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author:("Ikeno, fuji")
1.  Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology? 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.20833.
Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways. To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.
doi:10.3402/pba.v3i0.20833
PMCID: PMC3689900  PMID: 23799173
age-related pathology; Ames dwarf mice; calorie restriction; neoplastic disease; aging
2.  Pathology is a critical aspect of preclinical aging studies 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.22451.
Experimental design for mouse aging studies has historically involved lifespan, but it is now clear that survival data without pathology data limit the information that can be obtained on aging animals. This limitation becomes more serious when interventions of any sort are implemented. Pathology gives an insight into the health of an animal by revealing lesions not readily observable in the live animal. As such, it is a snapshot of disease conditions at the time of death. Therefore, a long-term goal is to establish pathology information as an essential component of studies involving health span and lifespan of aging animals. Given that pathology assessment is essential to help define the progression of lesions associated with aging, the real challenge is including it in aging studies because there is currently a lack of specialized expertise and resources. An increase in the level and scope of pathology assessment of tissues from old mice involved in aging studies is needed. A focus on the correlation of pathology data with longitudinal and cross-sectional lifespan data and health span physiology data can be established by enhancing standard histologic assessment of lesions observed in tissues from old mice. An environment for the development and integration of pathology data into aging studies of mice is needed to encourage more pathologists and other scientists to specialize in pathology of aging, and establish relevant standards to compare with other species including humans. Such results will have an important positive impact on aging studies because of the significant empowerment on data analyses and interpretation.
doi:10.3402/pba.v3i0.22451
PMCID: PMC3749367  PMID: 23970952
pathology; aging; mouse; histopathology grading; lifespan; health span
3.  Reduction of glucose intolerance with high fat feeding is associated with anti-inflammatory effects of thioredoxin 1 overexpression in mice 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.17101.
Aging is associated with reduced ability to maintain normal glucose homeostasis. It has been suggested that an age-associated increase in chronic pro-inflammatory state could drive this reduction in glucoregulatory function. Thioredoxins (Trx) are oxido-reductase enzymes that play an important role in the regulation of oxidative stress and inflammation. In this study, we tested whether overexpression of Trx1 in mice [Tg(TRX1)+/0] could protect from glucose metabolism dysfunction caused by high fat diet feeding. Body weight and fat mass gains with high fat feeding were similar in Tg(TRX1)+/0 and wild-type mice; however, high fat diet induced glucose intolerance was reduced in Tg(TRX1)+/0 mice relative to wild-type mice. In addition, expression of the pro-inflammatory cytokine TNF-α was reduced in adipose tissue of Tg(TRX1)+/0 mice compared to wild-type mice. These findings suggest that activation of thioredoxins may be a potential therapeutic target for maintenance of glucose metabolism with obesity or aging.
doi:10.3402/pba.v2i0.17101
PMCID: PMC3417639  PMID: 22953037
oxidative stress; diabetes; obesity; glucose homeostasis; aging
4.  The anti-tumor effects of calorie restriction are correlated with reduced oxidative stress in ENU-induced gliomas 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/pba.v1i0.7189.
The anti-tumor effects of calorie restriction (CR) and the possible underlying mechanisms were investigated using ethylnitrosourea (ENU)-induced glioma in rats. ENU was given transplacentally at gestational day 15, and male offspring were used in this experiment. The brain from 4-, 6-, and 8-month-old rats fed either ad libitum (AL) or calorie-restricted diets (40% restriction of total calories compared to AL rats) was studied. Tumor burden was assessed by comparing the number and size of gliomas present in sections of the brain. Immunohistochemical analysis was used to document lipid peroxidation [4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)], protein oxidation (nitrotyrosine), glycation and AGE formation [methylglyoxal (MG) and carboxymethyllysine (CML)], cell proliferation activity [proliferating cell nuclear antigen (PCNA)], cell death [single-stranded DNA (ssDNA)], presence of thioredoxin 1 (Trx1), and presence of heme oxygenase-1 (HO-1) associated with the development of gliomas. The results showed that the number of gliomas did not change with age in the AL groups; however, the average size of the gliomas was significantly larger in the 8-month-old group compared to that of the younger groups. Immunopositivity was observed mainly in tumor cells and reactive astrocytes in all histological types of ENU-induced glioma. Immunopositive areas for HNE, MDA, nitrotyrosine, MG, CML, HO-1, and Trx1 increased with the growth of gliomas. The CR group showed both reduced number and size of gliomas, and tumors exhibited less accumulation of oxidative damage, decreased formation of glycated end products, and a decreased presence of HO-1 and Trx1 compared to the AL group. Furthermore, gliomas of the CR group showed less PCNA positive and more ssDNA positive cells, which are correlated to the retarded growth of tumors. Interestingly, we also discovered that the anti-tumor effects of CR were associated with decreased hypoxia-inducible factor-1α (HIF-1α) levels in normal brain tissue. Our results are very exciting because they not only demonstrate the anti-tumor effects of CR in gliomas, but also indicate the possible underlying mechanisms, i.e. anti-tumor effects of CR observed in this investigation are associated with reduced accumulation of oxidative damage, decreased formation of glycated end products, decreased presence of HO-1 and Trx1, reduced cell proliferation and increased apoptosis, and decreased levels of HIF-1α.
doi:10.3402/pba.v1i0.7189
PMCID: PMC3417672  PMID: 22953030
calorie restriction; ethylnitrosourea; glioma; oxidative stress; HIF-1α

Results 1-4 (4)