Altered polyamine biosynthesis with aging after massive proximal small bowel resection in rat

We examined the effect of aging on polyamine biosynthesis in the small intestine. Two groups of male Wistar rats (young; 10-week-old,n=40; old; 24-month-old,n=40) underwent either a jejunal transection and reanastomosis or 90% proximal small bowel resection. The rats were sacrificed on the 1st, 2nd, 4th, and 7th postoperative day (POD). The mucosa was submitted for histological examination, weighed, and assayed for protein, DNA, RNA, and polyamine content. Ornithine decarboxylase (ODC) activity was measured and ODC mRNA in the mucosa was determined by Northern blot analysis. Compared with the values for wet weight and protein content in old rats, young rats showed significantly higher values for wet weight on the 1st and 2nd POD, and for protein content on the 1st POD, but there were no differences between young and old rats after the 4th POD. The values for ODC activity and ODC mRNA were significantly lower in old rats than in young rats on the 1st POD, but there were no differences between young and old rats after the 2nd POD. The value for putrescine in old rats was significantly lower on the 2nd POD, but was significantly higher on the 4th POD than that in young rats. The present study showed that, in old rats, the residual intestine after small bowel resection preserved sufficient adaptive capacity, but that the adaptive response was decreased. The findings in this study also suggest that a decrease in ODC mRNA expression is involved in the decreased adaptive response that occurs with aging.     

Dietary polyamines are essential luminal growth factors for small intestinal and colonic mucosal growth and development

Background—Polyamines are essentialfor cell growth. Dietary and probably gut bacterial derived polyaminescontribute significantly to the polyamine body pool.
Aims—To evaluate the influence ofdietary, luminal polyamines on growth and development of differentgastrointestinal organs in normally growing rats.
Methods—Male suckling Wistarrats were randomly allocated to four treatment groups: polyaminedeficient diet (PDD); PDD plus antibiotics (neomycin 2 g/kg andmetronidazole 34 mg/kg); PDD plus polyamine supplementation at normalconcentrations; or normal standard laboratory chow. After a six monthfeeding period 7-10 animals/group were sacrificed.
Results—No differences inbody weight gain, food consumption, or general behaviour could beobserved between the four groups of animals. Feeding of PDD alone orPDD plus antibiotics resulted in a highly significant decrease in organweight, protein content, and DNA content in small intestinal andcolonic mucosa whereas no alterations were found in the liver.
Conclusions—Long term feeding ofpolyamine deficient diets resulted in a significant hypoplasia ofsmall intestinal and colonic mucosa. Dietary, luminal polyaminesare important local factors for growth and the development of smallintestinal and colonic mucosa.

Keywords:colon; gut; nutrition; ornithine decarboxylase; polyamines; polyamine deficient diet

     

The trophic effect of epidermal growth factor on morphological changes and polyamine metabolism in the small intestine of rats

This study was undertaken to evaluate the effect of epidermal growth factor (EGF) on the morphological changes and polyamine metabolism in the atrophic small intestinal mucosa of rats caused by feeding elemental diet (ED; Elental^?, Ajinomoto, Tokyo) for several weeks. Four-week-old Wistar male rats were given ad libitum ED (1 kcal/ml) for 4 weeks. The body weight increased to the same extent as the control group fed a pellet diet. However, the small intestine became atrophic: the mucosal wet weight of the jejunum decreased to 70%, while that of the ileum decreased to 60%. EGF (10 Μg/kg) was subcutaneously injected into these rats every 8 hours. Ornithine decarboxylase (ODC) activities of the jejunal and ileal mucosa rose within 12 hours of the initial EGF administration. Mucosal DNA specific activities tended to increase. Next, EGF (30 Μg/kg/day) was intraperitoneally administered with a Mini-osmotic pump for one week. The wet weight, protein and DNA contents of the ileal mucosa increased significantly compared with those of the saline administered controls, while the crypt cell production rate (CCPR) also increased. Histologically, increases in both villus height and crypt depth were confirmed. These findings indicate that EGF causes mucosal proliferation through polyamine metabolism even in the atrophie small intestine of mature rats after ED administration for 4 weeks.     

Polyamine metabolism and cell-cycle-dependent gene expression in IMR-90 human diploid fibroblasts during senescence in culture

Aging of IMR-90 human diploid fibroblasts in culture is accompanied by specific changes of polyamine metabolism including: (a) a fivefold decrease of serum-induced activity of ornithine decarboxylase (ODC¹ EC 4.1.1.17); (b) a six to tenfold increase of polyamine catabolism; and (c) a reduction of putrescine uptake. These changes apparently led to a significant reduction of putrescine accumulation in senescent cells following serum stimulation. Since the induction of ODC is a mid-G₁ event, the change of polyamine metabolism may be related to changes of expression of other cell-cycle-dependent genes during cellular aging. In addition to ODC gene, we have examined the expression of two early G₁ genes, c-erbB and c-myc, and one late G₁/S gene thymidine kinase, at mRNA levels, in both young and old IMR-90 cells. We have also compared the enzyme activities of two late G₁/S genes, thymidine kinase and thymidylate synthetase, in young and old cells following serum stimulation. We did not observe significant changes of c-erbB, c-myc, and ODC mRNA levels during cellular senescence. However, we found that serum-induced mRNA level of thymidine kinase gene in old IMR-90 cells was significantly reduced compared to that in the young cells. Results also demonstrate that aging of IMR-90 cells was accompanied by significant decrease of both thymidine kinase and thymidylate synthetase activities. In view of the recognized importance of polyamines in growth regulation, it is possible that alteration of polyamine metabolism may contribute to the impairment of expression of some key G₁/S genes and such impairment may contribute to the ultimate loss of dividing potential in senescent cells.     

Age-related changes in duodenal adaptation after distal small bowel resection in rat

Two groups of male Fisher 344 rats (young: 4 months old; aged: 25 months old) underwent either 70% distal small bowel resection or sham operation (small bowel transection). Rats from each treatment group of each age were sacrificed on the 10th (N=15: young rats;N=13: aged rats) or 20th (N=15: young;N=13: aged) postoperative day (POD), and the duodenal mucosa was weighed and assayed for DNA, RNA, and protein contents, as well as for specific activities of the disaccharidase, sucrase, maltase, and lactase. Compared to the sham operation, distal small bowel resection significantly increased DNA by 48%, RNA by 122%, and protein by 75% in young rats and DNA by 40%, RNA by 92%, and protein by 71% in aged rats on the 20th POD. Both young and aged rats showed similar adaptive hyperplasia on the 10th POD. On the 20th POD after distal small bowel resection, specific activities of all tested enzymes were significantly increased in young rats (sucrase +86%, maltase +110% and lactase +64%), but showed no significant changes in aged rats. These findings suggest that the duodenum of aged rats may have sufficient proliferative potential to respond to distal small bowel resection, but that the mechanisms governing return of function in response to distal small bowel resection are inhibited in aged rats, compared to those mechanisms in the young.Supported by grants from the National Institutes of Health (5R37 DK15241, P01 DK 35608).     

Effect of difluoromethylornithine (DFMO) on NSAID-induced intestinal injury in rats

Combination therapy with difluoromethyl ornithine (DFMO) and a nonsteroidal antiinflammatory drug (NSAID) has been proposed for the chemoprevention of colonic neoplasia. The purpose of this study was to examine whether DFMO would affect NSAID-mediated intestinal injury. Male Sprague-Dawley rats were gavaged with 20 mg/kg of indomethacin, after seven days of exposure to drinking water with or without 2% DFMO. The rats were killed 24 or 48 hr later, and the small intestine removed for macroscopic and microscopic quantitation of intestinal injury by computerized image analysis. Seven days of DFMO alone had no effect on overall mucosal thickness, but did increase the depth of proximal intestinal crypts. Forty-eight hours after indomethacin, DFMO treatment decreased the number of indomethacin-induced ulcers and percent of the surface area ulcerated. However, DFMO also decreased the mucosal thickness, villus height, and crypt depth in indomethacin-treated rats. Thus although DFMO decreases macroscopic intestinal ulceration by indomethacin, the reduction in villus and crypt height suggests that it also impairs the mucosa's ability to recover from microscopic indomethacin-induced damage. This study shows DFMO does impact NSAID-mediated intestinal injury and therefore human trials with combinations of DFMO and NSAIDs should include monitoring for small intestinal injury.This work was supported in part by a grant from the Research Service of the Department of Veterans Affairs.     

Ornithine decarboxylase activity during gastric ulcer healing in dogs

Ornithine decarboxylase (ODC) activity has been associated with mucosal growth and injury, yet, little information is available on ODC activity during gastric ulcer healing. We measured ODC activity in the ulcer base submucosa and the surrounding mucosa at 1 cm and 2 cm and assessed ulcer surface healing and a histologic score in experimentally induced ulcers (Quinton ulcer-maker) at 0 and 5 hr and at one, two, three, four, and seven days. A total of 26 dogs were studied, eight of which received 2% difluoromethylornithine (DFMO, a specific inhibitor of ODC) in drinking water. Ulcer healing was assessed by digitizing initial (plug size), and final ulcer surface area and was expressed as percent ulcer surface reduction. A histologic score was assessed by two independent pathologists unaware of the treatment. ODC induction was observed in the submucosa of the ulcer base but not in the surrounding mucosa. The baseline submucosal ODC activity was measured at 0.2±0.1 pmol (¹⁴CO₂)/mg protein/hr, and at one day the ODC activity increased to 4.0±0.7, at three days to 15.2±5.5, and at seven days to 2.6±1.0 (P<0.001). DFMO treatment delayed GU healing significantly up to three days, but no difference was noted at seven days. The assessed histologic parameters did not correlate with ODC activity, and DFMO treatment did not alter the histologic score. These data suggest that polyamine biosynthesis occurs in the ulcer base submucosa during the first seven days of experimentally placed gastric ulcers. Suppression of ODC activity with DFMO delays ulcer surface reduction during the first three days, but the significance of ODC induction and polyamine biosynthesis during early ulcer healing remains in question.     

Effect of insulin treatment on the regeneration of the remnant pancreas after major pancreatectomy in dogs

The effect of exogenous insulin treatment on the pancreatic regeneration after major pancreatectomy was evaluated in dogs. More than 92% of the pancreas was removed near the duodenum with the main pancreatic duct left intact. All 26 dogs developed diabetes mellitus (DM) immediately after surgery, and these dogs were divided into two groups: insulin-treated group (n = 19) and noninsulin-treated group (n = 7). All seven dogs in the noninsulin-treated group died within seven weeks after surgery, whereas all dogs in the insulin-treated group survived until the twelfth week, except for six dogs sacrificed on the seventh week, and finally seven (53.8%) of 13 dogs recovered from DM. DNA and polyamine syntheses in the remnant pancreatic tissue at the third day increased more significantly in the insulin-treated group than in the noninsulin-treated group. SigmaIRI inIV-GTT was maintained more significantly in the insulin-treated group, and the regeneration rate at the seventh week was also significantly higher in the insulin-treated group than in the noninsulin treated group. Furthermore, the regeneration rate of the remnant pancreas at seventh week correlated well withDNA synthesis and ornithine decarboxylase activity on the third day. The exogenous insulin treatment after major pancreatectomy enhanced the proliferation of the remnant pancreas within the first week, and it maintained endogenous insulin secretion, promoting pancreatic regeneration.     

比格犬胃窦黏膜组织学与超微结构的增龄变化特点

目的探讨比格犬胃窦黏膜组织学与超微结构的增龄变化特点。 方法选取健康比格犬(犬龄1.5～11.0岁,体重14～20 kg)19只。按年龄分组：≥1.5岁且≤6岁8只(中青年组),>6岁且≤9岁5只(低龄老年组),>9岁且≤11岁6只(高龄老年组)。光镜下观察对比各组犬胃窦黏膜上皮细胞形态学变化、胃窦黏膜炎症程度、肠上皮化生和异型增生情况、固有膜厚度及黏液腺体实质比的变化;透射电镜下观察对比各组犬胃窦黏膜上皮细胞形态、细胞间连接、幽门腺细胞黏原颗粒面积分数的变化。3组间胃黏膜炎症指数、胃窦黏膜固有膜厚度及黏液腺体实质比的比较采用单因素方差分析。 结果光镜观察结果：各组犬胃窦黏膜上皮细胞未见明显形态学变化;胃窦黏膜内均未见肠上皮化生、异型增生,且无炎症或炎症表现轻微,各组间炎症指数无明显差异(F＝0.023,P>0.05);中青年组、低龄老年组及高龄老年组胃窦黏膜固有膜厚度分别为(1016.7±203.2)、(727.5±64.3)、(931.7±92.4) μm,差异有统计学意义(F＝5.952,P<0.05),其中高龄老年组黏膜内结缔组织增生明显;3组黏液腺体实质比分别为(45.3±6.4)%、(33.9±2.4)%、(34.5±6.3)%,差异有统计学意义(F＝8.981,P<0.01)。透射电镜观察结果：各组胃窦黏膜上皮细胞超微结构及细胞间紧密连接均未见明显改变,但细胞间中间连接及缝隙连接随增龄逐渐疏松,并可见空泡样缝隙;中青年组、低龄老年组及高龄老年组幽门腺细胞内黏原颗粒面积分数分别为(50.3±10.0)%、(44.4±3.9)%、(18.6±5.6)%,差异有统计学意义(F＝15.501,P<0.01)。 结论健康比格犬胃窦黏膜组织学和超微结构随增龄出现了一系列退化现象。     

Polyamine metabolism in reversible cerebral ischemia of Mongolian gerbils

Reversible cerebral ischemia was produced in Mongolian gerbils by occluding both common carotid arteries. Following 5 min of ischemia brains were recirculated for 8, 24, or 96 hr. At the end of the experiments tissue samples were taken from the cerebral cortex and CA1 subfield of the hippocampus for measuring putrescine content and ornithine decarboxylase (ODC) activity. In 5 of 10 animals subjected to 96 hr of recirculation pentobarbital (50mg/kg) was injected during early recirculation, and the density of ischemic cell damage was determined in the CA1 subfield of the hippocampus in treated and untreated animals. Reversible cerebral ischemia induced a drastic increase in ODC activity after 8 hr of recirculation (about 14-fold in the cortex and 7-fold in the hippocampus), which was markedly reduced following 24 hr of recirculation. Putrescine, in contrast, was high following 8 hr of recirculation and increased even further from 8 to 24 hr of recirculation. Postischemic pentobarbital treatment of animals significantly reduced both the increase in putrescine and the density of ischemic cell damage in the hippocampus. The results are discussed in view of the known activities of putrescine.     

Estradiol-17β modifies the induction of spermidine/spermine N1-acetyltransferase activity in the liver of lipopolysaccharide-treated mice

ABSTRACT— In an attempt to elucidate the effects of estrogen on polyamine metabolism in lipopolysaccharide (LPS)-treated mice, we assayed polyamine content and the activity of spermidine/spermine N¹-acetyltransferase (SAT) and ornithine decarboxylase (ODC) in some organs. LPS elevated N'-acetylspermidine levels in the liver and lung and putrescine levels in the liver, lung and spleen. LPS increased the activity of ODC at 6 h and that of SAT at 12 h in the liver. When estradiol-17β was simultaneously administered with LPS, the maximum increase in hepatic N¹-acetylspermidine levels was found 6 h earlier than in the LPS control. Likewise, the peak of the hepatic SAT activity after LPS-treatment was observed 6 h earlier in the estradiol-17β-treated mice than in the LPS control. No such effect of estradiol-17β was found in the lung and spleen. The LPS-induced ODC activity was not affected by estradiol-17β in the liver, lung or spleen. Estrone and 16β-ethylestradiol (an anti-estrogen) were also effective in enhancing the LPS-induced elevation of N¹-acetyl-spermidine and putrescine in the liver, while both diethylstilbestrol, which has a potent estrogenic activity without steroid structure and estradiol-17α (a non-estrogenic isomer of estradiol-17β) were without effect. Tamoxifen (an estrogen receptor antagonist) did not suppress the estrogen-induced increase in hepatic N¹-acetylspermidine levels.     

Role of polyamines in gastrointestinal mucosal growth

The polyamines [putrescine (PU), spermidine (SPD) and spermine (SPM)] are ubiquitous polycationiccompounds found in all prokaryotic and eukaryotic cells, are essentially involved in a variety of regulatorysteps during normal, adaptive, and malignant cell proliferation. Nearly four decades investigation about thepolyamines contributed to the synthesis and decomposition of polyamines and the active and passive enzymeswhich regulate them at different levels. This review focuses on the sources and homeostasis of intracellularpolyamines, the transport and role of the polyamines in the growth of the gastrointestinal mucosa and theirpossible mechanism. We tried to point out the gaps remaining in the story and give a working hypothesis forthe role of polyamines in gastrointestinal mucosal growth. We propose in the hypothesis that polyamine is a“key”to unlock the “door”of cell proliferation. How many “doors” between the “polyamine key” and the“real start” of proliferation? The polyamine might be the only key for cell proliferation. Another possibilityis that polyamine is the first key and its “unlocking-effect” resulting in getting another key for the next doorin the proliferation chain, for example, proto-oncogenes. To decide whether polyamine is an intermediatestep or just only one step of cell proliferation, the possible way is to keep polyamine to be a stimulus and finda way to deprive the function of proto-oncogene protein (or other possible gene expression product) to checkthe effect on the cell proliferation. Another important question is how polyamine can trigger the synthesis ofDNA in virtual. Arabinose operon model may give us some ideas to investigate about that. And furthermore,it is necessary to pay attention to the relationship between polyamine and other cell proliferation regulator,like growth factor, chalone, cAMP, cGMP, etc. Further studies are needed to investigate the mechanism ofpolyamine acted on the gastrointestinal mucosal growth.     

Roles of histamine and diamine oxidase in mucosa of rat small intestine after ischemia-reperfusion

To examine the roles of histamine and diamine oxidase in the intestine after ischemiareperfusion, we measured histamine content, diamine oxidase activity, and ornithine decarboxylase activity in rat intestinal mucosa 6 hr following various periods of ischemia. In addition, mortality rates of rats after various periods of ischemia were observed. The superior mesenteric artery was occluded for 15, 30, or 60 min. Ornithine decarboxylase activity increased in the 15-, 30-, and 60-min ischemic groups compared to the shamoperated control group. In the prolonged ischemic group (60-min ischemia), both histamine concentration and diamine oxidase activity in the mucosa decreased, contributing to an increase in circulating histamine. In the 60-min ischemic group, the mortality rate of rats was 25%, which was significantly larger than the control groups. Pretreatment with aminoguanidine, which suppressed diamine oxidase activity, increased the mortality rate. These results indicate that histamine released from the intestinal mucosa has a harmful effect on rats, and diamine oxidase activity plays an important role when the small intestine is subjected to prolonged period of ischemia.Grant support: Grant-in-Aid from the Ministry Education in Japan for Scientific Research 04770423, and Uehara Memorial Foundation.     

Age-related changes in thermoregulation in male albino rats

Male Sprague Dawley rats were followed longitudinally from 3 to 24 months of age. Resting oxygen consumption (VO2), measured in the thermal neutral zone (29 +/- 1.0 degrees C) decreased 47% between 3 and 24 months of age with a stable period from 6 to 9 months. Changes in rectal temperature in general followed changes in VO2. On the average the decline in rectal temperature from 3 to 24 months was 0.8 degrees C. Thermal conductance dropped initially from 3 to 6 months and remained stable during further age periods. Thermal circulation index rose slightly from 3 to 13 months, and dropped thereafter from 13 to 24 months. When animals were exposed to a mild cold challenge (18-19 degrees C for 90 min.), the increase in VO2 was the same from 3 to 13 months of age. At 24 months this increase was significantly higher. The capacity for non-shivering thermogenesis (NST) measured after norepinephrine stimulation declined from 3 to 6 months, remained stable from 6 to 9 months and declined to 13 months. The capacity for NST after a mild cold challenge was significantly decreased at 24 months of age. These results suggest that shivering thermogenesis (ST) may be the main source of heat production in the old organism when faced with a mild cold challenge. Since ST is more energy consuming than NST it may explain the accidental hypothermia which occurs often in the elderly.     

Age-related changes in human left and right atrial conduction

INTRODUCTION: Advancing age is an independent risk factor for atrial fibrillation (AF), which is considered to be initiated by ectopic triggers and maintained by an arrhythmogenic substrate. It is not known whether substrate changes produce this age-related increase in propensity toward AF. We addressed the hypothesis that advancing age is associated with changes in biatrial electrophysiology even in patients with no history of atrial arrhythmias. METHODS AND RESULTS: Patients with left-sided accessory pathways and requiring routine electrophysiological studies were recruited. Electroanatomic mapping was performed in the left and right atria of 23 patients (age ranging from 17 to 75 years) with structurally normal hearts and no history of AF during sinus rhythm and pacing. Unlike previous studies, a trigonometric method was used to quantify wavefront propagation velocities (WPV) precisely in the direction of propagation. Refractoriness was measured at 2 cycle lengths, at three different atrial sites. Both right (r =-0.77, P < 0.0001) and left (r =-0.79, P < 0.001) atrial WPV demonstrated strongly inverse correlation with age. Furthermore, left and right WPVs were highly correlated (r = 0.66, P < 0.01), with velocities being 6.4 +/- 2.2 cm/sec higher in the right atria (P < 0.01). Refractoriness was significantly correlated with increasing age only at the septum (r = 0.53, P < 0.01). Left atrial wavelength was inversely correlated with increasing age (r =-0.56, P = 0.03). P wave duration was associated with age (r = 0.42, P = 0.04) and left atrial size (r = 0.44, P = 0.04) but not atrial WPV. CONCLUSION: Aging human atria demonstrate progressive decline in WPV and increase in septal refractoriness. These age-related changes in biatrial electrophysiology are likely to be important factors in the age-related increase in AF prevalence.     

Age-related changes of isoprenoid biosynthesis in rat liver and brain

The physiological role of dolichol is not yet known but its accumulation in several tissues has been extensively reported in various physiological states or pathological conditions. Increased dolichol concentration in mammalian tissues during ageing has been also reported; in particular, we have previously indicated dolichol accumulation in liver as a new biomarker of ageing. However, the mechanism and the role of this accumulation is unknown. The aim of this work was to study the mechanism of the age-dependent dolichol accumulation analysing, in the liver and in the brain, the activity of the rate-limiting enzyme of isoprenoid biosynthesis, the 3-hydroxy 3-methylglutaryl CoA reductase, the dolichol and cholesterol synthesis on aged rats both fed ad libitum and caloric restricted. Furthermore, the dolichol and cholesterol levels in the plasma were assayed. The data shows that during ageing, the tissue dolichol accumulation is connected with the increase of 3-hydroxy 3-methylglutaryl CoA reductase activity and only in liver affected by diet restriction. In addition the aged rats maintain the capability to regulate their tissue cholesterol content by modifying cholesterol delivery into the blood. The amount of the 3-hydroxy 3-methylglutaryl CoA reductase enzyme detectable in liver and brain by Western blot analysis does not show significant changes during ageing. The presented data show that the accumulation of dolichol is related to the loss of enzymatic regulation characteristic of ageing. In fact, a higher mevalonate availability deriving from an increased expressed activity of HMGCoA-R could cause an increased production of dolichol.     

Age-related changes of circadian rhythms and sleep-wake cycles

OBJECTIVES: To compare relationships between the sleep-wake cycle and endogenous circadian rhythms in young and older adults and to examine correlates between evening naps and circadian rhythms in older adults. DESIGN: For 1 week of home recording, subjects wore wrist-activity monitors and kept daily sleep logs. After the home monitoring, subjects entered the laboratory on a 90-minute sleep-wake schedule and were monitored on this schedule for at least 30 hours. SETTING: Community living and laboratory. PARTICIPANTS: Sixty-seven young adults, aged 18 to 32, and 56 older adults, aged 60 to 75, who were healthy and had few sleep complaints. MEASUREMENTS: Times of nocturnal sleep, out-of-bed napping, and illumination were obtained at home. Sleep propensity and oral body temperature (OBT) were measured in the laboratory, along with circadian rhythms of cortisol and 6-sulfatoxymelatonin (aMT6s, assayed from urine samples collected every 90 minutes). RESULTS: Home sleep times and illumination acrophases (fitted peak times) were advanced in older adults. The phase angles (time intervals) between onset of aMT6s and sleep onset were not changed in older adults, but sleep offset was more advanced than acrophase and offset of aMT6s with aging. Acrophases of cortisol and sleep propensity were advanced in older adults to the same extent as sleep times, but OBT was less advanced than sleep times. Older adults who took evening naps showed more advanced sleep offset and circadian rhythms of aMT6s, but there were no differences in the phase angles of sleep onset and circadian rhythms of aMT6s and cortisol compared with older adults who did not take evening naps. CONCLUSION: Measuring different circadian markers suggested different phase relationships between the sleep-wake cycle and endogenous circadian rhythms in aging. Early awakening in older adults cannot be explained simply by a relative phase advance of the circadian system. Evening naps and advanced illumination may play a role in the advance of the circadian system in aging.     

Age-related changes in working memory and the ability to ignore distraction

A weakened ability to effectively resist distraction is a potential basis for reduced working memory capacity (WMC) associated with healthy aging. Exploiting data from 29,631 users of a smartphone game, we show that, as age increases, working memory (WM) performance is compromised more by distractors presented during WM maintenance than distractors presented during encoding. However, with increasing age, the ability to exclude distraction at encoding is a better predictor of WMC in the absence of distraction. A significantly greater contribution of distractor filtering at encoding represents a potential compensation for reduced WMC in older age.The number of items that can be held in working memory (WM) declines with increasing age (1). Our ability to effectively exclude distractors is one basis for this limited working memory capacity (WMC) (2, 3), with impaired inhibitory processing of distraction contributing to an age-related reduction in WM performance (4). A specific impairment in suppressing distractor representations in older adults has been linked to reduced WMC (5). Typically distractors are presented either with the items to be remembered (encoding distraction, ED, e.g., 6, 7) or while these items are held in mind (delay distraction, DD, e.g., 5, 8). We recently highlighted a distinction between the effects of these two types of distraction in younger adults (9). Although greater WMC is associated with an enhanced ability to exclude distractors in both cases, each makes a unique contribution to WMC (9). Here we examine the well-known age-related reduction in WMC. Previous work has identified an age-related delay in ED filtering (7) and an early age-related deficit in DD suppression (8). We directly compare the age-related decline in ED and DD to assess whether an ability to ignore a distraction at encoding or at delay provides the best predictor of general WMC.We obtained data from 29,631 users of a smartphone game (part of The Great Brain Experiment, www.thegreatbrainexperiment.com), a platform that has enabled us to replicate a range of laboratory studies (9, 10). Using this medium we implemented a WM task to enable us to directly compare the effects of age on WM in the absence of distractors (no distraction, ND; Fig. 1A), when distractors are presented at encoding (ED; Fig. 1B) and when distractors are presented during maintenance (DD; Fig. 1C). This large subject pool enabled us to consider data from six age groups (18–24 y: n = 7,658; 25–29 y: n = 5,702; 30–39 y: n = 8,225; 40–49 y: n = 4,667; 50–59 y: n = 2,359; and 60–69 y: n = 1,020). For each condition the number of items to be remembered (WM load) increased as a function of performance until either eight trials had been completed or a participant failed two successive trials of a given WM load. Data were excluded from participants who failed a “load 2” trial in any condition. For each condition, the participant’s score represents the maximum number of items for which they could report all items successfully, representing their WMC.Open in a separate windowFig. 1.The smartphone game. Red circles are presented simultaneously, followed by a delay of 1 s. Participants should then indicate the positions of the red circles. (A) No distraction (ND) condition; only red circles are shown. (B) Encoding distraction (ED) condition; two yellow circles (distractors) are presented with the red circles. (C) Delay distraction (DD) condition; two yellow circles (distractors) are presented during the delay.