Impaired autophagic function in rat islets with aging

Type 2 diabetes is characterized by a deficit in β-cell function and mass, and its incidence increases with age. Autophagy is a highly regulated intracellular process for degrading cytoplasmic components, particularly protein aggregates and damaged organelles. Impaired or deficient autophagy is believed to cause or contribute to aging and age-related disease. Autophagy may be necessary to maintain structure, mass, and function of pancreatic β-cells. In this study, we investigated the effects of age on β-cell function and autophagy in pancreatic islets of 4-month-old (young), 14-month-old (adult), and 24-month-old (old) male Wistar rats. We found that islet β-cell function decreased gradually with age. Protein expression of the autophagy markers LC3/Atg8 and Atg7 exhibited a marked decline in aged islets. The expression of Lamp-2, a good indicator of autophagic degradation rate, was significantly reduced in the islets of old rats, suggesting that autophagic degradation is decreased in the islets of aged rats. However, protein expression of beclin-1/Atg6, which plays an important role in the induction and formation of the pre-autophagosome structure by associating with a multimeric complex of autophagy regulatory proteins (Atg14, Vps34/class 3 PI3 kinase, and Vps15), was most prominent in the islets of adult rats, and was higher in 24-month-old islets than in 4-month-old islets. The levels of p62/SQSTM1 and polyubiquitin aggregates, representing the functions of autophagy and proteasomal degradation, were increased in aging islets. 8-Hydroxydeoxyguanosine, a marker of mitochondrial and nuclear DNA oxidative damage, exhibited strong immunostaining in old islets. Analysis by electron microscopy demonstrated swelling and disintegration of cristae in the mitochondria of aged islets. These results suggest that β-cell and autophagic function in islets decline simultaneously with increasing age in Wistar rats, and that impaired autophagy in the islets of older rats may cause accumulation of misfolded and aggregated proteins and reduce the removal of abnormal mitochondria in β-cells, leading to reduced β-cell function. Dysfunctional autophagy in islets during the aging process may be an important mechanism leading to the development of type 2 diabetes.     

Association of healthy aging with parental longevity

Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI₃₄ scores were computed from 34 common health variables and compared between the two groups. The FI₃₄ was better correlated than chronological age with mortality. The mean FI₃₄ value of the OSLP was 31 % higher than that of the OLLP (P = 0.0034). The FI₃₄ increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP (P = 0.024) and 2.7 % in the OSLP (P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group (P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI₃₄ scores, and heritability of the FI₃₄ was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI₃₄ is, in part, due to genetic variation; thus, the FI₃₄ can be a phenotypic measure suitable for genetic analyses of healthy aging.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-012-9472-0) contains supplementary material, which is available to authorized users.     

健康人D-二聚体随增龄升高

目的探讨血浆D-二聚体（D—D）在健康成人随增龄的变化。方法以随机整群抽样方式在北京15个社区筛选出健康人群305例,应用ELISA法检测血浆D—D。结果横断面分析显示老年组（≥65岁）D-D较青年组（〈65岁）升高（P〈0．01）。LogD—D与年龄呈正相关（r=0．446,P〈0．01）。10岁年龄分层分析显示,65岁以下LogD—D保持稳定,65岁后LogD—D随年龄增加升高（P〈0．01）。LogD-D没有性别差异。多元线性回归分析,年龄、纤维蛋白原和舒张压是D—D的独立相关因素（P〈0．01）。结论健康人65岁后血浆D-D随年龄增加而升高,D-D无性别差异。     

Association of pulmonary tuberculosis with increased dietary iron

To determine whether increased dietary iron could be a risk factor for active tuberculosis, dietary iron history and human immunodeficiency virus (HIV) status were studied in 98 patients with pulmonary tuberculosis and in 98 control subjects from rural Zimbabwe. Exposure to high levels of dietary iron in the form of traditional beer is associated with increased iron stores in rural Africans. HIV seropositivity was associated with a 17.3-fold increase in the estimated odds of developing active tuberculosis (95% confidence interval [95% CI], 7.4-40.6; P<.001), and increased dietary iron was associated with a 3.5-fold increase (95% CI, 1.4-8.9; P=.009). Among patients treated for tuberculosis, HIV seropositivity was associated with a 3.8-fold increase in the estimated hazard ratio of death (95% CI, 1.0-13.8; P=.046), and increased dietary iron was associated with a 1.3-fold increase (95% CI, 0.4-6.4; P=.2). These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis.     

Association of beta-blocker use with increased aortic wave reflection

Studies have found less cardiovascular risk reduction in patients treated with beta-blockers (BBs) compared with other agents. We compared the severity of aortic atherosclerosis, arterial stiffness, and wave reflection in patients treated and not treated with BBs. Seventy-two patients, 37 treated with BBs and 35 not treated, referred for transesophageal echocardiography were studied. Augmentation index (AI), heart-rate-corrected AI (AI-75), aortic systolic (SBP) and diastolic blood pressure, pulse wave velocity (PWV), and aortic intima-media thickness (MAIMT) were measured. There were no differences in MAIMT (2.8 ± 1.6 mm vs. 2.4 ± 1.2 mm, P = .20) and PWV (8.9 ± 2.0 m/s vs. 8.5 ± 2.6 m/s, P = .46) between the BB and non-BB groups. The BB group had higher AI (28.7 ±11.9% vs. 22.3 ± 14.1%, P = .04), AI-75 (27.7 ± 10.7% vs. 20.1± 11.0%, P = .005), aortic SBP (140 ± 21 mm Hg vs. 125 ± 21 mm Hg, P = .01), and aortic pulse pressure (62 ± 20 mm Hg vs. 47 ± 19 mm Hg, P = .01) than the non-BB group despite similar brachial blood pressure. BB use was associated with increased aortic wave reflection despite similar degree of aortic atherosclerosis.     

Nuclear inclusions: a study of aging in Drosophila.

Increased numbers and distribution of nuclear inclusions were correlated with aging in Drosophila imagoes. The various types of nuclear inclusions observed in the present study and those reported in the literature were categorized to their morphologies. It was noted that they may be located (a) in the nucleus proper, such as parallel fibrillar bundles, virus-like particles, tubulo-membraneous systems and amorphous fibrillo-granular deposits, (b) between the inner and outer nuclear membranes, such as cytoplasm-like intrusions, multilocular bodies and electron opaque vacuoles, and (c) outside the nucleus proper, such as those cytoplasmic invagination that interdigitate with infoldings of the nuclear membrane. A possible explanation of the relationship of these nuclear inclusions with aging and death is proposed.     

Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease

BACKGROUND: Infection with chronic hepatitis C virus (HCV) has been linked to glomerulonephritis. We undertook this study to determine whether having a positive HCV test result was associated with an increased risk for developing treated end-stage renal disease (ESRD). METHODS: Using data from Medicare, the Department of Veterans Affairs, and the United States Renal Data System, we performed a retrospective cohort study of 474,369 adult veterans who had serum creatinine levels measured between October 1, 2000, and September 30, 2001, and HCV antibody testing within 1 year of creatinine testing. Patients were followed up until October 1, 2004, for the outcome of treated ESRD, defined as the onset of chronic dialysis or renal transplantation. Cox proportional hazards models were used to determine the relative hazard for ESRD associated with HCV, adjusted for other covariates (age, sex, race/ethnicity, and comorbidities). RESULTS: Of 474,369 patients in the cohort, 52,874 (11.1%) had a positive HCV antibody test result. Patients with HCV were more likely to develop ESRD: the rate per 1000 person-years was 4.26 (95% confidence interval, 3.97-4.57) for HCV-seropositive patients vs 3.05 (95% confidence interval, 2.96-3.14) for HCV-seronegative patients. For patients aged 18 to 70 years with an estimated glomerular filtration rate of at least 30 mL/min per 1.73 m2, HCV seropositivity was associated with a greater than 2-fold risk for developing ESRD (adjusted hazard rate, 2.80; 95% confidence interval, 2.43-3.23). CONCLUSION: In this large national cohort of adult veterans, patients younger than 70 years with HCV seropositivity were at increased risk for developing ESRD treated with dialysis or transplantation.     

肺栓塞再发与血浆纤维蛋白原升高相关性研究

目的 观察并评价不同血浆纤维蛋白原水平与肺栓塞再发的关系.方法 回顾性分析77例初次肺栓塞患者治疗缓解后及24例肺栓塞再发患者的血浆纤维蛋白原水平,比较再发肺栓塞患者及未再发肺栓塞患者血浆纤维蛋白原水平是否存在显著差异,比较肺栓塞再发患者初次发病治疗缓解后及肺栓塞再发治疗前血浆纤维蛋白原水平之间的差异,同时分析肺栓塞再发患者栓塞灶分布与血浆纤维蛋白原升高之间的相关性.结果 再次发作肺栓塞患者血浆纤维蛋白原水平高于未再次发作肺栓塞患者(P＜0.05),肺栓塞再发组冶疗前血浆纤维蛋白原水平高于初次肺栓塞患者治疗缓解后血浆纤维蛋白原水平(P＜0.05),再次肺栓塞组血浆纤维蛋白原升高水平与患者的肺栓塞病灶分布无明显相关性(P＞0.05).结论 血浆纤维蛋白原升高与肺栓塞再发相关,纤维蛋白原升高是肺栓塞再发事件的重要危险因素,对肺栓塞再发有预测意义.     

Association of increased mycobacterium growth inhibitory factor with antituberculous immunity

Cell-mediated immune mechanisms (CMI) were studied in 51 patients of pulmonary tuberculosis to evaluate the role of mycobacterium growth inhibitory factor in prognosis of the infection, before and after the administration of anti-tubercular drugs. Twenty five Mantoux negative individuals who were subsequently bacille Calmette-Guérin (BCG) vaccinated and 25 Mantoux positive, non-tuberculous controls were included in the study. Their clinical assessment was compared with skin sensitivity (Mantoux); lymphocyte transformation (LT) after stimulation with phytohaemagglutinin (PHA) and purified protein derivative (PPD); macrophage migration inhibitory factor (MIF), mycobacteria growth inhibitory factor (Myco IF) and listerial growth inhibitory factor (List IF). The tests were carried out at the beginning of the treatment and at intervals of three months, extending to one year. In the case of Mantoux positive controls, tests were carried out only once. It was found that Mantoux reaction had no correlation with LT, MIF, Myco IF and List IF. Both MIF and Myco IF, were significantly elevated in improving patients, whereas increase in List IF was not significant. An important finding was that Myco IF was at a higher level in improving patients whereas in those not responding to chemotherapy it was low.     

Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behcet's disease

OBJECTIVE: The aim of this study was to investigate if the inheritance of specific polymorphisms of interleukin 1 (IL-1) A, IL-1B and IL-1 receptor antagonist (IL-1RN) genes could affect the susceptibility to Beh?et's disease (BD). METHODS: A total of 132 BD patients and 105 healthy controls were genotyped for IL-1A -889, IL-1B -511, -35, +5810, +5887, and IL-1RN +8006, +8061, +9589, +11,100 single nucleotide polymorphisms, and IL-1RN 86-bp variable number of tandem repeat polymorphism. chi 2-analysis was used to compare the allele and genotype frequencies of the cases and controls. IL-1A and IL-1B haplotypes were reconstructed using the Phase program. RESULTS: Inheritance of the C allele of the IL-1A -889 polymorphism was associated with BD (OR=2.0, P=0.01) and inheritance of the IL-1A -889C/IL-1B +5887T haplotype was identified as an increased risk for BD. The IL-1A -889 and IL-1B +5887 CC/TT combined genotype was significantly more observed in BD cases than in controls (57.5 vs 38.1%, OR=2.2, P=0.003). No association with BD was found for other investigated polymorphisms in the IL-1B and IL-1RN genes. CONCLUSION: Susceptibility to BD is increased in individuals carrying both the IL-1A -889C and IL-1B +5887T haplotype. Individuals who are both homozygous CC at IL-1A -889 and TT at IL-1B +5887 appear to have twice the risk of developing BD as individuals having other IL-1A -889/IL-1B +5887 genotypes.     

Association of human aging with a functional variant of klotho.

Mice deficient in Klotho gene expression exhibit a syndrome resembling premature human aging. To determine whether variation in the human KLOTHO locus contributes to survival, we applied two newly characterized polymorphic microsatellite markers flanking the gene in a population-based association study. In a cohort chosen for its homogeneity, Bohemian Czechs, we demonstrated significant differences in selected marker allele frequencies between newborn and elderly individuals (P < 0.05). These results precipitated a search for functional variants of klotho. We identified an allele, termed KL-VS, containing six sequence variants in complete linkage disequilibrium, two of which result in amino acid substitutions F352V and C370S. Homozygous elderly individuals were underrepresented in three distinct populations: Bohemian Czechs, Baltimore Caucasians, and Baltimore African-Americans [combined odds ratio (OR) = 2.59, P < 0.0023]. In a transient transfection assay, secreted levels of klotho harboring V352 are reduced 6-fold, whereas extracellular levels of the S370 form are increased 2.9-fold. The V352/S370 double mutant exhibits an intermediate phenotype (1.6-fold increase), providing a rare example of intragenic complementation in cis by human single nucleotide polymorphisms. The remarkable conservation of F352 among homologous proteins suggests that it is functionally important. The corresponding substitution, F289V, in the closest human klotho paralog with a known substrate, cBGL1, completely eliminates its ability to cleave p-nitrophenyl-beta-D-glucoside. These results suggest that the KL-VS allele influences the trafficking and catalytic activity of klotho, and that variation in klotho function contributes to heterogeneity in the onset and severity of human age-related phenotypes.     

血清支链氨基酸水平升高与颈动脉斑块的关系

目的研究血清支链氨基酸(BCAA)水平与颈动脉斑块的关系。方法采用横断面调查方法,对收集的中老年体检人群472例[42~97岁,平均(70.1±6.6)岁,男性272例]进行问卷调查、体格检查、血液检查和颈动脉超声检测,同位素稀释液相色谱串联质谱法测定血清BCAA水平,分析其与颈动脉斑块的关系。结果血清BCAA浓度呈偏态和尖态分布,男性的BCAA水平[466.5(423.6~514.7)μmol/L]显著高于女性[415.3(382.5~466.0)μmol/L],P<0.001。在校正年龄和性别后,血清BCAA水平与BMI、SBP、DBP、FBG、TG和LDL-C显著正相关(均为P<0.05),与HDL-C明显负相关(P<0.001)。颈动脉斑块组的BCAA水平[450.0(405.9~492.1)]明显高于正常组[430.4(395.1~495.2)](P=0.039)。多因素Logistic回归分析发现,年龄、吸烟史、SBP和BCAA水平升高是颈动脉斑块的独立危险因素,BCAA次高四分位水平发生颈动脉斑块的风险是最低四分位水平的2.68倍(P=0.002,P趋势=0.018)。结论血清BCAA水平升高是颈动脉斑块的独立危险因素,可能影响动脉粥样硬化的发生发展。     

Association of atherosclerosis with increased atrophy of brain matter in the elderly

The association of atherosclerosis with brain atrophy was studied in 101 subjects (75 men and 26 women) using computed tomography (CT). A calcification index (CI) was calculated as an indicator of atherosclerosis in the abdominal aorta: the calcified portion along the entire circumference of the abdominal aorta X 80. Both the cerebrospinal fluid (CSF) space volume and the volume percentage of the CSF space to the cranial cavity [brain atrophy index (BAI)] were calculated as indicators of brain atrophy. The CSF space volume increased with increasing age after the 70s. The BAI increased with increasing age after the 60s. Both the CSF space volume and the BAI in the 70s were 1.8 times those in the 40s. The CI increased with increasing age after the 50s very rapidly, and the CI in the 70s was 54 times that in the 40s. Both the CSF space volume and the BAI were greater in atherosclerotic (CI greater than or equal to 3.0) than in nonatherosclerotic (CI less than 3.0) subjects in the 60s and the 70s.     

Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis

Aging of the human skeleton is characterized by decreased boneformation and bone mass and these changes are more pronounced inpatients with osteoporosis. As osteoblasts and adipocytes share a commonprecursor cell in the bone marrow, we hypothesized that decreased boneformation observed during aging and in patients with osteoporosis is theresult of enhanced adipognesis versus osteoblastogenesis from precursorcells in the bone marrow. Thus, we examined iliac crest bone biopsiesobtained from 53 healthy normal individuals (age 30–100) and 26patients with osteoporosis (age 52–92). Adipose tissue volumefraction (AV), hematopoietic tissue volume fraction (HV) and trabecularbone volume fraction (BV) were quantitated as a percentage of totaltissue volume fraction (TV) (calculated as BV + AV + HV) usingthe point-counting method. We found an age-related increase in AV/TV(r = 0.53, p < 0.001, n =53) and an age-related decline in BV/TV (r =–0.46, p < 0.001, n = 53) as well asin the HV/TV (r = –0.318, p <0.05, n = 53). There was an age-related inversecorrelation between BV/TV and AV/TV (r =–0.58, p < 0.001). No significant correlation betweenthe AV/TV and the body mass index (r = 0.06, n.s.,n = 52) was detectable. Compared with age-matchedcontrols, patients with osteoporosis exhibited an increased AV/TV(P < 0.05) and decreased BV/TV (P < 0.05)but no statistically significant difference in HV/TV. Our datasupport the hypothesis that with aging and in osteoporosis an enhancedadipogenesis is observed in the bone marrow and that these changes areinversely correlated to decreased trabecular bone volume. The cellularand molecular mechanisms mediating these changes remain to bedetermined.     

Association of periodontitis with increased white blood cell count and blood pressure

This study was aimed to examine the association of periodontitis with white blood cell (WBC) count and blood pressure (BP). In 2002, 424 subjects (manufacturing workers) were investigated for periodontitis by a general dentist. All were Japanese. Among them, 364 subjects (269 men and 95 women) who also attended the next year's (2003) screening were enrolled for this study. Of the 364 subjects, 55 (15.1%) had periodontitis. We also measured the BP and WBC count in periodontitis and non-periodontitis subjects at baseline and 1-year later follow-up. The WBC count higher in subjects with periodontitis than in subjects without periodontitis, both at baseline [mean +/- standard error (SE) 6.6 x 10(3) +/- 0.2 x 10(3)/ml vs 5.8 +/- 0.3 x 10(3)/ml; p < 0.001] and follow-up (7.0 +/- 0.3(3)/ml vs 6.5 +/- 0.1(3)/ml; p = 0.003). The systolic BP was higher in subjects with periodontitis than in subjects without periodontitis, both at the baseline (128 +/- 2.1 mmHg vs 120.8 +/- 0.8 mmHg; p < 0.001) and follow-up (129.2 +/- 2.3 mmHg vs 123.0 +/- 0.8 mmHg; p = 0.011), and so was the diastolic BP both at baseline (76 +/- 1.5 mmHg vs 71.2 +/- 0.6 mmHg; p = 0.003) and follow-up (80.5 +/- 1.7 mmHg vs 75.4 +/- 0.7 mmHg; p = 0.004). Periodontitis is associated with increased BP and WBC count. This finding may provide one underlying pathway linking periodontitis and cardiovascular disease.     

Association of increased neopterin production with decreased humoral immunity in the elderly

Tetanus toxoid (TT) antibodies of 447 adult persons aged 27-69 years were investigated and analyzed in relationship with the time span since the last vaccination against tetanus as well as the serum concentration of neopterin. Neopterin is a pteridine, which is produced by monocytes/macrophages upon stimulation with the type 1 T cell-derived cytokine interferon-gamma. There was an inverse correlation between serum neopterin and TT antibody concentrations (Spearman's rank correlation coefficient: r(s)=-0.259; p<0.0001) which was even stronger when persons with neopterin concentrations and TT antibodies below the third quartile of the study population were excluded (residual group: n=210; r(s)=-0.718; p<0.0001).The study demonstrates that an immunoregulatory shift towards type 1 immunity as indicated by higher neopterin concentrations coincides with lower TT antibody concentrations in the elderly.