Ken Yamamura

Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity

Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse cholesterol transport (RCT). The role of CETP in atherosclerosis remains controversial. In this study we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), lipoprotein lipase (PvuII and HindIII), and ATP-binding cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190 healthy younger controls. Although heterozygous CETP deficiency and the B2 allele of the Taq1B polymorphism was consistently associated with higher HDL-C concentrations both in centenarians and controls, the allelic frequencies of those polymorphisms did not differ between the two groups. The allelic frequencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with lipoprotein lipase P(−/−) genotype had significantly higher HDL-C concentration than those with P(−/+) or with P(+/+), in contrast, there was no such a relationship among controls. In stepwise multiple regression analysis, serum albumin, CETP deficiency and lipoprotein lipase PvuII genotype were independently associated with HDL-C in centenarians. Sex, CETP deficiency, and the Taq1B genotype were also independently associated with HDL-C; however, lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in controls. In conclusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevity for Japanese centenarians.

Lipoprotein Metabolism in Japanese Centenarians: Effects of Apolipoprotein E Polymorphism and Nutritional Status

OBJECTIVES: To assess the complex interaction of apolipoprotein (apo) E polymorphisms and environmental factors on lipoprotein profile in centenarians.

Very low dose of the Na+/Ca2+ exchange inhibitor, KB-R7943, protects ischemic reperfused aged Fischer 344 rat hearts: considerable strain difference in the sensitivity to KB-R7943

OBJECTIVEnDecreased ischemic tolerance in the aged myocardium is associated with accelerated intracellular Ca(2+) overload. However, few drugs have been shown to attenuate reperfusion injury in aged hearts. Because the Na(+)/Ca(2+) exchanger (NCX1) has been reported to play an important role in Ca(2+) overload during reperfusion, we investigated whether KB-R7943 (KB-R), a novel inhibitor of the reverse mode of Na(+)/Ca(2+) exchange, can protect aged rat hearts against reperfusion injury.nnnMETHODSnIn the pilot study, isolated hearts from young Sprague-Dawley (SD) rats (12 weeks old), and young (12 weeks old) and aged (78 weeks old) Fischer 344 (F) rats were subjected to 25 min of global ischemia followed by 10 min of reperfusion with various concentrations of KB-R (0, 1 nM, 0.1 microM, 10 microM) and additional 20 min of reperfusion without agent. In subsequent studies with the same protocol in aged F rats, we added a protective dose of KB-R (1 nM) during the initial 10 min of reperfusion. In addition, we compared the amount of NCX1 and the sensitivity of the reverse mode of Na(+)/Ca(2+) exchange to KB-R under extracellular Na(+)-free condition in F rats with young SD rats.nnnRESULTSnIn the pilot study, protective effects were elicited with 1 nM of KB-R in both young and aged F rats, while 10 microM KB-R was needed for SD rats. In subsequent studies using aged F rats, there was better recovery of LV systolic function and high-energy phosphates with reduced creatine kinase release and the duration of reperfusion arrhythmias. 45Ca(2+) uptake via the reverse mode of Na(+)/Ca(2+) exchange was also inhibited with 1 nM of KB-R in young F rats, but not in young SD rats. Although the amount of NCX1 was not different among young SD, young F, and aged F rat hearts.nnnCONCLUSIONSnThese results demonstrated that KB-R could protect aged F rat hearts as well as young hearts of both strains against ischemia-reperfusion injury. Moreover, the sensitivity to KB-R is very different between these strains, suggesting serious caution when the agent is applied to human beings.

Preconditioning with heat shock further improved functional recovery in young adult but not in middle-aged rat hearts.

Ischemic preconditioning (PC) improves post-ischemic function, and heat shock (HS) mimics delayed PC in young animals. However, PC is not protective and the consequences of HS are not known in the aging hearts. This report examines the efficacy of HS and its synergy with PC in the middle-aged rat hearts. Hearts from 12- or 50-week-old rats were subjected to PC before 25 min ischemia followed by 30 min reperfusion 48 h after HS. HS induced HS proteins (HSP) in both age groups but that PC and HS translocated PKC-alpha and -delta only in young rats. The beneficial effects of HS and PC were additive and enhanced protein kinase C (PKC) translocation in young rats. However, neither HS alone nor in combination with PC conferred any functional advantage or accelerated PKC translocation in old rats. Similarly neither HS alone nor in combination with PC restore PC effects in old rats with impaired PKC activation, despite the induction of HSP, indicating that induction of HSP is insufficient for cytoprotection.

High adiponectin concentration and its role for longevity in female centenarians

Background:u2003 Evidence from experimental models of longevity indicates that maintenance of energy homeostasis could be indispensable for longevity across various species. In humans, it has been reported that maintenance of glucose homeostasis and vascular stability is one biomedical feature of centenarians, who have reached the maximum life‐span. We hypothesized that adiponectin, a novel anti‐inflammatory adipocytokine, could be a protective factor against age‐related metabolic alteration and atherogeneity in centenarians.

Long-term effect of lipid-lowering therapy on atherosclerosis of abdominal aorta in patients with hypercholesterolemia: Noninvasive evaluation by a new image analysis program

Recent clinical studies have demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase inhibitors are effective in the prevention of cardiovascular events and regres sion of atherosclerotic lesions evaluated by angiography. In this study, the authors investigated how lipid-lowering therapy effects on the progression of aortic atherosclerosis by using plain and enhanced computed tomography (CT) of the lower abdominal aorta. Twenty-nine hyper lipidemic patients (mean age 61.4 ±7.2 yr) were enrolled in a prospective open-labeled study. All patients underwent baseline CT scanning of abdominal aorta, screening for serum lipid profile and coagulation-fibrinolysis measurement, then treatment with simvastatin was begun. After 2 years, a follow-up CT scan was done and atherosclerotic lesions were compared between baseline and on-treatment scan. In spite of significant improvement of lipid and fibri nolytic profiles by simvastatin administration, mean aortic wall thickening volume (AWV) was increased during observation period. When patients were divided into subgroups by the levels of on-treatment LDL cholesterol (LDL-C), development rate of AWV was more potently suppressed in patients whose on-treatment LDL-C were below 125 mg/dL (median LDL-C). We could not find any associations of coagulation-fibrinolysis measurements with atheroscle rotic lesions. In regard to aortic calcification volume (ACV), low levels of total and HDL choles terol and higher age were associated with aortic calcification at baseline. These results suggest that aggressive treatment with LDL-C below 125 mg/dL may suppress the progres sion of wall thickening and factors that promote arterial calcifications and those for wall thick ening may be different.

Contribution of an affect-associated gene to human longevity : Prevalence of the long-allele genotype of the serotonin transporter-linked gene in japanese centenarians

Negative affect such as depression and anxiety has been reported to be associated with morbidity and mortality, and polymorphisms of the serotonin transporter (5HTT) gene may be associated with such affect disorders. Hypothesizing that 5HTT gene polymorphisms could influence human longevity via negative affect; we compared the polymorphic variation of the 5HTT gene between 265 Japanese centenarians and control subjects. In addition, we evaluated the relationships between the 5HTT genotype and the physical, cognitive, and biologic status of centenarians, as indicated by the Barthel Index, the Mini-Mental State Examination, and serum albumin concentration, respectively. The frequency of the l/l genotype and the l allele was significantly greater in centenarians than in younger control subjects, particularly women. A significant effect of the 5HTT genotype on serum albumin concentration was observed in both sexes. Although, there was sex optionality, the l allele may carry a longevity advantage possibly through behavioral mechanisms.

Aging abolishes the cardioprotective effect of combination heat shock and hypoxic preconditioning in reperfused rat hearts.

Abstract. Hypoxic preconditioning (HP) does not improve post-ischemic function in the hearts of aging rats secondary to failure of protein kinase C (PKC) activation, but the effect of heat shock (HS) or preconditioning has not been studied. We studied whether HS increases tolerance to ischemia and whether its combination with HP would restore the cardioprotective effect in aging rat hearts. HS was performed in 12- and 50-week-old rats. Hearts were isolated and subjected to HP by 10 min hypoxic perfusion before 25 min ischemia followed by 30 min reperfusion 48 h after HS. Both HP and HS improved recovery of left ventricular function with translocation of PKC-δ from the cytosol to the nuclear fraction and induction of heat shock proteins, HSP27, HSP70, and αB-crystallin. The combination of HS and HP enhanced the translocation of PKC-δ in young rats, resulting in further improvement in functional recovery. In older rats, HP translocated PKC-δ from the membrane to the cytosol fraction, but did not improve functional recovery, although the combination of HS with HP induced HS proteins and translocated PKC-δ from the cytosol to the nuclear fraction. HS provided cardioprotection and had additive effects to HP with additional PKC-δ activation in young rats. However, in hearts from aging rats, HS alone was not cardioprotective, nor was its combination with HP, despite the induction of HS proteins and the activation of PKC-δ, resulting in its translocation to the nuclear fraction.

Cognitive Function in Japanese Centenarians according to the Mini-Mental State Examination

Background/Aims: We examined the effect of aging on cognitive function at the limit of human life expectancy by characterizing state of cognition in centenarians without clinical cognitive impairment. Methods: Participants were 68 centenarians without cognitive impairment (Clinical Dementia Rating (CDR) 0), 96 controls 60 to 74 years old, and 46 controls 75 to 89 years old. We visited the places where centenarians were living and administered the Mini-Mental State Examination (MMSE) individually. Control subjects came to the assembly hall within their dwelling area, to be administered the MMSE. Results: Mean total scores of centenarians (22.3) were lower than for either 60–74 (27.2) or 75–89 (26.2). Comparison of scores in each of five cognitive domains measured by MMSE showed a significant age-group effect upon orientation, memory, and attention. Centenarians’ scores were lower than for younger groups in every domain except for the language and praxis, concentration, and for repetition. Conclusion: The centenarians’ scores in memory and orientation declined as in earlier studies of normal aging. Centenarians’ scores for attention and concentration differed from those in previous studies. The present result suggests that even primary memory is influenced by advanced age in centenarians, while ability to store information declines, ability to process is maintained.

Association analysis of the SHC1 gene locus with longevity in the Japanese population

The SHC1 gene encodes a signaling and transforming protein that has been implicated in the aging process in worms and mammals. In this study we examined 230 Japanese centenarians and 180 healthy younger controls and looked at the SHC1 locus as a candidate region that may be associated with longevity. We identified 12 single nucleotide polymorphisms (SNPs) within a 10-kb region encompassing the entire SHC1 gene from the DNA of 30 centenarians and 24 healthy younger controls. Five SNPs, including three nonsynonymous sites, lay within coding elements, six were located within introns, and one was in the 3′ untranslated region. All of these SNPs were relatively rare, with a minor allele frequency of less than 5% in our subjects. A pairwise linkage disequilibrium analysis using the r2 statistic showed that two of the SNP pairs are in tight linkage disequilibrium at this locus. We investigated the possible association of SHC1 with longevity using association analyses with allelotypes and haplotypes but found that the SNPs identified in SHC1 had no impact on longevity for Japanese centenarians.