Effects Of Long-term Dietary Restriction Research Articles

2,2-Dichloroacetamide exposure induces behavior and memory disorders in mice: Detrimental effects of long-term dietary restriction on neurotoxicity

2, 2-dichloroacetamide (DCAcAm), a nitrogen-containing disinfection byproduct (DBPs), is commonly found in potable water. This study aimed to compare the neurotoxicity of DCAcAm in C57/BL6 mice at both environmentally relevant and higher doses through oral exposure over a 28-day period. Furthermore, the potential effects of dietary restriction (DR) on the cerebral toxicity induced by 20 ppb DCAcAm were examined. The findings indicated that DCAcAm exposure and DR treatment resulted in reduced memory retention and cognitive adaptability in mice. Additionally, higher doses of DCAcAm exposure induced severe brain inflammation and oxidative stress. Metabolic profiling revealed disruptions in fatty acid, energy, and amino acid metabolism in the brain. Remarkably, the negative impacts of 20 ppb DCAcAm on the mice brain were worsened by DR treatment. Analysis of 16S rRNA sequencing revealed notable changes in the composition and structure of intestinal microorganisms after exposure to DCAcAm. This study discovered that DCAcAm has both direct effects on the brain and indirect effects through the microbial-brain-intestinal axis, which collectively result in neurotoxicity and dietary restriction exacerbates these effects. This study provides emerging views on the assessment of the toxicity of nitrogen containing DBPs.

Long-term lifestyle intervention is superior to transient modification for neuroprotection in D-galactose-induced aging rats

AimsTo investigate whether transient dietary restriction or aerobic exercise in young adulthood exert long-lasting protection against brain aging later in life. Main methodsSeven-week-old male Wistar rats were divided into 2 groups and given either normal saline as a vehicle (n = 8) or 150 mg/kg/day of D-galactose (n = 40) for 28 weeks, the D-galactose being used to induce aging. At week 13 of the experiment, D-galactose-treated rats were further divided into 5 groups, 1) no intervention, 2) transient dietary restriction for 6 weeks (week 13–18), 3) transient exercise for 6 weeks (week 13–18), 4) long-term dietary restriction for 16 weeks (week 13–28), and 5) long-term exercise for 16 weeks (week 13–28). At the end of week 28, cognitive function was examined, followed by molecular studies in the hippocampus. Key findingsOur results showed that either long-term dietary restriction or aerobic exercise effectively attenuated cognitive function in D-galactose-treated rats via the attenuation of oxidative stress, cellular senescence, Alzheimer's-like pathology, neuroinflammation, and improvements in mitochondria, brain metabolism, adult neurogenesis, and synaptic integrity. Although transient interventions provided benefits in some brain parameters in D-galactose-treated rats, an improvement in cognitive function was not observed. SignificanceOur findings suggested that transient lifestyle interventions failed to exert a long-lasting protective effect against brain aging. Hence, novel drugs mimicking the neuroprotective effect of long-term dietary restriction or exercise and the combination of the two since young age appear to be more appropriate treatments for the elderly who are unable to engage in long-term dietary restriction or exercise.

Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction.

BackgroundChronic dietary restriction (DR) has been shown to have beneficial effects on glucose homeostasis and insulin sensitivity. These factors show rapid and robust improvements when rodents were crossed over from an ad libitum (AL) diet to DR in mid life. We aimed to determine whether the beneficial effects induced by short-term exposure to DR can be retained as a ‘metabolic memory’ when AL feeding is resumed (AL-DR-AL) and vice versa: whether the effects of long-term DR can be reversed by a period of AL feeding (DR-AL-DR). C57BL/6 male and female mice were used to examine sex differences (N = 10/sex/group). Mice were fed AL or DR from 3 until 15 months (baseline) and each dietary crossover lasted approximately 5 months.ResultsIn females, body and fat mass were proportional to the changes in feeding regime and plasma insulin and glucose tolerance were unaffected by the crossovers. However, in male mice, glucose tolerance and plasma insulin levels were reversed within 6 to 12 weeks. When males returned to AL intake following 5 months DR (AL-DR-AL), body mass was maintained below baseline, proportional to changes in fat mass. Glucose tolerance was also significantly better compared to baseline.ConclusionsMale mice retained a metabolic memory of 5 months of DR feeding in terms of reduced body mass and improved glucose tolerance. This implies that some of the beneficial effects induced by a period of DR in adult life may be beneficial, even when free feeding is resumed at least in males. However, under continuous DR, lifespan extension was more prominent in females than in males.

Biogerontology in Serbia

Aging is caused by gradual accumulation of cell and tissue damage. Accumulation of damage begins early and continues progressively throughout life, resulting after several decades in the overt frailty, disability and diseases associated with aging. In Serbia during the last few years, several different institutions participated in the investigation in the aging process: (1) Changes in hormone signaling with aging-the age-related increase in insulinemia and glucose metabolism deregulation was found to be attributed to changes in insulin signaling as demonstrated on murine models. (2) Changes in immunological response in aging-along with involution of thymic lymphoepithelial tissue, it has been demonstrated on a murine model that early thymocyte differentiational steps within the CD4-8-double negative developmental stage are age-sensitive. (3) Changes in cholesterol metabolism and oxidative processes in aging-the beneficial effect of long-term dietary restriction on ageing, was explained as effect on cholesterol metabolism. (4) Alzheimer's disease-the connection between neurodegenerative processes associated to the Alzheimer's disease and the function of the Na-K-ATPase which is known to be altered by ageing has been experimentally shown. The recent work of Serbian investigators suggest some new evidence that aging process influences the hormone signaling, immunological response, cholesterol metabolism and oxidative processes.

Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction.

Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p <.05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. The oldest monkey was a diabetic female (AL) that lived to be 40 years of age. These results suggest that dietary restriction leads to an increased average age of death in primates, associated with the prevention of hyperinsulinemia and the mitigation of age-related disease.

Life-long diet restriction failed to retard cognitive aging in Fischer-344 rats☆

Although the beneficial effects of diet restriction on longevity and the retardation of many somatic age-related processes are well established, the answer to the question of whether anti-aging effects of diet restriction extend to the brain and cognitive function remains unclear. In the present study, the effects of long-term dietary restriction (60% of ad-libitum calories) on an age-related alteration of memory and sensorimotor function have been investigated in Fischer 344 male rats at four different ages: 6 months, 12 months, 18 months, and 24 months. A major drop in reference memory of DR and AL rats occurred at the age of 18 months. The performance deficits in working memory tasks were observed in both diet groups at the age of 24 months. These results indicate that diet restriction failed to provide protection against age-related deficits in memory. Although DR rats outperformed AL rats in sensorimotor tasks throughout the life-span, the slope of the declining function in DR rats paralleled those of AL rats, suggesting that diet restriction failed to alter the rate of aging in sensorimotor performance, as well.

Effects of long-term dietary restriction on cardiovascular function and plasma catecholamines in the rat.

To examine the relationship between heart function and plasma catecholamines upon food restriction, normal adult rats were fed 12 g or 6 g food/day for 14 days and 12 g food/day for 28 days. Food-restricted rats exhibited bradycardia, hypotension, and decreased rates of cardiac contraction (+dP/dt) as well as relaxation (-dP/dt) at 14 (12 or 6 g food/day) and 28 (12 g food/day) days. Plasma norepinephrine and epinephrine levels were significantly elevated in the 6 g food/day group at 14 days, whereas in the 12 g food/day group, plasma norepinephrine was elevated at 14 days but was significantly decreased at 28 days. Heart norepinephrine and epinephrine concentrations were elevated at both 14 and 28 days of food restriction in the 12 g food/day group as well as at 14 days in the 6 g food/day group. Thus, dietary restriction appears to result in depressed indices of heart function, while the circulating levels of catecholamines were elevated at early stages.

Dietary restriction modulates the norepinephrine content and uptake of the heart and cardiac synaptosomes.

The present study was designed to examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad libitum fed animals, while the heart weight to body weight ratios were higher. The norepinephrine (NE) content of hearts from restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38 ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly, the cardiac synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves.

Undernutrition in relation to changed tissue composition in red deer (Cervus elaphus)

The effect of long-term dietary restriction on the composition of the liver, the kidney, and several muscles was studied in red deer (Cervus elaphus). Food-restricted animals (n = 3) received approximately 20% of the ration of control animals (n = 3) for 13–23 weeks. Extreme undernutrition was associated with a reduction in body mass and a relatively large reduction in mass of the liver and kidney. Total protein and total DNA content as well as the protein/DNA ratio of the liver and kidney of food-restricted animals were lower, whereas the DNA concentration was higher, than in the control animals. The findings suggest a reduction in organ mass through a reduction in both cell size and cell number. The lower protein/DNA ratio and the increased DNA concentration in muscle of food-restricted animals suggest a reduction of cell size. The results obtained from different muscles indicate considerable variation in response to undernutrition among muscles. It is concluded that protein mobilization contributes to a depression of ketone body formation. The quantity of protein loss differed between anatomical sites. The concentration of protein and DNA and the protein/DNA ratio in the liver, kidney, and several muscles provide information about the nutritional status of red deer.

Dietary restriction does not alter retinal aging in the Fischer 344 rat

In the present study, the effects of long-term dietary restriction (60% of the calories in the ad lib diet, beginning at 16 weeks of age) on quantitative morphometric measures and histopathologic indications of aging have been investigated in the retina of Fischer 344 male rats. The animals were maintained by the NIA Biomarkers Program, National Center for Toxicological Research. Group size ranged from 8 to 15 rats. A gradual thinning of the outer nuclear layer (ONL) of photoreceptor nuclei occurred with aging in control ad lib groups. The restricted diet did not affect retinal aging in 18-, 21-, 26-, or 27-month-old rats, as judged by photoreceptor cell death, ONL thickness, and pattern of cell loss. Retinal thickness (RT) was unaffected by restricted diet, except in the 21-month-old group; in that group, the RT was reduced significantly in thickness as compared to ad lib animals. These results are in contrast to studies of dietary restriction on most nonneuronal markers of aging and suggest that a different mechanism may modulate at least some aspects of brain aging.

The effect of chronic and acute dietary restriction on the growth and protein turnover of fast and slow types of rat skeletal muscle

1. 1. Changes in the growth and protein turnover of the anterior tibialis and soleus muscles were studied in response to acute and chronic dietary restriction (50% of ad libitum intake) between 3 and 149 weeks post partum. 2. 2. The effect of long-term dietary restriction from weaning to senescence was to retard the growth and normal developmental of the two types of skeletal muscle. This was evident from measurements of various parameters of growth, i.e. total protein, RNA and DNA and protein/DNA-P, which were reduced by approximately 50% when compared with age-matched controls. These decreases, however, were not accompanied by a decline in the fractional rate of synthesis (%day) or ribosomal activity (mg protein/day per mg RNAP). The slowing down of the age-related decline in muscle growth has been attributed to a reduction in RNA capacity (RNA/protein), with similar responses in the fast- and slow-twitch skeletal muscles. 3. 3. The initial effects of piecemeal feeding of this restricted diet on the two types of muscle were also monitored. Short term starvation effects, i.e. 24 hr after feeding a reduced ration, were measured on the protein content and RNA/prtein of both the anterior tibialis and soleus muscles; both parameters were unchanged within 24 hr. In contrast, a rapid and significant decline in the ribosomal synthetic activity (mg/d per mg RNAP), and a corresponding fall in the fractional rate of synthesis, occurred within 24 hr of feeding.