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author:("Ikeno, fuji")
1.  Decreased insulin sensitivity and increased oxidative damage in wasting adipose tissue depots of wild-type mice 
Age  2011;34(5):1225-1237.
Unintentional weight loss (wasting) in the elderly is a major health concern as it leads to increased mortality. Several studies have focused on muscle loss, but little is known about the mechanisms giving rise to loss of fat mass at old ages. To investigate potential mechanisms, white adipose tissue (WAT) characteristics and proteomic profiles were compared between adult (10–12-month-old) and aged (22–24-month-old) wild-type mice. Four individual WAT depots were analyzed to account for possible depot-specific differences. Proteomic profiles of WAT depots, along with body weights and compositions, plasma levels of insulin, leptin and adiponectin, insulin tolerance, adipocyte sizes, and products of oxidative damage in each WAT depot were determined. We found that lean mass remained constant while fat mass and insulin tolerance were decreased in old age, as were adipocyte sizes in the WAT depots. Proteomic results showed increased levels of enolase, pyruvate dehydrogenase E1β, NAD+−dependent isocitrate dehydrogenase α, and ATP synthase subunit β, and decreased levels of carbonic anhydrase 3 in WAT of aged mice. These data suggest increased aerobic glucose oxidation in wasting WAT, consistent with decreased insulin signaling. Also, Cu/Zn superoxide dismutase and two chaperones were increased in aged WAT depots, indicating higher stress resistance. In agreement, lipid peroxidation (HNE-His adducts) increased in old age, although protein oxidation (carbonyl groups) showed no increase. In conclusion, features of wasting WAT were similar in the four depots, including decreased adipocyte sizes and alterations in protein expression profiles that indicated decreased insulin sensitivity and increased lipid peroxidation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9304-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3448990  PMID: 21953241
Wasting; Aging; White adipose tissue depots; Proteomics; Oxidative damage; Stress resistance; Insulin resistance
2.  Thioredoxin 1 Overexpression Extends Mainly the Earlier Part of Life Span in Mice 
We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)+/0]. The Tg(TRX1)+/0 mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)+/0 mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1)+/0 mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1)+/0 mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1)+/0 mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.
PMCID: PMC3210956  PMID: 21873593
Thioredoxin; Transgenic mouse; Oxidative stress; Protein carbonylation; Aging
4.  Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging? 
PLoS ONE  2011;6(11):e26891.
Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo- insufficiency of the IGF-1 receptor (Igf1r+/−) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r+/− mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r+/− mice show reduced IGF-1 signaling. Aged male, but not female Igf1r+/− mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r+/− mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r+/− mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r+/− and wild type mice was observed; and the mean lifespan of the Igf1r+/− females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r+/− and wild type mice. These data show that the Igf1r+/− mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.
PMCID: PMC3223158  PMID: 22132081
5.  Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense 
BMC Cancer  2011;11:43.
Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.
The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors
We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.
We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.
PMCID: PMC3038980  PMID: 21276246
6.  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.
PMCID: PMC3417672  PMID: 22953030
calorie restriction; ethylnitrosourea; glioma; oxidative stress; HIF-1α

Results 1-6 (6)