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1.  An association of metabolic syndrome constellation with cellular membrane caveolae 
Pathobiology of Aging & Age Related Diseases  2014;4:10.3402/pba.v4.23866.
Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that can predispose an individual to a greater risk of developing type-2 diabetes and cardiovascular diseases. The cluster includes abdominal obesity, dyslipidemia, hypertension, and hyperglycemia – all of which are risk factors to public health. While searching for a link among the aforementioned malaises, clues have been focused on the cell membrane domain caveolae, wherein the MetS-associated active molecules are colocalized and interacted with to carry out designated biological activities. Caveola disarray could induce all of those individual metabolic abnormalities to be present in animal models and humans, providing a new target for therapeutic strategy in the management of MetS.
doi:10.3402/pba.v4.23866
PMCID: PMC3926988  PMID: 24563731
metabolic syndrome; caveolae; dyslipidemia; hypertension; hyperglycemia; caveolins
2.  The quality control theory of aging 
Pathobiology of Aging & Age Related Diseases  2014;4:10.3402/pba.v4.24835.
The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society.
doi:10.3402/pba.v4.24835
PMCID: PMC4033319  PMID: 24891937
quality control theory of aging; endoplasmic reticulum; histone deacetylase; AMPK; beta-adrenergic receptor; aging intervention with drug combinations
3.  Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging 
Pathobiology of Aging & Age Related Diseases  2014;4:10.3402/pba.v4.24932.
Laboratory mice develop naturally occurring lesions that affect biomedical research. Hydronephrosis is a recognized pathologic abnormality of the mouse kidney. Acquired hydronephrosis can affect any mouse, as it is caused by any naturally occurring disease that impairs free urine flow. Many etiologies leading to this condition are of particular significance to aging mice. Non-invasive ultrasound imaging detects renal pelvic dilation, renal enlargement, and parenchymal loss for pre-mortem identification of this condition. High-frequency ultrasound transducers produce high-resolution images of small structures, ideal for detecting organ pathology in mice. Using a 40 MHz linear array transducer, we obtained high-resolution images of a diversity of pathologic lesions occurring within the abdomen of seven geriatric mice with acquired hydronephrosis that enabled a determination of the underlying etiology. Etiologies diagnosed from the imaging results include pyelonephritis, neoplasia, urolithiasis, mouse urologic syndrome, and spontaneous hydronephrosis, and were confirmed at necropsy. A retrospective review of abdominal scans from an additional 149 aging mice shows that the most common etiologies associated with acquired hydronephrosis are mouse urologic syndrome and abdominal neoplasia. This report highlights the utility of high-frequency ultrasound for surveying research mice for age-related pathology, and is the first comprehensive report of multiple cases of acquired hydronephrosis in mice.
doi:10.3402/pba.v4.24932
PMCID: PMC4119937  PMID: 25143818
ultrasound; hydronephrosis; renal pelvic dilation; mice; abdominal imaging; kidney; pathology; mouse urologic syndrome; abdominal neoplasia
4.  An immunohistochemical approach for monitoring effects of exercise on tumor stromal cells in old mice 
Pathobiology of Aging & Age Related Diseases  2014;4:10.3402/pba.v4.24824.
Epidemiological evidence supports a protective effect of physical activity for breast cancer in older women, but the mechanisms are not well understood. We used 18-month-old BALB/c mice injected in the mammary fat pad with syngeneic 4T1 tumor cells as a model of invasive breast cancer. During the tumor progression phase, there was a significant decrease in labeling for F4/80, a marker for mouse macrophages, and CD34, a marker for vascular endothelial cells, in primary tumors from mice that ran higher average distances compared to mice that ran lower average distances (p≤0.05). These observations suggest that immunohistochemistry can be used to monitor stromal cell populations in tumors from old mice under exercise conditions.
doi:10.3402/pba.v4.24824
PMCID: PMC4131002  PMID: 25147645
breast cancer; exercise; aging; tumor stromal cells; tumor microenvironment; immunohistochemistry
5.  Fatal myocardial fibrosis in an aged chimpanzee (Pan troglodytes) 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.21073.
A 36-year-old male chimpanzee (Pan troglodytes) assigned to a life-long sign language communication project presented for sudden death. No other clinical or clinical pathological abnormalities were noted and given the signalment, death due to cardiac failure was suspected. Necropsy findings revealed moderate cardiomegaly and other chronic age-related findings including focal renal tubular cystic dilation and gingival hyperplasia. Histologic evaluation of the heart revealed interstitial fibrosing cardiomyopathy characterized by severe interstitial myocardial fibrosis replacing and separating myofibers within all chambers of the heart, especially the left ventricle, interventricular septum and subvalvular areas. This case report represents an additional case of sudden death associated with interstitial myocardial fibrosis in a chimpanzee. This process has been previously cited as the most common cause of sudden death in aged chimpanzees.
doi:10.3402/pba.v3i0.21073
PMCID: PMC3679521  PMID: 23762500
interstitial myocardial fibrosis; great apes; sudden death
6.  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
7.  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
8.  A novel radial water tread maze tracks age-related cognitive decline in mice 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.20679.
There is currently no treatment and cure for age-related dementia and cognitive impairment in humans. Mice suffer from age-related cognitive decline just as people do, but assessment is challenging because of cumbersome and at times stressful performance tasks. We developed a novel radial water tread (RWT) maze and tested male C57BL/6 (B6) and C57BL/6 x Balb/c F1 (CB6F1) mice at ages 4, 12, 20, and 28 months. B6 mice showed a consistent learning experience and memory retention that gradually decreased with age. CB6F1 mice showed a moderate learning experience in the 4 and 12 month groups, which was not evident in the 20 and 28 month groups. In conclusion, CB6F1 mice showed more severe age-related cognitive impairment compared to B6 mice and might be a suitable model for intervention studies. In addition, the RWT maze has a number of operational advantages compared to currently accepted tasks and can be used to assess age-related cognition impairment in B6 and CB6F1 mice as early as 12 months of age.
doi:10.3402/pba.v3i0.20679
PMCID: PMC3791354  PMID: 24106580
memory impairment; aging; water tread radial maze; mouse cognition
9.  p53 as an intervention target for cancer and aging 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.22702.
p53 is well known for suppressing tumors but could also affect other aging processes not associated with tumor suppression. As a transcription factor, p53 responds to a variety of stresses to either induce apoptosis (cell death) or cell cycle arrest (cell preservation) to suppress tumor development. Yet, the effect p53 has on the non-cancer aspects of aging is complicated and not well understood. On one side, p53 could induce cellular senescence or apoptosis to suppress cancer but as an unintended consequence enhance the aging process especially if these responses diminish stem and progenitor cell populations. But on the flip side, p53 could reduce growth and growth-related stress to enable cell survival and ultimately delay the aging process. A better understanding of diverse functions of p53 is essential to elucidate its influences on the aging process and the possibility of targeting p53 or p53 transcriptional targets to treat cancer and ameliorate general aging.
doi:10.3402/pba.v3i0.22702
PMCID: PMC3794078  PMID: 24124625
DNA damage; cell growth; cellular senescence; apoptosis; anaerobic glycolysis
11.  Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation 
Obesity is a significant risk factor for developing osteoarthritis in weight-bearing and non-weight-bearing joints. Although the pathogenesis of obesity-associated osteoarthritis is not completely understood, recent studies indicate that pro-inflammatory metabolic factors contribute to an increase in osteoarthritis risk. Adipose tissue, and in particular infrapatellar fat, is a local source of pro-inflammatory mediators that are increased with obesity and have been shown to increase cartilage degradation in cell and tissue culture models. One adipokine in particular, leptin, may be a critical mediator of obesity-associated osteoarthritis via synergistic actions with other inflammatory cytokines. Biomechanical factors may also increase the risk of osteoarthritis by activating cellular inflammation and promoting oxidative stress. However, some types of biomechanical stimulation, such as physiologic cyclic loading, inhibit inflammation and protect against cartilage degradation. A high percentage of obese individuals with knee osteoarthritis are sedentary, suggesting that a lack of physical activity may increase the susceptibility to inflammation. A more comprehensive approach to understanding how obesity alters daily biomechanical exposures within joint tissues may provide new insight into the protective and damaging effects of biomechanical factors on inflammation in osteoarthritis.
doi:10.3402/pba.v2i0.17470
PMCID: PMC3364606  PMID: 22662293
arthritis; physical activity; adipokines; exercise; mechanobiology; cartilage; aging; anti-inflammatory; oxidative stress
12.  Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.17470.
Obesity is a significant risk factor for developing osteoarthritis in weight-bearing and non-weight-bearing joints. Although the pathogenesis of obesity-associated osteoarthritis is not completely understood, recent studies indicate that pro-inflammatory metabolic factors contribute to an increase in osteoarthritis risk. Adipose tissue, and in particular infrapatellar fat, is a local source of pro-inflammatory mediators that are increased with obesity and have been shown to increase cartilage degradation in cell and tissue culture models. One adipokine in particular, leptin, may be a critical mediator of obesity-associated osteoarthritis via synergistic actions with other inflammatory cytokines. Biomechanical factors may also increase the risk of osteoarthritis by activating cellular inflammation and promoting oxidative stress. However, some types of biomechanical stimulation, such as physiologic cyclic loading, inhibit inflammation and protect against cartilage degradation. A high percentage of obese individuals with knee osteoarthritis are sedentary, suggesting that a lack of physical activity may increase the susceptibility to inflammation. A more comprehensive approach to understanding how obesity alters daily biomechanical exposures within joint tissues may provide new insight into the protective and damaging effects of biomechanical factors on inflammation in osteoarthritis.
doi:10.3402/pba.v2i0.17470
PMCID: PMC3364606  PMID: 22662293
arthritis; physical activity; adipokines; exercise; mechanobiology; cartilage; aging; anti-inflammatory; oxidative stress
13.  Growth hormone, inflammation and aging 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.17293.
Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals. During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines. This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.
doi:10.3402/pba.v2i0.17293
PMCID: PMC3417471  PMID: 22953033
Ghowth hormone; obesity; inflammation; calorie restriction; aging
14.  Breast tumors in PyMT transgenic mice expressing mitochondrial catalase have decreased labeling for macrophages and endothelial cells 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.17391.
We show by immunohistochemical labeling that prominent cell types in the tumor microenvironment of PyMT transgenic mice are tumor-associated macrophages (TAMs) and endothelial cells, and that both populations are decreased in the presence of mitochondrial targeted catalase (mCAT). This observation suggests that mitochondrial ROS can drive tumor invasiveness in conjunction with the presence of TAMs and increased angiogenesis. Since primary PyMT tumor cells expressing mCAT undergo increased apoptosis, mitochondrial antioxidants might be attractive anti-tumor agents.
doi:10.3402/pba.v2i0.17391
PMCID: PMC3417526  PMID: 22953034
immunohistochemistry of mouse breast cancer; tumor associated macrophages; endothelial cells; mitochondrial catalase; reactive oxygen species
15.  Potential of chromatin modifying compounds for the treatment of Alzheimer's disease 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.14980.
Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.
doi:10.3402/pba.v2i0.14980
PMCID: PMC3417541  PMID: 22953035
Alzheimer's disease; histone acetylation; histone deacetylase inhibitor; Trichostatin A; sirtuins; resveratrol
16.  Rapamycin selectively alters serum chemistry in diabetic mice 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.15896.
The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed. Serum samples were analyzed for the measurement of glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT), total cholesterol, total triglyceride, and total protein, using the automated dry chemistry analysis. Rapamycin elevated serum glucose in female diabetic mice. Serum creatinine tended to be higher in diabetic mice but was not affected by rapamycin; there was no difference in BUN levels among the groups. Serum ALP was elevated in diabetic mice and rapamycin lowered it only in female diabetic mice; serum ALT levels were increased in female diabetic mice, unaffected by rapamycin. Serum total protein was elevated in diabetic mice of both genders but was not affected by rapamycin. Diabetic mice from both genders had elevated serum cholesterol and triglycerides; rapamycin did not affect serum cholesterol but decreased serum total triglycerides in male diabetic mice. We conclude that rapamycin elicits complex metabolic responses in aging diabetic mice, worsening hyperglycemia in females but improving ALP in female diabetic and total triglycerides in male diabetic mice, respectively. The metabolic effects of rapamycin should be considered while performing studies with rapamycin in mice.
doi:10.3402/pba.v2i0.15896
PMCID: PMC3417581  PMID: 22953036
alkaline phosphatase; alanine aminotransferase; cholesterol; triglycerides
17.  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
18.  Investigation of the biological properties of Cinnulin PF in the context of diabetes: mechanistic insights by genome-wide mRNA-Seq analysis 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.11905.
The accumulating evidence of the beneficial effects of cinnamon (Cinnamomum burmanni) in type-2 diabetes, a chronic age-associated disease, has prompted the commercialisation of various supplemental forms of the spice. One such supplement, Cinnulin PF®, represents the water soluble fraction containing relatively high levels of the double-linked procyanidin type-A polymers of flavanoids. The overall aim of this study was to utilize genome-wide mRNA-Seq analysis to characterise the changes in gene expression caused by Cinnulin PF in immortalised human keratinocytes and microvascular endothelial cells, which are relevant with respect to diabetic complications. In summary, our findings provide insights into the mechanisms of action of Cinnulin PF in diabetes and diabetic complications. More generally, we identify relevant candidate genes which could provide the basis for further investigation.
doi:10.3402/pba.v2i0.11905
PMCID: PMC3417697  PMID: 22953038
cinnulin PF; diabetes; diabetic complications; diabetic ulcer; mRNA-Seq
19.  Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta) 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.18052.
Aged individuals are more susceptible to infections due to a general decline in immune function broadly referred to as immune senescence. While age-related changes in the adaptive immune system are well documented, aging of the innate immune system remains less well understood, particularly in nonhuman primates. A more robust understanding of age-related changes in innate immune function would provide mechanistic insight into the increased susceptibility of the elderly to infection. Rhesus macaques have proved a critical translational model for aging research, and present a unique opportunity to dissect age-dependent modulation of the innate immune system. We examined age-related changes in: (i) innate immune cell frequencies; (ii) expression of pattern recognition receptors (PRRs) and innate signaling molecules; (iii) cytokine responses of monocytes and dendritic cells (DC) following stimulation with PRR agonists; and (iv) plasma cytokine levels in this model. We found marked changes in both the phenotype and function of innate immune cells. This included an age-associated increased frequency of myeloid DC (mDC). Moreover, we found toll-like receptor (TLR) agonists lipopolysaccharide (TLR4), fibroblast stimulating ligand-1 (TLR2/6), and ODN2006 (TLR7/9) induced reduced cytokine responses in aged mDC. Interestingly, with the exception of the monocyte-derived TNFα response to LPS, which increased with age, TNFα, IL-6, and IFNα responses declined with age. We also found that TLR4, TLR5, and innate negative regulator, sterile alpha and TIR motif containing protein (SARM), were all expressed at lower levels in young animals. By contrast, absent in melanoma 2 and retinoic acid-inducible gene I expression was lowest in aged animals. Together, these observations indicate that several parameters of innate immunity are significantly modulated by age and contribute to differential immune function in aged macaques.
doi:10.3402/pba.v2i0.18052
PMCID: PMC3417700  PMID: 22953039
nonhuman primate; innate immunity; myeloid; immune senscence; pattern recognition receptor
20.  B16 melanoma tumor growth is delayed in mice in an age-dependent manner 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.19182.
A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×105 tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6) and C57BL/6×BALB/c F1 (CB6 F1) mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm3. The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm3, respectively (p≤0.001). The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm3. The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm3, respectively (p≤0.01). The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm3 for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm3, respectively (p≤0.05). The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm3 for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm3 (p≤0.01). In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average tumor volumes of 417.62 and 216.34 mm3 in the 16- and 24-month age groups, respectively (p≤0.005). Histologically, implanted tumors in young mice exhibited characteristics of aggressive, rapidly growing tumor cells including high vascularity, mitosis, and invasiveness compared to tumors in old mice. We contend that the decrease in B16 melanoma tumor growth seen with increasing age in B6 and CB6 F1 mice represents a biological process, which we are calling age-dependent cancer resistance (ADCR). Our data provide a detailed description of conditions necessary to use the model to investigate the mechanisms of ADCR and determine its biological and clinical relevance.
doi:10.3402/pba.v2i0.19182
PMCID: PMC3424493  PMID: 22953040
aging; cancer; cancer resistance; B16 melanoma
21.  Mouse Health Span: Why Lifespan is No Longer Enough 
Pathobiology of Aging & Age Related Diseases  2012;2:10.3402/pba.v2i0.20276.
doi:10.3402/pba.v2i0.20276
PMCID: PMC3535693
22.  Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/pba.v1i0.7013.
Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa), the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD) with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC) with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.
doi:10.3402/pba.v1i0.7013
PMCID: PMC3417547  PMID: 22953026
colon cancer; high fat diet; curcumin; DNA damage; apoptosis; oxidative stress
23.  Pathobiology of aging: an old problem gets a new look 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/pba.v1i0.7281.
doi:10.3402/pba.v1i0.7281
PMCID: PMC3417555  PMID: 22953027
24.  Resveratrol has protective effects against airway remodeling and airway hyperreactivity in a murine model of allergic airways disease 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/PBA.v1i0.7134.
Background
New therapies for asthma which can address three main interrelated features of the disease, airway inflammation, airway remodeling and airway hyperreactivity, are urgently required. Resveratrol, a well known red wine polyphenol has received much attention due to its potential anti-aging properties. This compound is an agonist of silent information regulator two histone deacetylases and has many effects that are relevant to key aspects of the pathophysiology of asthma including inflammation, cell proliferation and fibrosis. Therefore, resveratrol may offer a novel asthma therapy that simultaneously inhibits airway inflammation, and airway remodeling which are the main contributors to airway hyperreactivity and irreversible lung function loss.
Methods
We evaluated the effects of systemic resveratrol treatment in a murine model of chronic allergic airways disease which displays most of the clinicopathological features of severe human asthma. Wild-type Balb/c mice with allergic airways disease were treated with 12.5 mg/kg resveratrol or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and histological examination of lung tissue sections. Further, remodeling was assessed by morphometric analysis and lung function was assessed by invasive plethysmography measurement of airway resistance and dynamic compliance.
Results
Mice treated with resveratrol exhibited reduced tissue inflammation as compared to vehicle treated mice (p<0.05). Additionally, resveratrol treatment resulted in reduced subepithelial collagen deposition as compared to vehicle treated mice (p<0.05) and attenuated airway hyperreactivity (p<0.05).
Conclusions
These novel findings demonstrate that treatment with resveratrol can reduce structural airway remodeling changes and hyperreactivity. This has important implications for the development of new therapeutic approaches to asthma.
doi:10.3402/pba.v1i0.7134
PMCID: PMC3417665  PMID: 22953028
resveratrol; asthma; airway remodeling; allergic airways disease; fibrosis
25.  Broad segmental progeroid changes in short-lived Ercc1−/Δ7 mice 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/pba.v1i0.7219.
Genome maintenance is considered a prime longevity assurance mechanism as apparent from many progeroid human syndromes that are caused by genome maintenance defects. The ERCC1 protein is involved in three genome maintenance systems: nucleotide excision repair, interstrand cross-link repair, and homologous recombination. Here we describe in-life and post-mortem observations for a hypomorphic Ercc1 variant, Ercc1−/Δ7, which is hemizygous for a single truncated Ercc1 allele, encoding a protein lacking the last seven amino acids. Ercc1−/Δ7 mice were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively. Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1−/Δ7 mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters. Together they define a segmental progeroid phenotype of the Ercc1−/Δ7 mouse model.
doi:10.3402/pba.v1i0.7219
PMCID: PMC3417667  PMID: 22953029
Ercc1; mouse; aging; life span; cross sectional; pathology; immunosenescense; body weight; organ weight; FVB; C57BL/6; genome maintenance

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