Motoji Sawabe

Telomere lengths are characteristic in each human individual.

BACKGROUND A great deal of attention has been focused on telomeres in relation to cellular aging, immortality, and cancer. However, there is no simple link between telomeres and tissue turnover. We recently proposed a hypothesis that telomere shortening with aging and telomere lengths in different organs are characteristic for human individuals. METHODS To test this, telomere lengths were measured using DNA from cerebral cortex, myocardium, liver, renal cortex and spleen tissues obtained from human subjects ranging in age from neonates to centenarians. RESULTS Regression analyses demonstrated telomere reduction rates of 29-60 base pair (bp) per year in the liver, renal cortex and spleen, but no such decrease in the cerebral cortex and myocardium. Significant correlation was found between tissues within individuals, such as cerebral cortex versus (vs) myocardium, cerebral cortex vs liver, cerebral cortex vs renal cortex, myocardium vs liver, myocardium vs renal cortex, and liver vs renal cortex. In most cases, the longest telomeres were observed in the myocardium and the shortest in the liver or renal cortex. CONCLUSIONS Telomere lengths did not show clear correlation with tissue renewal times in vivo, but rather were characteristic for individuals.

Age-related mitochondrial DNA deletion in human heart: Its relationship with cardiovascular diseases

Background and aims: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. Methods: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977- bp deletion and long- PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. Results: The common 4977- bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long- PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p<0.05). Female predominance was significantly found in the group with the mtDNA deletion (p<0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. Conclusions: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.

Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma

Many publications focusing on the background or original mucosa of Barrett adenocarcinoma have maintained that adenocarcinoma arises in intestinal-type mucosa with goblet cells in the columnar-lined esophagus, and this has become a central dogma. The mucosa on each side of a series of 141 minute esophageal adenocarcinomas (almost all of which were mucosal carcinomas) resected by endoscopic mucosal resection was recorded as the background mucosa. All 141 cases had endoscopic evidence of an esophageal origin, and for 113 of them, histologic evidence of an esophageal origin was also available. The mucosae were classified into 4 types--squamous, cardiac, fundic, and intestinal--based on routine histology and immunohistochemical staining. The present joint pathologic examination of the background mucosa of Barrett adenocarcinoma conducted by Japanese and German pathologists and gastroenterologists found that more than 70% of primary small adenocarcinomas (<2 cm) of the esophagus were adjacent to cardiac/fundic-type rather than intestinal-type mucosa. Moreover, intestinal metaplasia was not observed in any areas of the endoscopic mucosal resection specimens in 64 (56.6%) of the 113 cases. In other words, there was no evidence to support the previously held view that Barrett adenocarcinoma is nearly always accompanied and preceded by intestinal-type mucosa. Our study has demonstrated a close relationship between esophageal adenocarcinoma and cardiac-type mucosa. Therefore, it is not proven histogenetically that the background mucosa of esophageal adenocarcinoma is the intestinal type. Also, it seems better to define Barrett esophagus as metaplastic columnar-lined esophagus alone, without requiring the presence of goblet cells, in accordance with histogenetic and practical standpoints.

Reviewing the definition of “elderly”

Conventionally, “elderly” has been defined as a chronological age of 65 years old or older, while those from 65 through 74 years old are referred to as “early elderly” and those over 75 years old as “late elderly.” However, the evidence on which this definition is based is unknown. We have attempted to review the definition of elderly by analyzing data from long‐term longitudinal epidemiological studies, and clinical and pathological studies that have been accumulated at the Tokyo Metropolitan Geriatric Hospital and the Tokyo Metropolitan Institute of Gerontology. Our recommendation might be a starting point in developing a strategy for a successful society by reviewing the definition of elderly based on comprehensive evidence in all aspects of social, cultural and medical sciences.

Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations

AbstractCoronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR) = 1.30, 95% confidence interval (CI); 1.13–1.49, p = 0.00027, allele count model] and Koreans (OR = 1.19, 95% CI; 1.02–1.38, p = 0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

Vascular aging: from molecular mechanism to clinical significance.

The large and medium‐sized arteries in elderly people show varying degrees of intimal and medial change. The medial change is known as age‐related medial degeneration and sclerosis (ARMDS). The ARMDS results in systolic hypertension and left ventricular hypertrophy of the heart as a result of loss of arterial elasticity. It also causes aortic dilatation, or even aortic aneurysm. The ARMDS and atherosclerosis are distinct entities, but are often overlapped and confused with each other. The present review mainly focuses on ARMDS and briefly addresses atherosclerosis, and aging of arterioles, capillaries and veins. The smooth muscle cells in the inner half of the aortic media of elderly people degenerate and undergo apoptosis. This causes degradation of elastin fibers and the accumulation of collagen fibers in the media, but the inflammatory infiltrates are scarce. Biochemical studies showed an age‐related decrease of elastin and its crosslinks, and an increase of collagen and its crosslink. Because the turnover of elastin is very long, it likely suffers from glycation (Maillard reaction) and glyco‐oxidative reaction. The advanced glycation end‐products accumulate in the aortic media with increasing age. Alcian‐blue positive mucin accumulates in aortic media in elderly people. The major component of the increase of aortic mucin is chondroitin‐6‐sulfate. Microcalcification is frequent in the inner acellular portion of the aortic media in elderly people. Calcium contents increase with age. In conclusion, the ARMDS is a distinct pathological entity with clinical significance. The pathogenesis of ARMDS is unclear; the mechanical stress of elastin, endothelial dysfunction, and glycation of elastin are proposed. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S213–S220.

Early squamous cell carcinoma of the oesophagus: the Japanese viewpoint.

In Japan, more than 90% of oesophageal malignancies are squamous cell carcinomas, and superficial and early carcinomas now account for about 40% and 20%, respectively, of all oesophageal carcinomas. Definition of early carcinoma has changed on the basis of new data. As of 2007, early carcinoma is defined as intramucosal carcinoma with or without metastasis. In the subclassification based on depth of cancer invasion, m1 and m2 carcinomas have no metastasis and are considered curable by endoscopic mucosal resection alone, whereas < 10% of m3 carcinomas and about 20% of sm1 carcinomas have lymph node metastasis. The relationship between various pathological findings and the incidence of lymph node metastasis has been reviewed. High‐grade squamous dysplasia (squamous cell carcinoma in situ in Japan) requires surgical or endoscopic removal. Very minute carcinomas have recently been detected by magnifying endoscopy and/or narrowband imaging. Endocytoscopy could replace biopsy histopathological examination for diagnosis of oesophageal squamous cell carcinoma, and endocytoscopic diagnosis and endoscopic therapy may be performed simultaneously. As a result of advances in the development of endoscopes, pathologists are now expected to diagnose very minute lesions, < 1 mm in size, in the oesophagus.

Incidence and Extent of Lewy Body-Related α-Synucleinopathy in Aging Human Olfactory Bulb

We investigated the incidence and extent of Lewy body (LB)-related &agr;-synucleinopathy (LBAS) in the olfactory bulb (OB) in 320 consecutive autopsy patients from a general geriatric hospital (mean age, 81.5 ± 8.5 years). Paraffin sections were immunostained with anti-phosphorylated &agr;-synuclein, tyrosine hydroxylase, phosphorylated tau, and amyloid &bgr; antibodies. LBAS was found in 102 patients (31.9%) in the central nervous system, including the spinal cord; the OB was involved in 85 (26.6%). Among these 85 patients, 2 had LBAS only in the anterior olfactory nucleus, 14 in the peripheral OB only, and 69 in both areas. In 5 patients, Lewy bodies were found only in the OB by hematoxylin and eosin stain; 3 of these patients had Alzheimer disease, and all had LBAS. Very few tyrosine hydroxylase-immunoreactive periglomerular cells exhibited LBAS. All 35 LBAS patients with pigmentation loss in the substantia nigra had LBAS in the OB. LBAS in the amygdala was more strongly correlated with LBAS in the anterior olfactory nucleus than with that in the OB periphery. LBAS did not correlate with systemic tauopathy or amyloid &bgr; amyloidosis. These results indicate a high incidence of LBAS in the aging human OB; they also suggest that LBAS extends from the periphery to the anterior olfactory nucleus and results in clinical manifestations of LB disease.

Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in lewy body disease.

Abstract Lewy body disease is defined as Lewy body-related neuronal degeneration involving the nigrostriatal system, limbic-neocortical system, and peripheral autonomic nervous system (PANS). We investigated whether the adrenal gland, which is evolutionarily related to sympathetic ganglia and is routinely examined in general autopsy, could be used to assess pathology of the PANS in Lewy body disease. Brains, spinal cords, and adrenal glands from 783 consecutive autopsy cases from a general geriatric hospital were examined immunohistochemically with antiphosphorylated &agr;-synuclein antibodies and routine staining. Parkinson disease (PD) with dementia and dementia with Lewy bodies (DLB) were defined using 1996 Consensus Guidelines for DLB and the secondary Lewy body-related &agr;-synucleinopathy or amygdala variants using previously established criteria. Lewy body-related &agr;-synucleinopathy was found in 207 (26.4%) of 783 cases, with 1 case solely in the adrenal gland. In all 18 PD cases with or without dementia and in 33 of 38 DLB cases, the adrenal gland was involved, but it was spared in all cases of amygdala variants. Our results indicate that the adrenal gland can provide useful information for evaluation of the PANS in Lewy body disease.

Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study

OBJECTIVE We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to ischemic stroke. METHODS A total of 6341 individuals from three independent populations was examined. Subject panel A comprised 131 individuals with ischemic stroke and 135 controls; subject panel B comprised 790 individuals with ischemic stroke and 3435 controls; and subject panel C comprised 71 individuals with ischemic stroke and 1779 controls. A GWAS for ischemic stroke was performed in subject panel A with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS The relation of 100 single nucleotide polymorphisms (SNPs) selected by the GWAS to ischemic stroke was examined in 705 subjects with ischemic stroke and 3426 controls selected from subject panel B. Three SNPs (rs1671021 of LLGL2, rs9615362 of CELSR1, and rs753307 of RUVBL2) were significantly (P<0.05) associated with ischemic stroke. After DNA sequencing of linkage disequilibrium blocks containing these SNPs, three tag SNPs (rs6007897 of CELSR1, rs1671021 of LLGL2, and rs1062708 of RUVBL2) and a nonsynonymous SNP (rs4044210 of CELSR1) were examined for their relation to ischemic stroke in subject panels B and C. Both rs6007897 (A-->G, Thr2268Ala) and rs4044210 (A-->G, Ile2107Val) of CELSR1 as well as rs1671021 (T-->C, Phe479Leu) of LLGL2 were significantly associated with ischemic stroke in subject panel B. The rs6007897 and rs4044210 polymorphisms of CELSR1 were also significantly associated with ischemic stroke in subject panel C. CONCLUSION CELSR1 is a susceptibility gene for ischemic stroke in Japanese individuals, although the functional relevance of the identified SNPs was not determined.