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PubMed1975

Effects of obesity and caloric intake on biliary lipid metabolism in man.

The effects of obesity and caloric intake on biliary lipid metabolism were investigated in a series of related studies. The degree of saturation of gallbladder bile with cholesterol was found to be significantly higher in a group of 23 obese healthy subjects than in a group of 23 nonobese controls matched for age, sex, and race. Bile was also significantly more saturated in 11 obese subjects before than after weight reduction. To determine whether supersaturated bile in obesity is due to excessive secretion of cholesterol or to deficient secretion of bile acids and phospholipids, the hepatic outputs of these three lipids were measured during constant duodenal infusion of formula in the same 11 subjects before and after weight reduction. Weight reduction resulted in significant reduction of cholesterol output but not of bile acid or phospholipid output. Moreover, very obese subjects were found to have cholesterol secretion rates markedly higher than less obese subjects previously studied by the same method. In obese subjects, bile was supersaturated with cholesterol despite increased bile acid pool sizes and increased secretion rates of bile acids and phospholipids. Supersaturated bile in the obese could therefore be attributed to a single defect in lipid secretion, namely, an excessive output of cholesterol. To determine whether the rate of caloric intake can account for the effects of obesity on biliary lipid composition and secretion, nine obese white men were studied on a weight maintenance diet and then during weight reduction on a 1,000 cal diet. As compared to weight maintenance, chronic caloric restriction resulted in reduced outputs of cholesterol, bile acids, and phospholipids, reduced bile acid pool size, and reduced synthesis and fecal excretion of cholesterol. Saturation of bile with cholesterol did not decrease during weight reduction, evidently because of the mobilization of cholesterol from adipose stores and the marked reduction in bile acid and phospholipid output observed during chronic caloric restriction. Acute alterations in caloric infusion rates did not fully reproduce the effects of chronic administration of high and low calorie diets. Likewise, chronic intake of hypercaloric diets by nonobese subjects did not reproduce the cholesterol hypersecretion characteristic of the obese. Thus, increased cholesterol secretion in obese subjects could not be fully explained by the amount of calories they ingested to maintain stable weight. It is concluded that obesity is characterized by excessive hepatic secretion of cholesterol which results in supersaturated bile.

Adipose Tissue↗

PubMed2005

Molecular events in kidney ageing.

PURPOSE OF REVIEW: Ageing of the kidney is a problem of clinical and basic interest. The problem of renal dysfunction and end-stage renal disease is a major burden on the health system, and old donor age is a major limitation on the use of donor organs and on survival of transplanted kidneys. Moreover, stresses linked to nephropathies, postoperative stress, inflammation and allograft rejection can lead to premature senescence of renal cells thus accelerating organ atrophy. Age-related and disease or stress-related nephron loss could reflect both the limited ability of epithelial cells to repair and replicate in the face of environmental stresses, and limitations on the number of cell replications caused by telomere shortening. Therefore, elucidating cellular senescence mechanisms is relevant to kidney diseases and kidney transplantation. RECENT FINDINGS: Recent findings suggest additive effects of replicative and environmental stress-induced senescence in cellular and organ ageing. In particular, ATM/p53/p21 and Ras/p38/p16 pathways have been shown to co-contribute to the overall cellular senescence, which is caused by extrinsic and intrinsic stimuli. Moreover, the role of epigenetic factors, including protein acylation/deacetylation, chromatin remodeling or caloric restriction, is the focus of recent studies on ageing and senescence. SUMMARY: Despite significant progress, cellular senescence is still better understood in vitro than in vivo. So far, p16 remains the best marker of chronological age in the kidney, and can be considered as an indicator of premature senescence caused by stresses or disease. The beneficial effects of caloric restriction on organ ageing and the role of histone acetylation in pathologic states in rodents are of considerable interest, and deserve future studies.

Aging↗

PubMed2006

Effects of food restriction on synthesis and expression of brain-derived neurotrophic factor and tyrosine kinase B in dentate gyrus granule cells of adult rats.

We have previously found that the dendritic trees of dentate gyrus granule cells are selectively vulnerable to food restriction but there are reorganizational morphological events that minimize functional impairments. As the neurotrophin brain-derived neurotrophic factor (BDNF) and the cognate receptor tyrosine kinase B (TrkB) are involved in the maintenance of the structure of dendritic trees, we thought of interest to verify if there are alterations in its synthesis and expression in granule cells. To investigate this issue, 2-month-old rats were submitted to 40% caloric restriction for 6 months and compared to controls fed ad libitum. The numbers of granule cells containing BDNF and TrkB proteins were estimated from immunostained sections and the respective mRNA levels of individual neurons evaluated using nonradioactive in situ hybridization. After dietary treatment there was a 15% reduction of BDNF-immunoreactive granule cells with no changes of the number of TrkB-immunostained neurons. No alterations were found in the levels of BDNF and TrkB mRNAs of individual granule cells. As caloric restriction extends the lifespan of animals, the restrictive dietary regimens are generally regarded as beneficial to the organisms, but the present results suggest that caution is needed when extrapolating to some neuronal populations.

Animals↗

PubMed2005

SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes.

SIRT3 is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene, which mediates the effect of caloric restriction on life span extension in yeast and Caenorhabditis elegans. Because adipose tissue is essential in energy homeostasis and also plays a role in life span determination, we decided to investigate the function of sirtuin members in fat. We report here that murine SIRT3 is expressed in brown adipose tissue and is localized on the mitochondria inner membrane. Caloric restriction activates SIRT3 expression in both white and brown adipose. Additionally, cold exposure up-regulates SIRT3 expression in brown fat, whereas elevated climate temperature reduces the expression. Enforced expression of SIRT3 in the HIB1B brown adipocytes enhances the expression of the uncoupling protein PGC-1alpha, UCP1, and a series of mitochondria-related genes. Both ADP-ribosyltransferase and deacetylase activities of SIRT3 are required for this action. Furthermore, the SIRT3 deacetylase mutant exhibits a dominant negative effect by inhibiting UCP1 expression. This inhibitive effect can be abolished by the coexpression of PGC-1alpha, indicating a major role of PGC-1alpha in the SIRT3 action. In addition, SIRT3 stimulates CREB phosphorylation, which reportedly activates PGC-1alpha promoter directly. Functionally, sustained expression of SIRT3 decreases membrane potential and reactive oxygen species production while increasing cellular respiration. Finally, SIRT3, along with genes related to mitochondrial function, is down-regulated in the brown adipose tissue of several genetically obese mice. In summary, our results demonstrate that SIRT3 activates mitochondria functions and plays an important role in adaptive thermogenesis in brown adipose.

ADP Ribose Transferases↗

PubMedDate not supplied

Lifestyle and prevention of cardiovascular disease in the elderly: an Italian perspective.

The life span of human beings is partially influenced by genetic factors, but outcomes of aging are profoundly influenced by lifestyle and other environmental factors. Age-related modifications of the cardiovascular system are preserved by antiaging lifestyle interventions such as physical activity and caloric restriction. Accordingly, physical activity and low body mass index reduce mortality in older men with cardiovascular diseases. Several mechanisms have been proposed to explain the protective effect of lifestyle interventions against cardiovascular diseases in the elderly, including a reduction of vulnerability (i.e., the age-related reduction of endogenous mechanisms protective against pathologic insults). The age-related reduction of ischemic preconditioning, the most powerful endogenous protective mechanism against myocardial ischemia, is restored by both physical activity and caloric restriction. Thus, older persons can implement lifestyle practices that minimize their risk of death from cardiovascular diseases.

Aged↗

PubMed2004

Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice.

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and the rate of glucose disappearance (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2(-/-) mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the Adeno-IRS-2-infected Irs2(-/-) mice. Irs2(-/-) mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3-kinase activation. Continuous intracerebroventricular leptin infusion or caloric restriction yielded Irs2(-/-) mice whose adiposity was comparable to that of Irs2(+/+) mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd albeit partially. Finally combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous intracerebroventricular leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2(-/-) mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2(-/-) mice.

Adenoviridae↗

PubMed1978

Neural and endocrine development after chronic tryptophan deficiency in rats: I. Brain monoamine and pituitary responses.

Caloric restriction and tryptophan deficient diets have been shown to delay aging in the immature laboratory rat. Studies of monoamine levels in the brain of developing female rats fed on these diets show changes in serotonin but not norepinephrine or dopamine levels: in tryptophan-restricted rats serotonin levels were reduced in all brain areas studied, whereas in caloric-restricted animals serotonin levels were increased in the cerebral hemispheres only. Another group of animals, in which growth and maturation was delayed by feeding d,1-parachlorophenylalanine (PCPA) showed decreases in serotonin, norepinephrine and dopamine concentrations in all brain regions investigated. All treatments employed to arrest growth and maturation resulted in pituitary alterations manifested by gross, histological and ultrastructural changes. It is postulated that there maturation- and age-retarding treatments delay the development of the central nervous system resulting in postponed maturation of the neuroendocrine axis, with consequent hypoactivity of certain pituitary functions and a resultant delay in the onset of maturation and senescence.

Animals↗

PubMedDate not supplied

[In vivo study of mitochondrial oxidation in obese patients treated by means of calorie restriction].

The energy restriction is the most common nutritional approach to treat obesity, whose efficiency depends on oxidative response against changes in body weight. In that context, the aim of the present work was to in vivo examine the mitochondrial oxidation of obese volunteers by the 2-keto[1-(13)C]isocaproate breath test, before and after weight loss. Thirty-two volunteers (men and women) participated: 16 controls (body mass index: 19.0-27.0 kg/m2), and 16 obese (body mass index: 30.0-41.6 kg/m2) who followed a caloric restriction program for 10 weeks (-500 kcal). Before and after dieting, the 2-keto[1-(13)C]isocaproate breath test was performed by ingestion of 1 mg/kg tracer and 20 mg/kg L-leucine, dissolved in 200 ml orange juice. Breath samples were recovered at baseline and at 10 min intervals for 2 h after ingestion. The 13C-enrichment in breath was measured by isotope ratio mass spectrometry and the percentage of mitochondrial oxidation of tracer (%13C) was calculated. The percentage of oxidized tracer marginally tended to be lower in obese than in controls (25.1 +/- 5.5%, vs 27.5 +/- 4.0%, p = 0.175). After the intervention, the mean of weight loss was -7.8% +/- 3% p < 0.001), and the mitocondrial oxidation of the tracer statistically increased (25.1 +/- 5.5% vs 34.3 +/- 5.2%, p < 0.001). In fact, the body weight and the percentage of oxidized 2-keto[1-(13)C]isocaproate were inversely related (r = -0.34, p = 0.018). Thus, the 2-keto[1-(13)C]isocaproate in vivo showed the mitochondrial adaptation of obese volunteers treated by caloric-restriction intake and provided new information about the weight loss process induced by an hypocaloric diet.

Adult↗

PubMed2004

Long-lived alpha MUPA transgenic mice exhibit increased mitochondrion-mediated apoptotic capacity.

Caloric restriction (CR) is currently the only therapeutic intervention known to attenuate aging in mammals, but the mechanisms underlying this phenomenon are still poorly understood. To study this issue, the transgenic model of alpha MUPA mice, which previously were reported to spontaneously eat less and live longer compared with their wild-type (WT) control mice, were used. Currently, two transgenic lines that eat less are available, thus implicating the transgenic enzyme, that is, the urokinase-type plasminogen activator (uPA), in causing the reduced appetite. Recently, several changes in the alpha MUPA liver were noted, at the mitochondrial and cellular level, which consistently pointed to an enhanced capacity to induce apoptosis. In addition, alpha MUPA mice showed a reduced level of serum IGF-1 and a reduced incidence of spontaneously occurring or carcinogen-induced tumors in several tissues. Overall, the alpha MUPA model suggests that long-lasting, moderately increased apoptotic capacity, possibly linked in part to modulation of serum IGF-1 and mitochondrial functions, could play a role in the attenuation of aging in calorically restricted mice.

Aging↗

PubMed2003

Extended longevity in mice lacking the insulin receptor in adipose tissue.

Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of approximately 134 days (18%), with parallel increases in median and maximum life-spans. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.

Adipose Tissue↗

PubMed2004

Protein-caloric food restriction affects insulin-like growth factor system in fetal Wistar rat.

We have previously shown that fetuses from protein-caloric undernourished pregnant rats (35% of control diet during the last week of pregnancy) at 21.5 d post coitum exhibit increased beta-cell mass. This alteration is correlated with increased insulinemia and total pancreatic insulin content, a pattern similar to that reported in infants of mild diabetic mothers. In this work, we investigated in undernourished fetuses: 1) whether availability of growth factors such as insulin, GH, and IGFs and their binding proteins (IGFBPs) could be implicated in this alteration, and 2) the beta-cell mitogenic response to IGFs in vitro. The results show that maternal undernutrition increases pancreatic IGF-I expression and islet IGF-I receptor content in undernourished fetuses, whereas hepatic IGF-I expression and serum IGF-I levels were decreased. No changes were observed in serum IGF-II, and its expression was diminished in undernourished pancreases and unchanged in the liver, compared with control fetuses. Serum levels and liver and pancreatic mRNA expression of IGFBP-1 were found to be normal in undernourished fetuses, whereas the serum concentration and abundance of IGFBP-2 mRNA in pancreas were increased. Finally, the beta-cell mitogenic response to IGFs in vitro was significantly increased in undernourished fetal islets, compared with controls. In conclusion, in undernourished fetuses the increased beta-cell mass can be related to the stimulation of replicative beta-cell response due to locally increased pancreatic IGF-I mRNA; this effect is perhaps potentiated or favored by the enhanced islet IGF-I receptor content and pancreatic IGFBP-2 gene expression.

Animals↗

PubMed2006

Glucose-induced replicative senescence in mesenchymal stem cells.

Mesenchymal stem cells (MSCs) show great promise for use in a variety of cell-based therapies. Because isolated primary mesenchymal stem cells are low in numbers, in vitro expansion is necessary. However, the expansion potential is limited and in vitro aging leads to loss of multipotency and replicative senescence. Stress induced by culture conditions is likely to be a major cause of replicative senescence and reduced multipotency of MSC and optimization of culture conditions might be able to reduce this. Caloric restriction (CR) is the only established method to delay aging and extend lifespan. In vitro caloric restriction experiments are rare, but have demonstrated beneficial effects. Therefore, we investigated the effect of culture medium glucose concentration on the proliferative and differentiation potential of mesenchymal stem cells. Reduction in glucose concentrations led to decreased apoptosis and an increased rate of MSC proliferation and increased the number and size of fibroblastic colonies in the colony-forming unit assay.

Animals↗

PubMed1994

Influence of dietary restriction and soyabean supplementation on the growth of a murine lymphoma and host immune function.

A comparative study was made to reveal the influence of caloric restriction with or without soyabean in the diet on the growth of a murine lymphoma, host survival, serum profile of vitamin A and E and immune status of the host. Caloric restriction delayed and inhibited tumour growth and improved host survival; inclusion of soyabean during restriction enhanced this effect. Dietary restriction both in the absence and presence of soyabean improved the proliferative response of peripheral blood lymphocytes. This was accompanied by increased cytolytic activity of peritoneal macrophages and elevation in serum immunoglobulins (IgG and IgM). Levels of vitamins A and E, which is found to be low in tumour bearing animals, decreased further when maintained in the restricted diet without soyabean, but was raised to normal levels following addition of soyabean in the diet. These observations imply that tumour growth is arrested possibly by insufficient nutrition available due to dietary restriction, for actively proliferating tumour cells and by improvement in host immune mechanism in the presence of soyabean in the diet.

Animals↗

PubMed2004

Effect of food restriction on hemorheological variables in a rat model of spontaneous hypertriglyceridemic obesity and diabetes.

Few studies have been performed in humans to investigate the effect of caloric restriction and consequent biomass reduction on hemorheologic parameters and their results are not concurrent. In a previous paper we analyzed the rheological behavior of the blood in the IIMb/Fmbeta inbred obese and hypertriglyceridemic strain in relation to its eumetabolic control [G.N. Hernández, C. Dabin, M.C. Gayol and M.L. Rasia, Hemorheological variables in a rat model of hypertriglyceridemic obesity and diabetes, Veterinary Res. Commun. 26 (2002), 625-635]. In this obese line it was shown a higher blood and plasma viscosity and an impaired red cell deformability compared to the eumetabolic one. The increased plasma viscosity was significantly and positively associated with fibrinogenaemia and lipidaemia and the impaired erythrocyte deformability with cholesterolemia and hypertriglyceridaemia. The present study has been designed to find out the effect of a 30% food restriction on several biochemical and hemorheological parameters of these obese rats. Restriction resulted in a mean body weight 45% lower than ad libitum controls, preventing obesity and hypertriglyceridemia with minimal effect on glucose metabolism. Regarding hemorheological parameters, caloric restriction led to a decrease in blood viscosity, due to the reduction in erythrocyte concentration, but not because of any improvement in erythrocyte deformability.

Animals↗

PubMed2006

Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha.

Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1alpha interaction with hepatocyte nuclear factor 4alpha (HNF4alpha, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1alpha in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4alpha is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1alpha, HNF4alpha, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.

Adrenergic Agonists↗

PubMed1999

[Nutrition and aging].

Genetic and environmental factors influence the process of aging. Longevity is extraordinarily constant along species and there are several genes that regulate it. Special consideration deserve apoprotein E alleles, specially allele eee4 that is associated with development of Alzheimer disease, atheroesclerosis and a shorter life. However environmental influences on longevity are of utmost importance. In rats, mice and non human primates, caloric restriction prolongs life and retards the appearance of several conditions associated with aging. This effect of caloric restriction is probably due mainly to a reduction in the generation of primary and secondary reactive oxygen species. Noteworthy is the reduction of DNA oxidative damage and the consequent reduction in transcriptional defects. Telomeres, special structures located in the extremes of chromosomes, are specially susceptible to oxidative damage. This structures have been postulated to act as biological clocks of cells, since their progressive shortening is a signal to stop replication. In humans, telomeres shorten throughout life and in some diseases associated with premature aging such as trisomy 21 and Werner syndrome, the loss of telomeric bases occurs at a higher rate. The knowledge about environmental influences on aging will allow us to increase our life span and to reduce the disabilities associated with aging.

Aging↗

PubMed1992

Dietary fat, calories, and mammary gland tumorigenesis.

In this communication, a vast array of studies designed to examine the relationship between dietary fat and experimental mammary gland tumorigenesis was reviewed and critiqued. It is clear, as reported by many laboratories, that as the fat content of the diet is increased from a low or standard level to a high level, a consistent and substantial increase in the development of rodent mammary gland tumors is observed. The longer the duration the high-fat diet is fed, the greater the enhancing effect on tumorigenesis. Furthermore, the stimulatory effect of a high-fat diet is observed even when fed commencing late in an animal's life. A multitude of studies also have provided evidence that the type of fat can markedly influence the development of rodent mammary gland tumors. In general, high dietary levels of unsaturated fats (e.g., corn oil, sunflower-seed oil) stimulate this tumorigenic process more than high levels of saturated fats (e.g., beef tallow, coconut oil); diets rich in certain fish oils (e.g., Menhaden oil, Max EPA) are often the most inhibitory to this tumorigenic process. Importantly, however, supplementation of saturated fat or fish oil diets with modest amounts of unsaturated fats, e.g., corn oil, often negates the mammary tumor inhibitory activities of these fats. Thus, rather extreme differences in the types of fat are required for a differential in mammary gland tumorigenesis; common proportionate blends of different fats of animal, plant, and/or fish origin are often unable to differentially influence this tumorigenic process. Diets rich in monoenoic fatty acids, e.g., those containing high levels of olive oil, have been examined in a number of studies; results from these studies have been inconsistent. A number of reports suggest that the increase in development of mammary tumors in rodents fed a high-fat diet, compared with those fed a low-fat diet, is due to specific metabolic activities of the fat per se, activities independent of a caloric mechanism. Careful analysis of these reports suggest that such a conclusion may not be totally warranted. Indeed, persuasive evidence is accumulating indicating that the major mammary tumor development enhancing activities of a high-fat diet may be via a caloric (energy) mechanism. Caloric restriction, even in animals fed a high-fat diet, significantly suppresses mammary tumor development. Even mild caloric restriction (e.g., 12%) can significantly suppress development of mammary tumors in rodents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Amelioration of age-related deficits in the stimulation of synapsin phosphorylation.

In a previous report we demonstrated that aged (24-26 month) rats have deficits in long-term potentiation, a form of synaptic enhancement that is dependent on protein phosphorylation (Moore et al., Hippocampus, 3:57-66; 1993). In the present study we demonstrate that aged rats have a deficit in the phosphorylation of the synaptic vesicle associated protein synapsin I. Specifically, aged animals exhibit defective phorbol ester-induced stimulation of synapsin phosphorylation at its calcium/calmodulin dependent protein kinase II sites. We also examined the effects of caloric restriction and antioxidant therapy on this age-related deficit. We found that either life-long caloric restriction or treatment with 16 mg/kg N-tert-butyl-alpha-phenylnitrone (PBN) for 2 weeks can at least partially ameliorate the age-related deficit in the phorbol ester stimulation of synapsin phosphorylation.

Aging↗