Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences

The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease(CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction(CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas:(1) mechanisms underlying age-related cardiac remodeling;(2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women;(3) we select a few polyphenol or polyamine rich compounds as the CRmimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

The effect of caloric restriction on genetical pathways

Energy restriction is defined as reducing nutrient intake without dragging the organism into malnutrition. Energy restriction is preferred because it is a non-genetic intervention that increases life expectancy. Nicotinamide adenine dinucleotide(NAD~+)and adenosine monophosphate(AMP)levels, which are the indicators of intracellular energy deficiency, increase with energy restriction. The increase in NAD~+ level stimulates sirtuin(SIRT)enzymes, and the increase in AMP level stimulates AMP-activated protein kinase(AMPK). Various mechanisms are regulated by stimulating these enzymes. By Forkhead box O(FoxO)transcription factors, the ability of resistance to oxidative stress increases, and antioxidant genes, DNA repair, and autophagy genes are stimulated. Apoptosis is induced by stimulation of the p53 protein, and tumor growth is suppressed by the disruption of aging cells. The suppression of phosphoinositide 3-kinase(PI3K)-/-Akt, and therefore mTOR signal stimulates autophagy and mitophagia, and cleanses damaged cells and organelles. Mitochondrial biogenesis is stimulated, antioxidant capacity increases, and inflammatory response decreases. Adipose tissue and lipid metabolism are regulated by the regulation of fatty acid synthesis and oxidation. As a consequence, the effects of caloric restriction on cellular metabolism are regulated through the genetic pathways.

Protective effects of estrogens and caloric restriction during aging on various rat testis parameters

Aim： To investigate the effects of 17β-estradiol （E2）, Peganum harmala extract （PHE） and caloric restriction （CR） on various testis parameters during aging. Methods： Twelve-month-old male rats were treated for 6 months with either E2 or PHE, or submitted to CR （40%）. Results： Our results show that estrogens and CR are able to protect the male gonad by preventing the decrease of testosterone and E2 levels as well as the decrease of aromatase and estrogen receptor gene expressions. Indeed, E2, PHE and CR treatments induced an increase in the superoxide dismutase activities and decreased the activity of testicular enzymes： gamma-glutamyl transferase, alkaline phosphatase, lactate deshydrogenase as well as the aspartate and lactate transaminases in aged animals. In addition, the testicular catalase and gluthatione peroxidase activities were enhanced in E2, PHE and CR-treated rats compared to untreated animals at 18 months of age. Moreover, the positive effects of estradiol, PHE and CR were further supported by a lower level of lipid peroxidation. Recovery of spermatogenesis was recorded in treated rats. Conclusion： Besides a low caloric diet which is beneficial for spermatogenesis, a protective antioxydant role of estrogens is suggested. Estrogens delay testicular cell damage, which leads to functional senescence and, therefore, estrogens are helpful in protecting the reproductive functions from the adverse effects exerted by reactive oxygen species （ROS） produced in large quanti- ties in the aged testis.

Inhibitory Effect of Estrogens,Phytoestrogens,and Caloric Restriction on Oxidative Stress and Hepato-toxicity in Aged Rats

Objective To investigate the protective effect of 17β-estradiol （E2）, peganum harmala extract （PHE） administration and calorie restriction （CR） treatment （60%） on oxidative stress and hepato-toxicity in aged rats. Methods Eighteen months old animals that were treated at the age of 12 months were divided into 4 groups： normal control group with free access to food, E2 treatment group, PHE treatment group and CR treatment group of the food given to control group. Six male rats at the age of 4 months were used as a reference group. Results Aging significantly decreased superoxide dismutase （SOD）, catalase （CAT） and glutathione peroxidase （GPX）, and increased lactate deshydrogenase （LDH）, gamma-glyiamyl transferase （GGT）, pbosphatase alkalines （PAL）, aspartate and lactate transaminase （AST and ALT） activities in the liver. Aging also induced an increased lipid peroxidation level, histological changes and a decreased E2 level. However, treatment with E2, PHE, and CR increased 17β-estradiol, and decreased hepatic dysfunction parameters and lipid peroxidation as well as histological changes in the liver of aged rats. Conclusion The antioxidant and hepatoprotective activity of PHE and CR is possibly attributed to its ability to increase E2 level, which as an antioxidant, acts as a scavenger of ROS. Further studies on the pharmaceutical functions of E2 in males may contribute to its clinical application.

Weight Loss and Improved Metabolic Health Measures Using a One-Week Active Nutrition Jumpstart Program in Overweight and Obese Men and Women

Background: The prevalence of individuals who are obese or overweight is an increasing global epidemic that is associated with a multitude of adverse health conditions. Multiple strategies are available to promote weight loss in these populations, including the use of caloric restriction and/or liquid diets. We determined the impact of a low-calorie, nutrient-dense, primarily liquid diet on body weight and associated measures of metabolic health in overweight and obese men and women. Methods: Twenty-six men and women (age: 42.6 ± 10.8) completed a seven-day intervention using the USANA Active Nutrition Jumpstart program, which consisted of consuming three meal replacement shakes and three to four servings of fruits and vegetables, along with a probiotic, three metabolism supplements, and two vitamin packs each day. Pre-post measurements included body composition—determined (via DXA), fasting levels of lipids and glucose in heparinized whole blood, weight, waist circumference, hip circumference, heart rate, and blood pressure. Subjective mood and hunger were also assessed. Results: The dietary program was well-tolerated, and the intervention resulted in a mean weight loss of approximately 4.5 pounds. Clinically relevant reductions were noted in systolic and diastolic blood pressure, cholesterol (total and LDL), and glucose. In addition, there were favorable changes in self-esteem, energy, motivation, and physical appearance. Conclusion: A one-week period of adherence to the Active Nutrition Jumpstart program positively impacted subjective feelings, while resulting in significant weight loss and other health benefits that may have clinical relevance. Longer-term interventions are needed to sustain these initial results.

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer＇s disease

Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

Strategies to improve regenerative potential of mesenchymal stem cells

In the last few decades,stem cell-based therapies have gained attention worldwide for various diseases and disorders.Adult stem cells,particularly mesenchymal stem cells(MSCs),are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials.Although MSCs have high self-renewal as well as differentiation potential,such abilities are compromised with“advanced age”and“disease status”of the donor.Similarly,cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells.It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies,however;autologous use of stem cells for such patients(aged and diseased)does not seem to give optimal results due to their compromised potential.In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs.It is therefore essential to improve the regenerative potential of stem cells compromised due to“in vitro expansion”,“donor age”and“donor disease status”for their successful autologous use.The current review has been organized to address the age and disease depleted function of resident adult stem cells,and the strategies to improve their potential.To combat the problem of decline in the regenerative potential of cells,this review focuses on the strategies that manipulate the cell environment such as hypoxia,heat shock,caloric restriction and preconditioning with different factors.

The promise of neuroprotection by dietary restriction in glaucoma

Glaucoma,a progressive age-related optic neuropathy characterized by the death of retinal ganglion cells,is the most common neurodegenerative cause of irreversible blindness worldwide.The therapeutic management of glaucoma,which is limited to lowering intraocular pressure,is still a challenge since visual loss progresses in a significant percentage of treated patients.Restricted dietary regimens have received considerable attention as adjuvant strategy for attenuating or delaying the progression of neurodegenerative diseases.Here we discuss the literature exploring the effects of modified eating patterns on retinal aging and resistance to stressor stimuli.

3D imaging of the mitochondrial redox state of rathearts under normal and fasting conditions

The heart requires continuous ATP availability that is generated in the mitochondria.Althoughstudies using the cell culture and perfiused organ models have been carried out to investigate thebiochemistry in the mitochondria in response to a change in substrate supply,mitochondrialbioenergetics of heart under normal feed or fasting conditions has not been studied at the tissuelevel with a sub-millimeter spatial resolution either in vivo or er vivo.Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+couple acting as a central electron carrier.We employed the Chance redox scanner thelow-temperat ure fluorescence scanner to image the three-dimensional(3D)spatial distribution of themitochondrial redox states in heart tissues of rats under normai feeding or an overnight star-vation for 14.5 h.Multiple consecutive sections of each heart were imaged to map three redoxindices,i.e,NADH,oxidized favoproteins Fp,including flavin adenine dinucleotide(FAD)andthe redox ratio NADH/Fp.The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices.The quantitative analysis showed that in the fasted hearts thestandard deviation of both NADH and Fp,ie.,SD NADH and SDFp,significantly decreasedwith a p value of 0.032 and 0.045,respectively,indicating that the hearts become relatively morehomogeneous after fasting.The fasted hearts contained 28.6%less NADH(p=0.038).No sig.nificant change in Fp was foumnd(p=0.4).The NADH/Fp ratio decreased with a marginalP value(0.076).The decreased NADH im the fasted hearts is consistent with the cardiac celsreliance of fatty acids consumption for energy metabolism when glucose becomes scarce.Theexperimental o bservation of N ADH decrease induced by dietary restriction in the heart at tissuelevel has not been reported to our best knowledge.The Chance redox scanner demonstrated thefeasibility of 3D imaging of the mitochondrial redox st ate in the heart and provides a usefil toolto study heart metabolism and fiunction under normal,dietary-change and pathological con-ditions at tisue level. We would like to thank Dr.Joseph Baur for thehelpful discussion and Dr.Hui Qiao for animalpreparation and organ harvesting.

Lower Concentrations of Glucose or Insulin Decrease the Risk of Various Types of Cancer in the Long-Lived Ames Dwarf Mouse by Increasing the Expression of p27Kip1, a Cell-Cycle Repressor Protein

Introduction. The molecular biological mechanism of the increased incidence of the various types of cancer in obesity or type 2 diabetes in rodents or humans has largely been resolved in recent years. By contrast, the molecular biological mechanism of the decreased, not increased, incidence of the various types of cancer in the homozygous long-lived Ames dwarf mice still remains unresolved. Objective. The first objective of the present study was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the increase, not decrease, in the expression of p27Kip1, a cell cycle repressor protein. The second objective was to investigate whether the decrease in the incidence of cancer in the homozygous long-lived Ames dwarf mice is due to the decrease, not increase, in the levels of glucose or insulin. Methods. To achieve these objectives, we first performed western immunoblot analysis of the hepatic expression of p27Kip1 protein. We then performed, using a human breast cancer cell line in vitro, the luciferase reporter plasmid assay to determine whether the translation initiation activity of the p27Kip1 mRNA is increased when the concentrations of either glucose or insulin are decreased. Results and Conclusion. The results of the first objective indicated that the hepatic expression of p27Kip1 protein was up-regulated in the homozygous long-lived Ames dwarf mice as expected. We also found that the lower concentrations of glucose or insulin increased the translation initiation activity of the p27Kip1 mRNA.

Fargeting tissue-specific metabolic signaling ）athways in aging： the promise and limitations

It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dys- function. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti- aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross- talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.