Short-term Dietary Restriction Research Articles

Short-Term Dietary Restriction Potentiates an Anti-Inflammatory Circulating Mucosal-Associated Invariant T-Cell Response.

Short-term protein-calorie dietary restriction (StDR) is a promising preoperative strategy for modulating postoperative inflammation. We have previously shown marked gut microbial activity during StDR, but relationships between StDR, the gut microbiome, and systemic immunity remain poorly understood. Mucosal-associated invariant T-cells (MAITs) are enriched on mucosal surfaces and in circulation, bridge innate and adaptive immunity, are sensitive to gut microbial changes, and may mediate systemic responses to StDR. Herein, we characterized the MAIT transcriptomic response to StDR using single-cell RNA sequencing of human PBMCs and evaluated gut microbial species-level changes through sequencing of stool samples. Healthy volunteers underwent 4 days of DR during which blood and stool samples were collected before, during, and after DR. MAITs composed 2.4% of PBMCs. More MAIT genes were differentially downregulated during DR, particularly genes associated with MAIT activation (CD69), regulation of pro-inflammatory signaling (IL1, IL6, IL10, TNFα), and T-cell co-stimulation (CD40/CD40L, CD28), whereas genes associated with anti-inflammatory IL10 signaling were upregulated. Stool analysis showed a decreased abundance of multiple MAIT-stimulating Bacteroides species during DR. The analyses suggest that StDR potentiates an anti-inflammatory MAIT immunophenotype through modulation of TCR-dependent signaling, potentially secondary to gut microbial species-level changes.

Influences of the short-term dietary carbohydrate restriction on the chicken cecal tonsil

This study aims to clarify influences of the short-term carbohydrate (CHO)restriction on plasmacells in chicken cecal tonsil (CT) using immunohistochemical and morphometrical techniques. Healthy male layer chickens were randomly divided into the control and three experimental groups. The three experimental groups were fed with diets containing 50%, 25%, and 0% CHO of that in the control diet, respectively. Following the experimental period for 7 days, CTs were collected from each chicken. Immunohistochemistry was performed to detect immunoglobulin (Ig) A, G and M. The density of IgA-immunoreactive cells was significantly lower in the lymphoid follicles (LFs) and diffuse lymphoid tissues (DLTs) in CTs of the 0% group compared to those of the other groups. There was a positive correlation between daily CHO intake and the density of IgA-immunoreactive cells in the DLTs and LFs. The density of IgM-immunoreactive cells was significantly decreased as daily CHO intake decreased, and there was a positive correlation between these two factors in both DLTs and LFs. The density of IgG-immunoreactive cells was significantly lower in DLTs of the 0% group than those in the controland 50% groups. The density of IgG-immunoreactive cells was significantly decreased with a decrease in daily CHO intake in DLT but not in LF. These findings demonstrated that dietary CHO had a significant effect on the density of plasma cells in the CTs exhibiting a declining trend with a decrease of ingested CHO volume.

Dietary restriction alters insulin signaling pathway in the brain.

Insulin is known to be a key hormone in the regulation of peripheral glucose homeostasis, but beyond that, its effects on the brain are now undisputed. Impairments in insulin signaling in the brain, including changes in insulin levels, are thought to contribute significantly to declines in cognitive performance, especially during aging. As one of the most widely studied experimental interventions, dietary restriction (DR) is considered to delay the neurodegenerative processes associated with aging. Recently, however, data began to suggest that the onset and duration of a restrictive diet play a critical role in the putative beneficial outcome. Because the effects of DR on insulin signaling in the brain have been poorly studied, we decided to examine the effects of DR that differed in onset and duration: long-term DR (LTDR), medium-term DR (MTDR), and short-term DR (STDR) on the expression of proteins involved in insulin signaling in the hippocampus of 18- and 24-month-old male Wistar rats. We found that DR-induced changes in insulin levels in the brain may be independent of what happens in the periphery after restricted feeding. Significantly changed insulin content in the hippocampus, together with altered insulin signaling were found under the influence of DR, but the outcome was highly dependent on the onset and duration of DR.

In Vivo Methylation Capacity Is Not Impaired in Healthy Men during Short-Term Dietary Folate and Methyl Group Restriction

Ten healthy adult men were fed a diet low in folate and exogenous methyl groups to study the effects on in vivo methylation capability. The men were housed in a metabolic unit for the entire 108 d of the study. After a 9-d baseline period (Period 1), the men were fed a soy-product-amino acid defined diet for 45 d, which provided 25 µg/d of folate for 30 d (Period 2) and, with a folate supplement, 99 µg/d for 15 d (Period 3). During Period 2 and Period 3, the low methionine and choline diet was supplemented with methionine for half the subjects to vary the dietary methyl group intake. The periods were then repeated over the next 54 d (Periods 4–6), with a crossover of methionine intakes in Period 5 and Period 6. A 1-g oral dose of nicotinamide was given at the end of each period and methylated urine metabolites determined. Other measures related to in vivo methylation capability included urine creatinine, and plasma and urine carnitine. Even with moderate folate depletion, none of these measures was decreased by low methionine and choline intakes. Plasma methionine concentrations were unchanged throughout. Limiting exogenous methyl group intake by restricting dietary methionine and choline did not impair in vivo methylation capabilities for the variables tested, even at low folate intake.

Twenty-four-hour Urinary Salt Excretion on Admission Predicts Significant Weight Loss with Seven-day Dietary Salt Restriction in Hospitalized Patients with Chronic Kidney Disease: A Single-center Study.

In patients with chronic kidney disease (CKD), restricting dietary salt is recommended to prevent fluid retention. Rapid weight loss is often observed when CKD patients with a high salt intake are hospitalized and started on a low-salt diet. We investigated the effects of 7-day dietary salt restriction on weight loss in hospitalized patients with CKD. During the 7-day hospitalization, a low-salt (6 g/day) and low-protein (0.6-0.8 g/kg/day ideal body weight) diet was served to all patients. Urine samples were collected for the first 24 h after admission, and patients were divided into quartiles (Q1-Q4) by urinary salt excretion. Body weight was measured on days 1 and 7. Weight loss after admission was compared among the groups. Factors associated with weight loss were evaluated by multivariate logistic regression. The mean age of the patients was 70.3 ± 11.7 years, and 73% were male. Mean weight loss was 1.6 ± 1.7 kg on day 7. Weight loss was significantly greater in Q3 and Q4 than in Q1 (P = 0.009 and P <0.001, respectively). In the univariate analysis, weight loss correlated positively with 24-h urinary salt excretion on admission (γ2 = 0.146) and body mass index (γ2 = 0.223). The 24-h urinary salt excretion on admission and BMI were independently associated with weight loss of >2 kg. The adjusted odds ratios (95% confidence interval) were 1.24 (1.13-1.36) and 1.15 (1.07-1.22), respectively. Twenty-four-hour urinary salt excretion on admission is useful for predicting significant weight loss with short-term dietary salt restriction.

High-protein diet prevents fat mass increase after dieting by counteracting Lactobacillus-enhanced lipid absorption.

Dietary restriction is widely used to reduce fat mass and lose weight in individuals with or without obesity; however, weight regain after dieting is still a big challenge, and the underlying mechanisms remain largely elusive. Here we show that refeeding after various types of dieting induces quick fat accumulation in mice and enhanced intestinal lipid absorption contributes to post-dieting fat mass increase. Moreover, refeeding after short-term dietary restriction is accompanied by an increase in intestinal Lactobacillus and its metabolites, which contributes to enhanced intestinal lipid absorption and post-dieting fat mass increase; however, refeeding a high-protein diet after short-term dietary restriction attenuates intestinal lipid absorption and represses fat accumulation by preventing Lactobacillus growth. Our results provide insight into the mechanisms underlying fat mass increase after dieting. We also propose that targeting intestinal Lactobacillus to inhibit intestinal lipid absorption via high-protein diet or antibiotics is likely an effective strategy to prevent obesity after dieting.

Temporal Dynamics of the Intestinal Microbiome Following Short-Term Dietary Restriction.

Short-term dietary restriction has been proposed as an intriguing pre-operative conditioning strategy designed to attenuate the surgical stress response and improve outcomes. However, it is unclear how this nutritional intervention influences the microbiome, which is known to modulate the systemic condition. Healthy individuals were recruited to participate in a four-day, 70% protein-restricted, 30% calorie-restricted diet, and stool samples were collected at baseline, after the restricted diet, and after resuming normal food intake. Taxonomy and functional pathway analysis was performed via shotgun metagenomic sequencing, prevalence filtering, and differential abundance analysis. High prevalence species were altered by the dietary intervention but quickly returned to baseline after restarting a regular diet. Composition and functional changes after the restricted diet included the decreased relative abundance of commensal bacteria and a catabolic phenotype. Notable species changes included Faecalibacterium prausnitzii and Roseburia intestinalis, which are major butyrate producers within the colon and are characteristically decreased in many disease states. The macronutrient components of the diet might have influenced these changes. We conclude that short-term dietary restriction modulates the ecology of the gut microbiome, with this modulation being characterized by a relative dysbiosis.

Effect of short-term dietary protein restriction before slaughter on meat quality and skeletal muscle metabolomic profile in culled ewes

Tenderness is one of the most important meat quality traits. It has been suggested that a short-term dietary protein restriction prior to slaughter could change muscle protein turnover and improve meat tenderness without affecting animal performance. Therefore, the aim of this study was to evaluate the effect of a short-term dietary protein restriction in the end of the finishing phase on skeletal muscle metabolome and meat quality traits of culled ewes. Fourteen crossbred ewes (3 years of age) averaging 39.3 ± 9.4 kg of body weight (BW) were enrolled in this study. Culled ewes were grouped (n = 7) and randomly assigned to one of the following treatments, consisting of: continuously fed the control diet with 13.3% of crude protein (CTRL); fed the control diet to reach the target body weight (45 kg) followed by 14 days feeding a low protein diet (4.33% crude protein; STR). The experiment lasted 46 days. Short-term dietary protein restriction increased meat shear-force at 1 day postmortem (3.67 vs. 3.02 kgf; P = 0.04), which could be partially explained by the higher total collagen content (P = 0.02) in STR compared to CTRL group (2.35 vs. 2.05 mg/g). The protein restriction did not affect final body weight nor carcass weight (P > 0.05), but decreased backfat thickness (3.19 vs. 5.10 mm; P = 0.04). Excreted and retained nitrogen were respectively 80.4% and 70% lower in STR (P < 0.01) than in the CTRL group. A lower abundance of valine (P = 0.02) and asparagine (P = 0.01) was observed in skeletal muscle of STR ewes compared to the CTRL group. Of the muscle metabolites identified, progesterone, succinic acid, and tartronic acid were positively correlated with meat shear-force (toughness), while lysine was negatively correlated (P < 0.05) with the same trait. Collectively, our data shows that despite the changes observed in the skeletal muscle for the abundance of metabolites involved in energy and protein metabolism, the short-term dietary protein restriction near maintenance level prior to slaughter did not improve quality of ewes’ meat quality traits.

The Impact of Short-Term Dietary Restriction on Stem Cell Function

Stem cells play a critical role in the maintenance of tissue function and their proliferative/regenerative capacity is essential to this role. Because stem cells persist over the lifespan of an animal, they are susceptible to gradual accumulation of age-associated damage, resulting in the loss of regenerative function that can impair organ function. Understanding the mechanism(s) that regulates stem cell function is essential for retarding the aging process, and stem cells are attractive targets for aging interventions. Dietary restriction (DR), the most robust anti-aging intervention to-date, has been shown to enhance the activity and integrity of stem cells in a variety of tissues (e.g., muscle, bone marrow, and intestine), and it is believed that effect of DR on stem cells plays an important role in the anti-aging action of DR. For example, DR has been shown to preserve and increase the number of intestinal stem cells (ISCs) and enhance their regenerative capacity in young animals. Data from my lab shows that ISCs from old mice have limited proliferation activity and form few if any organoids in vitro (a surrogate for a fully functional crypt) and that ISCs isolated from old mice on life-long DR show an improved ability to form organoids. While it is well accepted that life-long DR increases lifespan and has anti-aging effects an important aspect of DR that has been largely overlooked is that DR implemented only for a short time early in life can increase lifespan of rodents even when rodents are fed ad libitum the remainder of their life. In line with this, we recently found that ISCs from old mice fed DR for only a short-period resulted in a dramatic increase in ability of the ISCs to form organoids. This is the first evidence that short-term DR administrated late in life can rescue the loss in ISC function that occurs with age.

Persistence: A key factor in understanding the circumstances under which dietary restraint predicts restriction of caloric intake

Dietary restraint refers to the intention to restrict caloric intake, whereas dietary restriction refers to the actual intentional and sustained restriction of caloric intake for weight-control purposes. Findings regarding the relation between dietary restraint and restriction to date are inconsistent. Our study sought to clarify this complex relationship using a novel laboratory task. Participants (N = 103; 56.3% female) completed a Paced Visual Serial Addition Task (PVSAT). Participants were provided a choice between ending each of eight PVSAT rounds at any time and drinking a high-calorie Kool-Aid® mixture or correctly completing 10 consecutive computations to access to a zero-calorie mixture for each round. We measured participants' dietary restraint using the Three-Factor Eating Questionnaire – Restraint Subscale and measured persistence and dietary restriction using the PVSAT. Results indicated a positive association between persistence and restriction. Female participants demonstrated higher eating disorder psychopathology, dietary restraint, and dietary restriction compared to male participants. Restraint was positively associated with restriction the more individuals persisted, indicating that persistence is a potentially important modifier of the relation between dietary restraint and restriction. Our findings highlight the complexity of the relation between dietary restraint and restriction; that is, measures of dietary restraint alone may not reliably predict short-term dietary restriction during laboratory consumption tasks; however, other factors, such as persistence, may play critical roles.

Short-term dietary restriction maintains synaptic plasticity whereas short-term overfeeding alters cellular dynamics in the aged brain: evidence from the zebrafish model organism

Increased caloric intake (OF) impairs quality of life causing comorbidities with other diseases and cognitive deficits, whereas dietary restriction (DR) increases healthspan by preventing age-related deteriorations. To understand the effects of these opposing dietary regimens on the cellular and synaptic dynamics during brain aging, the zebrafish model, which shows gradual aging like mammals, was utilized. Global changes in cellular and synaptic markers with respect to age and a 12 week dietary regimen of OF and DR demonstrated that aging reduces the levels of the glutamate receptor subunits, GLUR2/3, inhibitory synaptic clustering protein, GEP, synaptic vesicle protein, SYP, and early-differentiated neuronal marker, HuC. DR significantly elevates levels of glutamate receptor subunits, GLUR2/3, and NMDA clustering protein, PSD95, levels, while OF subtly increases the level of the neuronal protein, DCAMKL1. These data suggest that decreased caloric intake within the context of aging has more robust effects on synapses than cellular proteins, whereas OF alters cellular dynamics. Thus, patterns like these should be taken into account for possible translation to human subjects.

Effects of short-term dietary restriction on plasma metabolites and the subcutaneous fat area according to metabolic status in obese individuals: a case\u2013control study

BackgroundResearch elucidating the metabolic mechanisms that differentiate subtypes of obesity has been increasing. We aimed to investigate the effects of a 12-week dietary intervention on the metabolomic profiles of obese subjects.MethodsSubjects followed a 12-week dietary restriction protocol consisting of a 300 kcal/day reduction in their usual caloric intake. Twenty-nine obese subjects were included and divided into two groups: the metabolic status maintenance group (n = 17, controls) and the metabolic status improvement group (n = 12, tests). We analyzed the somatometric and biochemical parameters and performed ultra-performance liquid chromatography-mass spectrometry analysis of the plasma metabolites.ResultsAt 12 weeks, the fat percentage, whole fat area (WFA), subcutaneous fat area (SFA) at the L1 vertebra, and the levels of triglycerides, gamma-glutamyltransferase (gamma-GT), and leptin were markedly decreased in the metabolic status improvement group, while the level of high-density lipoprotein cholesterol increased compared with that in the metabolic status maintenance group. Metabolomic profiling at 12 weeks showed substantial differences in 4-aminobutyraldehyde (p = 0.005) and 4’-apo-β-carotenal (p = 0.024) between the two groups. Furthermore, an AUC value of 0.89 was obtained for the following seven featured biomarkers: triglycerides, gamma-GT, leptin, fat percentage, WFA, and SFA at the L1 vertebra, and 4-aminobutyraldehyde.ConclusionsWe demonstrated that 4-aminobutyraldehyde and related regional fat distribution parameters were strongly associated with obesity according to metabolic status. Thus, these biomarkers are potentially valuable in confirming the efficacy of short-term interventions and predicting metabolic status in obese individuals.Trials registration: This study was registered at ClinicalTrials.gov under NCT03135132 (registered 1 May 2017—retrospectively registered).

Preconditioning with Short-term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload.

Left ventricular (LV) hypertrophy and associated heart failure are becoming a more prevalent and critical public health issue with the aging of society, and are exacerbated by reactive oxygen species (ROS). Dietary restriction (DR) markedly inhibits senescent changes; however, prolonged DR is difficult. We herein investigated whether preconditioning with short-term DR attenuates chronic pressure overload-induced cardiac hypertrophy and associated oxidative stress. Male c57BL6 mice were randomly divided into an ad libitum (AL) diet or 40% restricted diet (DR preconditioning, DRPC) group for 2 weeks prior to ascending aortic constriction (AAC), and all mice were fed ad libitum after AAC surgery. Two weeks after surgery, pressure overload by AAC increased LV wall thickness in association with LV diastolic dysfunction and promoted myocyte hypertrophy and cardiac fibrosis in the AL+AAC group. Oxidative stress in cardiac tissue and mitochondria also increased in the AL+AAC group in association with increments in cardiac NADPH oxidase-derived and mitochondrial ROS production. LV hypertrophy and associated cardiac dysfunction and oxidative stress were significantly attenuated in the DRPC+AAC group. Moreover, less severe mitochondrial oxidative damage in the DRPC+AAC group was associated with the suppression of mitochondrial permeability transition and cardiac apoptosis. These results indicate that chronic pressure overload-induced cardiac hypertrophy in association with cardiac and mitochondrial oxidative damage were attenuated by preconditioning with short-term DR.

Dietary magnesium restriction affects hematopoiesis and triggers neutrophilia by increasing STAT-3 expression and G-CSF production

Magnesium (Mg2+) is able to modulate the differentiation and proliferation of cells. Mg2+ restriction can trigger neutrophilia, but the processes that result in this change have yet to be investigated and are not fully understood. Hematopoiesis is a complex process that is regulated by many factors, including cytokines and growth factors, and is strongly influenced by nutrient availability. In this context, our objective was to investigate the impact of the short-term restriction of dietary Mg2+ on bone marrow hematopoietic and peripheral blood cells, especially in processes related to granulocyte differentiation and proliferation. Male C57BL/6 mice were fed a Mg2+ restricted diet (50mgMg2+/kg diet) for 4 weeks. Cell blood count and bone marrow cell count were evaluated. Bone marrow cells were also characterized by flow cytometry. Gene expression and cytokine production were evaluated, and a colony-forming cell assay related to granulocyte differentiation and proliferation was performed. Short-term dietary restriction of Mg2+ resulted in peripheral neutrophilia associated with an increased number of granulocytic precursors in the bone marrow. Additionally, Mg2+ restriction resulted in an increased number of granulocytic colonies formed invitro. Moreover, the Mg2+ restricted group showed increased expression of CSF3 and CEBPα genes as well as increased production of G-CSF in association with increased expression of STAT3 protein. Short-term dietary restriction of Mg2+ induces granulopoiesis by increasing G-CSF production and activating the CEBPα and STAT-3 pathways, resulting in neutrophilia in peripheral blood.

Short-term dietary restriction ameliorates brain injury after cardiac arrest by modulation of mitochondrial biogenesis and energy metabolism in rats.

BackgroundDietary restriction (DR) is a well-known intervention that increases lifespan and resistance to multiple forms of acute stress, including ischemia reperfusion injury. However, the effect of DR on neurological injury after cardiac arrest (CA) remains unknown.MethodsThe effect of short-term DR (one week of 70% reduced daily diet) on neurological injury was investigated in rats using an asphyxial CA model. The survival curve was obtained using Kaplan-Meier survival analysis. Serum S-100β levels were detected by enzyme linked immunosorbent assay. Cellular apoptosis and neuronal damage were assessed by terminal deoxyribonucleotide transferase dUTP nick end labeling assay and Nissl staining. The oxidative stress was evaluated by immunohistochemical staining of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Mitochondrial biogenesis was examined by electron microscopy and mitochondrial DNA copy number determination. The protein expression was detected by western blot. The reactive oxygen species (ROS) and metabolite levels were measured by corresponding test kits.ResultsShort-term DR significantly improved 3-day survival, neurologic deficit scores (NDS) and decreased serum S-100β levels after CA. Short-term DR also significantly attenuated cellular apoptosis, neuronal damage and oxidative stress in the brain after CA. In addition, short-term DR increased mitochondrial biogenesis as well as brain PGC-1α and SIRT1 protein expression after CA. Moreover, short-term DR increased adenosine triphosphate, β-hydroxybutyrate, acetyl-CoA levels and nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) ratios as well as decreased serum lactate levels.ConclusionsReduction of oxidative stress, upregulation of mitochondrial biogenesis and increase of ketone body metabolism may play a crucial role in preserving neuronal function after CA under short-term DR.

Temporal Dynamics of the Intestinal Microbiome after Short-Term Dietary Protein Restriction

Temporal Dynamics of the Intestinal Microbiome after Short-Term Dietary Protein Restriction

Our Strategy to Overcome Hepatic Ischemia Reperfusion Injury -From Bench to Bedside-

Background: In the field of liver surgery, especially transplantation, ischemia reperfusion injury (IRI) causes approximately 10% of early graft failure and leads to a higher incidence of acute and chronic rejection. It is an urgent issue to overcome IRI from the viewpoint of organ preservation. This study aims to reveal the molecular mechanism and develop the effective protective way to prevent the liver IRI for a safer liver surgery. Methods :We applied the established partial warm hepatic IRI model in mice and investigated changes of immune responses due to IR, and compared the efficacy of various biological molecules (neutrophil elastase inhibitor, recombinant Galectin-9, recombinant thrombomodulin and so on), antioxidant agents (vitamins C and E) and maneuvers (preoperative short-term fasting). The liver damage was assessed by serum alanine aminotransferase (sALT) level, histological observations, change in expression profile of various cytokines and analysis of intracellular molecules. Results: The most effective way to improve IRI was the preoperative short-term (12 hours) fasting. It exhibited a remarkable therapeutic effect compared with any other drug or diet we have so far examined. The up-regulation of Forkhead Box O1 (FOXO-1) induced by the raised acetylated histone and β-hydroxybutyric acid was a crucial factor for the short-term fasting to ameliorate the liver injury due to IR. Conclusion: Preoperative short-term dietary restriction might play an important role to overcome liver IRI and have a therapeutic potential for clinical setting.

Short-term protein restriction at advanced age stimulates FGF21 signalling, energy expenditure and browning of white adipose tissue.

Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age-related decline in metabolic flexibility on the effects of dietary protein restriction has not been addressed. Therefore, we investigated the effect of short-term dietary protein restriction on metabolic health in young and aged mice. Young adult (3months old) and aged (18months old) C57Bl/6J mice were subjected to a 3-month dietary protein restriction. Outcome parameters included fibroblast growth factor 21 (FGF21) levels, muscle strength, glucose tolerance, energy expenditure (EE) and transcriptomics of brown and white adipose tissue (WAT). Here, we report that a low-protein diet had beneficial effects in aged mice by reducing some aspects of age-related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous WAT, increased body temperature and EE, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low-protein diet used in this study was well-tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity and muscle performance. In conclusion, our study demonstrates that a short-term reduction in dietary protein intake can impact age-related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce EE and browning of WAT in aged individuals.

Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats.

Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.

Long-term mid-onset dietary restriction rejuvenates hematopoietic stem cells and improves regeneration capacity of total bone marrow from aged mice.

Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early‐onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid‐onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15‐ to 18‐month‐old mice (equivalent to 50–60 human years) for short‐term (4 months) and long‐term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short‐term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long‐term mid‐onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long‐term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short‐term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid‐onset DR ameliorates the function of aging HSCs and long‐term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available.