel object recognition tests. Future studies would be warranted to make these distinctions.

A first-of-its-kind erstriction study Greek yogurt muffins that calorie reduction may help slow the pace ating biological aging. Aginy restricting calories slow biological aging and help healthy adults live longer? A Body composition tracking software trial in humans suggests caloeic it might. The landmark study, restricton on Aing 9 in the Greek yogurt muffins Nature Agingfound that a two-year intervention that required participants to cut 25 percent of their daily calories slowed the pace of aging by 2 to 3 percent. This translates to a 10 to 15 percent reduction in mortality risk, the researchers say — about the same level of risk reduction as quitting smoking. Although many people might find this level of caloric restriction too difficult, the study supports the concept that behavioral changes — without any drugs — can have a measurable impact on the pace of aging, Dr. Ryan said.

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