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jtitle_s:("Age (dorer)")
1.  Psychological stress and aging: role of glucocorticoids (GCs) 
Age  2011;34(6):1421-1433.
Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.
doi:10.1007/s11357-011-9319-0
PMCID: PMC3528378  PMID: 21971999
Chronic psychological stress; Glucocorticoid; Glucocorticoid receptor; Aging
2.  Exercise effects on bone mineral density in older adults: a meta-analysis of randomized controlled trials 
Age  2011;34(6):1493-1515.
The purpose of the study was to assess the effects of exercise interventions with different impact loading characteristics on lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) in older adults. We searched electronic databases and hand searched selected journals up to February 2011 for randomized controlled trials (RCTs) investigating the effects of impact exercise interventions on LS and FN BMD in older adults. Exercise protocols were categorized according to impact loading characteristics. Weighted mean difference (WMD) meta-analyses were undertaken. Heterogeneity amongst trials and publication bias was tested. Random-effects models were applied. Trial quality assessment was also undertaken. Nineteen RCTs, including 1577 subjects, met the inclusion criteria. Twenty-two study group comparisons reported BMD data at the LS. Meta-analysis showed a significant change in BMD at this site (WMD 0.011 g/cm2, 95% CI 0.003 to 0.020; p = 0.007), although results were moderately inconsistent (I2 = 52.2%). BMD data at the FN were available from 19 study group comparisons among older adults. Results were inconsistent (I2 = 63.6%) in showing a significant positive effect of exercise on BMD at this site (WMD 0.016 g/cm2, 95% CI 0.005 to 0.027; p = 0.004). Combined loading studies of impact activity mixed with high-magnitude joint reaction force loading through resistance training were effective at LS (WMD 0.016 g/cm2, 95% CI 0.002 to 0.036; p = 0.028), and no inconsistency existed among these trials. Odd-impact protocols were also effective in increasing BMD at LS (WMD 0.039 g/cm2, 95% CI 0.002 to 0.075; p = 0.038) and FN (WMD 0.036 g/cm2, 95% CI 0.012 to 0.061; p = 0.004), although heterogeneity was evident (I2 = 87.5% and I2 = 83.5%, respectively). We found consistency among results for low-impact and resistance exercise studies on LS and FN, although non-significant BMD changes were evident amongst these types of protocols at any site and amongst the RCTs that provided a combined loading impact exercise at FN. Funnel plots showed no evidence of publication bias. Trial quality was moderate to high. The findings from our meta-analysis of RCTs support the efficacy of exercise for increasing LS and FN BMD in older adults.
doi:10.1007/s11357-011-9311-8
PMCID: PMC3528362  PMID: 21922251
Systematic review; Meta-analysis; Bone density; Exercise; Aging
3.  Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span 
Age  2011;34(1):111-120.
Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or “enfeebled” rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. Fifth, drug dosages should be chosen based on surrogate endpoints or accepted cross-species scaling factors. These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9224-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9224-6
PMCID: PMC3260350  PMID: 21424790
Longevity therapeutics; CR mimetics; Geroprotectors; Health span; Life span; Longevity; Drug discovery; Pharmaceutical testing
4.  Cellular senescence, ageing and disease 
Age  2008;31(1):1-9.
Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence display a radically altered phenotype that is thought to impair tissue function and predispose tissues to disease development and/or progression as they gradually accumulate. However, in the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease.
doi:10.1007/s11357-008-9075-y
PMCID: PMC2645988  PMID: 19234764
Ageing; Disease; Cellular senescence; Senescent phenotype
5.  Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study 
Age  2006;28(4):313-332.
Centenarians represent a rare phenotype appearing in roughly 10–20 per 100,000 persons in most industrialized countries but as high as 40–50 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90 years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.
doi:10.1007/s11357-006-9020-x
PMCID: PMC3259160  PMID: 22253498
longevity; genetics; centenarians; Okinawa; longevity genes
6.  Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?—a pathological point of view 
Age  2006;28(2):163-171.
Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the growth hormone/insulin like growth factor-1 axis in the aging process. Interestingly, these studies demonstrate that these long-lived mutant mice have physiological characteristics that are similar to the effects of calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, a question remains to be answered: do these long-lived mutant and calorie-restricted mice extend their lifespan through a common underlying mechanism?
doi:10.1007/s11357-006-9007-7
PMCID: PMC2464730  PMID: 19943137
aging; growth hormone receptor/binding protein; knockout mouse; neoplastic disease
7.  The age of heterozygosity 
Age  2006;28(2):201-208.
Two mutant mouse models of longevity in which the loss of only one copy of the gene leads to a significantly increased lifespan have recently been described: Igf1r+/- and mclk1+/-. Igf1r encodes a transmembrane receptor kinase for the insulin-like growth factor-1, and mclk1 encodes a hydroxylase that is necessary for the biosynthesis of ubiquinone. Interestingly, the motivation for testing the longevity of both of these mutants came from observations in the nematode Caenorhabditis elegans. IGF-1R protein is homologous to DAF-2 and mCLK1 is the mouse orthologue of the C. elegans enzyme CLK-1. In worms, the homozygous inactivation of both of these longevity genes is viable and no dominant mutations are known. In addition to aging slowly, old mclk1+/- mice were found to undergo loss-of-heterozygosity at the mclk1 locus, which results in clones of mclk1-/- cells in the liver, presumably because mclk1-/- cells can outcompete mclk1+/- cells under certain conditions. We will discuss how these observations suggest novel directions of research, but also call for some caution in the interpretation of past and future results.
doi:10.1007/s11357-006-9006-8
PMCID: PMC2464728  PMID: 19943141
aging; evolutionary conservation; loss-of-heterozygosity; mclk1; mouse models of longevity; ubiquinone
8.  Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice 
Age  2006;28(2):191-200.
Since generation of the growth hormone receptor/binding protein (GHR/BP) gene-disrupted mouse nearly 10 years ago, use of this mouse model has become widespread in the elucidation of the physiological roles of GH and insulin-like growth factor-1 (IGF-1). In particular, it serves as a useful model to study mechanisms of aging. This review highlights the evidence demonstrating that the loss of GH signaling leads to lifespan extension in mice, and presents the multiple characteristics of this mouse line that suggest the life extension is due to alteration of the aging process.
doi:10.1007/s11357-006-9004-x
PMCID: PMC2464722  PMID: 19943140
aging; gene disruption; growth hormone receptor/binding protein; longevity; mice

Results 1-8 (8)