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1.  Effects of calorie restriction on chromosomal stability in rhesus monkeys (Macaca mulatta) 
Age  2006;29(1):15-28.
The basic tenet of several theories on aging is increasing genomic instability resulting from interactions with the environment. Chromosomal aberrations have been used as classic examples of increasing genomic instability since they demonstrate an increase in numerical and structural abnormalities with age in many species including humans. This accumulating damage may augment many aging processes and initiate age-related diseases, such as neoplasias. Calorie restriction (CR) is one of the most robust interventions for reducing the frequency of age-related diseases and for extending life span in many short-lived organisms. However, the mechanisms for the anti-aging effects of CR are not yet well understood. A study of rhesus monkeys was begun in 1987 to determine if CR is also effective in reducing the frequency of age-related diseases and retarding aging in a long-lived mammal. Male monkeys were begun on the diet in 1987, and females were added in 1992 to examine a possible difference in response to CR by sex. The CR monkeys have been maintained for over 10 years on a low-fat nutritional diet that provides a 30% calorie reduction compared to a control (CON) group. Because of the greater similarity of nonhuman primates to humans in life span and environmental responses to diet compared with those of rodents, the rhesus monkey provides an excellent model for the effects of CR in humans. This study examined the effects of CR on chromosomal instability with aging. Significant age effects were found in both CR and CON groups for the number of cells with aneuploidy: old animals had a higher loss and a higher gain than young animals. However, there was no effect of age on chromosomal breakage or structural aberrations in either diet group. Diet had only one significant effect: the CR group had a higher frequency of chromatid gaps than did the CON group. CR, implemented in adult rhesus monkeys, does not have a major effect on the reduction of numerical or structural aberrations related to aging.
PMCID: PMC2267682  PMID: 19424827
aging; calorie restriction; chromosomal stability; diet; rhesus monkeys
2.  Lifespan modification by glucose and methionine in Drosophila melanogaster fed a chemically defined diet 
Age  2006;29(1):29-39.
Experimentally restricting dietary calories, while maintaining adequate dietary nutrient content, extends lifespan in phylogenetically diverse species; thus suggesting the existence of conserved pathways which can modify lifespan in response to energy intake. However, in some cases the impact on longevity may depend on the quality of the energy source. In Drosophila, restriction of dietary yeast yields considerable lifespan extension whereas isocaloric restriction of dietary sugar yields only modest extension, indicating that other diet-responsive pathways can modify lifespan in this species. In rodents, restricting intake of a single amino acid – methionine – extends lifespan. Here we show that dietary methionine can modify lifespan in adult female, non-virgin Oregon-R strain Drosophila fed a chemically defined media. Compared to a diet containing 0.135% methionine and 15% glucose, high dietary methionine (0.405%) shortened maximum lifespan by 2.33% from 86 to 84 days and mean lifespan by 9.55% from 71.7 to 64.9 days. Further restriction of methionine to 0.045% did not extend maximum lifespan and shortened mean lifespan by 1.95% from 71.1 to 70.3 days. Restricting glucose from 15% to 5% while holding methionine at a concentration of 0.135%, modestly extended maximum lifespan by 5.8% from 86 to 91 days, without extending mean lifespan. All these diet-induced changes were highly significant (log-rank p < 0.0001). Notably, all four diets resulted in considerably longer life spans than those typically reported for flies fed conventional yeast and sugar based diets. Such defined diets can be used to identify lifespan-modifying pathways and specific gene-nutrient interactions in Drosophila.
PMCID: PMC2267680  PMID: 19424828
aging; amino acid; caloric restriction; demography; dietary restriction; Drosophila; longevity; methionine; mortality; nutrition
3.  Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study 
Age  2006;28(4):363-374.
Age trajectories of physiological indices contain important information about aging-related changes in the human organism and therefore may help us understand human longevity. The goal of this study is to investigate whether shapes of such trajectories earlier in life affect the residual life span distribution. We used longitudinal limited access data from seven physiological indices and life spans of respective individuals collected in the Framingham Heart Study (FHS). These include: diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), serum cholesterol (SCH), blood glucose (BG), hematocrit (HC), and pulse rate (PR). We developed a method for assigning individuals to groups of potentially long-lived (PLL) and potentially medium-lived (PML) groups using age trajectories of physiological indices at the age interval between 40 and 60 years. The analysis shows that the longevity of individuals who survived to age of 65 depends on the behavior of the physiological indices between 40 and 60 years of age.
PMCID: PMC1994150  PMID: 17895962
Age trajectories; Aging; Exceptional longevity; Longitudinal data; Physiological indices; The Framingham Heart Study
4.  Do personality characteristics predict longevity? Findings from the Tokyo Centenarian Study 
Age  2006;28(4):353-361.
To explore whether personality influences longevity we examined the personality characteristics of centenarians. We developed a new method that compares an actual personality test score for centenarians with a predicted test score for a 100-year-old, calculated from younger controls. The participants consisted of 70 cognitively intact Japanese centenarians aged 100–106 years and 1812 elderly people aged 60–84 years, all residents of Tokyo. The NEO five factor inventory (NEO-FFI) was used to assess the “big five” personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. The results showed higher openness in both male and female centenarians, and higher conscientiousness and extraversion in female centenarians, as compared to controls. These results suggest that high scores in the specific personality traits conscientiousness, extraversion, and openness, are associated with longevity. We speculate that these personality traits contribute to longevity through health-related behavior, stress reduction, and adaptation to the challenging problems of the “oldest old”.
PMCID: PMC3259156  PMID: 22253501
centenarian; longevity factors; NEO-FFI; personality traits
5.  Age editorial 
Age  2006;28(4):309-311.
PMCID: PMC3259158  PMID: 22253497
6.  Personality and longevity: findings from the Georgia Centenarian Study 
Age  2006;28(4):343-352.
Centenarians are thought of as unique and exceptional survivors. This study evaluated specific personality traits and configurations of traits among participants of the Georgia Centenarian Study. Two hundred and eighty five centenarians and their nominated proxies participated in this study. Self ratings and proxy informant ratings were obtained for different traits and facets of the Big-5 personality typology. Results suggested that centenarians overall had low levels of Neuroticism, but high levels of Extraversion, Competence, and Trust. When compared to centenarian self ratings, proxies provided significantly higher ratings for Neuroticism, Hostility, and Vulnerability, but lower ratings for Competence and Trust. Among Centenarians, the personality configuration of low Neuroticism, high Competence, and high Extraversion traits is over-represented relative to chance. The results confirm that centenarians show several unique single traits, but that a special combination of traits (i.e., low levels of Neuroticism, high Competence, and high Extraversion) are also notable in this group of exceptional survivors.
PMCID: PMC3259159  PMID: 22253500
centenarians; longevity; proxy rating; self rating; traits
7.  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.
PMCID: PMC3259160  PMID: 22253498
longevity; genetics; centenarians; Okinawa; longevity genes
8.  Dietary differences between centenarians residing in communities and in skilled nursing facilities: the Georgia Centenarian Study 
Age  2006;28(4):333-341.
The purpose of this study was to examine the dietary habits among centenarians residing in community settings (n=105) and in skilled nursing facilities (n=139). The sample was a population-based multi-ethnic sample of adults aged 98 years and older (N=244) from northern Georgia in the US. Compared to centenarians in skilled nursing facilities, those residing in the community were more than twice as likely to be able to eat without help and to receive most of their nourishment from typical foods, but they had a lower frequency of intake of all of the food groups examined, including dairy, meat, poultry and fish, eggs, green vegetables, orange/yellow vegetables, citrus fruit or juice, non-citrus fruit or juice, and oral liquid supplements. A food summary score was created (the sum of the meeting recommendations for five food groups). In multiple regression analyses, the food summary scores were positively associated with residing in a nursing facility and negatively associated with eating without help and receiving most nourishment from typical foods. These data suggest that centenarians residing in communities may have limited access to foods that are known to provide nutrients essential to health and well-being. Also, centenarians who are able to eat without help and/or who eat mainly typical foods may have inadequate intakes of recommended food groups. Given the essential role of foods and nutrition to health and well-being throughout life, these findings require further exploration through the detailed dietary analyses of centenarians living in various settings.
PMCID: PMC3259161  PMID: 22253499
Dietary habits; centenarian; community-dwelling; nursing home
9.  Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study 
Age (Dordrecht, Netherlands)  2006;28(4):363-374.
Age trajectories of physiological indices contain important information about aging-related changes in the human organism and therefore may help us understand human longevity. The goal of this study is to investigate whether shapes of such trajectories earlier in life affect the residual life span distribution. We used longitudinal limited access data from seven physiological indices and life spans of respective individuals collected in the Framingham Heart Study (FHS). These include: diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), serum cholesterol (SCH), blood glucose (BG), hematocrit (HC), and pulse rate (PR). We developed a method for assigning individuals to groups of potentially long-lived (PLL) and potentially medium-lived (PML) groups using age trajectories of physiological indices at the age interval between 40 and 60 years. The analysis shows that the longevity of individuals who survived to age of 65 depends on the behavior of the physiological indices between 40 and 60 years of age.
PMCID: PMC1994150  PMID: 17895962
age trajectories; aging; exceptional longevity; longitudinal data; physiological indices; the Framingham Heart Study; BG blood glucose; BMI body mass index; CVD cardiovascular disease; DBP diastolic blood pressure; FHS the Framingham Heart Study; HC hematocrit; LL long-lived; ML medium-lived; PLL potentially long-lived; PML potentially medium-lived; PP pulse pressure; PR pulse rate; SCH serum cholesterol; SL short-lived
10.  Age-related disruptions of circadian rhythm and memory in the senescence-accelerated mouse (SAMP8) 
Age  2006;28(3):283-296.
Common complaints of the elderly involve impaired cognitive abilities, such as loss of memory and inability to attend. Although much research has been devoted to these cognitive impairments, other factors such as disrupted sleep patterns and increased daytime drowsiness may contribute indirectly to impaired cognitive abilities. Disrupted sleep–wake cycles may be the result of age-related changes to the internal (circadian) clock. In this article, we review recent research on aging and circadian rhythms with a focus on the senescence-accelerated mouse (SAM) as a model of aging. We explore some of the neurobiological mechanisms that appear to be responsible for our aging clock, and consider implications of this work for age-related changes in cognition.
PMCID: PMC3259149  PMID: 22253495
aging; C-Fos; circadian rhythms; mouse; running wheel; SAMP8; suprachiasmatic nucleus
11.  Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia 
Age  2006;28(3):297-307.
Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer’s disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.
PMCID: PMC3259150  PMID: 22253496
Alzheimer’s disease; hippocampus; ischemia; middle cerebral artery; stroke; vascular dementia
12.  Individual differences in neurocognitive aging of the medial temporal lobe 
Age  2006;28(3):221-233.
A wide spectrum of outcomes in the cognitive effects of aging is routinely observed in studies of the elderly. Individual differences in neurocognitive aging are also a characteristic of other species, such as rodents and non-human primates. In particular, investigations at behavioral, brain systems, cellular and molecular levels of analysis have provided much information on the basis for individual differences in neurocognitive aging among healthy outbred rats. These findings are likely to be relevant to an understanding of the effects of aging on the brain, apart from neurodegenerative conditions, such as Alzheimer’s disease, which do not naturally occur in rodents. Here we review and integrate those findings in a model supporting the concept that certain features of cognitive decline are caused by distributed alterations in the medial temporal lobe, which alter the information processing functions of the hippocampal formation. An additional emerging concept from this research is that preserved abilities at older ages may depend on adaptive changes in the hippocampal system that distinguish successful aging.
PMCID: PMC3259151  PMID: 22253491
spatial memory; hippocampal formation; successful aging; rats; cognitive impairment
13.  Rodent models of brain aging and neurodegeneration 
Age  2006;28(3):219-220.
PMCID: PMC3259152
14.  Relationships among cognitive function, fine motor speed and age in the rhesus monkey 
Age  2006;28(3):255-264.
Declines in fine motor skills and cognitive function are well known features of human aging. Yet, the relationship between age-related impairments in motor and cognitive function remains unclear. Rhesus monkeys, like humans, show marked decline in cognitive and fine motor function with age and are excellent models to investigate potential interactions between age-related declines in cognitive and motor functioning. We investigated the relationships among cognition, motor function and age in 30 male and female rhesus monkeys, 5–28 years of age, tested on a battery of cognitive tasks [acquisition of the delayed non-matching-to-sample (DNMS), DNMS-120s, DNMS-600s, acquisition of delayed recognition span test (DRST), spatial-DRST and object-DRST] and a fine motor task (Lifesaver test). Global cognitive ability, as assessed by the cognitive performance index (CPI), was impaired with age in both sexes, while age-related motor slowing was found only in males. After age was controlled for, half the variance in CPI was predicted by motor speed, with better cognitive ability associated with slower motor skills. Analyses at the level of each cognitive task revealed that motor speed and age predicted the rate of acquisition of the DNMS. This relationship was robust in males and absent in females. Motor speed was not a significant predictor of any other cognitive variable. We conclude that the relationship between cognition and motor function (1) may be limited to non-spatial tasks; (2) exists independently of age; (3) may reflect different contributions of the fronto-striatal system; (4) may be particularly evident in males.
PMCID: PMC3259153  PMID: 22253493
aging; learning; macaque; motor skills; memory; sex differences
15.  Profiling psychomotor and cognitive aging in four-way cross mice 
Age  2006;28(3):265-282.
In part due to their genetic uniformity and stable characteristics, inbred rodents or their F1 progeny are frequently used to study brain aging. However, it is recognized that focus on a single genotype could lead to generalizations about brain aging that might not apply to the species as a whole, or to the human population. As a potential alternative to uniform genotypes, genetically heterogeneous (HET) mice, produced by a four-way cross, were tested in the current study to determine if they exhibit age-related declines in cognitive and psychomotor function similar to other rodent models of brain aging. Young (4 months) and older (23 months) CB6F1 × C3D2F1 mice were administered a variety of tests for cognitive, psychomotor, and sensory/reflexive capacities. Spontaneous locomotion, rearing, and ability to turn in an alley all decreased with age, as did behavioral measures sensitive to muscle strength, balance, and motor coordination. Although no effect of age was found for either startle response amplitude or reaction time to shock stimuli, the old mice reacted with less force to low intensity auditory stimuli. When tested on a spatial swim maze task, the old mice learned less efficiently, exhibited poorer retention after a 66-h delay, and demonstrated greater difficulty learning a new spatial location. In addition, the older mice were less able to learn the platform location when it was identified by a local visual cue. Because there was a significant correlation between spatial and cued discrimination performance in the old mice, it is possible that age-related spatial maze learning deficits could involve visual or motor impairments. Variation among individuals increased with age for most tests of psychomotor function, as well as for spatial swim performance, suggesting that four-way cross mice may be appropriate models of individualized brain aging. However, the analysis of spatial maze learning deficits in older CB6F1 × C3D2F1 mice may have limited applicability in the study of brain aging, because of a confounding with visually cued performance deficits.
PMCID: PMC3259154  PMID: 22253494
BALB/c; BCCD HET mice; brain aging; C3H; C57BL/6; CB6F1 × C3D2F1; DBA/2; psychomotor function; spatial memory; visual function
16.  Spatial learning and psychomotor performance of C57BL/6 mice: age sensitivity and reliability of individual differences 
Age  2006;28(3):235-253.
Two tests often used in aging research, the elevated path test and the Morris water maze test, were examined for their application to the study of brain aging in a large sample of C57BL/6JNia mice. Specifically, these studies assessed: (1) sensitivity to age and the degree of interrelatedness among different behavioral measures derived from these tests, (2) the effect of age on variation in the measurements, and (3) the reliability of individual differences in performance on the tests. Both tests detected age-related deficits in group performance that occurred independently of each other. However, analysis of data obtained on the Morris water maze test revealed three relatively independent components of cognitive performance. Performance in initial acquisition of spatial learning in the Morris maze was not highly correlated with performance during reversal learning (when mice were required to learn a new spatial location), whereas performance in both of those phases was independent of spatial performance assessed during a single probe trial administered at the end of acquisition training. Moreover, impaired performance during initial acquisition could be detected at an earlier age than impairments in reversal learning. There were modest but significant age-related increases in the variance of both elevated path test scores and in several measures of learning in the Morris maze test. Analysis of test scores of mice across repeated testing sessions confirmed reliability of the measurements obtained for cognitive and psychomotor function. Power calculations confirmed that there are sufficiently large age-related differences in elevated path test performance, relative to within age variability, to render this test useful for studies into the ability of an intervention to prevent or reverse age-related deficits in psychomotor performance. Power calculations indicated a need for larger sample sizes for detection of intervention effects on cognitive components of the Morris water maze test, at least when implemented at the ages tested in this study. Variability among old mice in both tests, including each of the various independent measures in the Morris maze, may be useful for elucidating the biological bases of different aspects of dysfunctional brain aging.
PMCID: PMC3259155  PMID: 22253492
brain aging; bridge walking; elevated path test; balance beam; inbred mice; individual differences; Morris maze; psychomotor function; spatial learning
17.  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?
PMCID: PMC2464730  PMID: 19943137
aging; growth hormone receptor/binding protein; knockout mouse; neoplastic disease
18.  The aging brain: is function dependent on growth hormone/insulin-like growth factor-1 signaling? 
Age  2006;28(2):173-180.
The role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in normal brain function is not well understood. Studies looking at cognition in humans with GH deficiency have produced controversial results. Experiments in which GH is administered to rodents have shown an apparent improvement in learning and memory. However, studies in which GH deficient or resistant mice were tested in learning and memory tasks reveal that these animals have normal cognitive performance and that their neural function does not deteriorate with age at the same rate as their normal siblings. Further research into this phenomenon revealed that these animals have elevated GH and IGF-1 expression in the hippocampus compared to normal animals. Additional studies with GH deficient and resistant mice suggested that these mutants experience a delay in age-related decline in locomotor activity and exploratory behavior. Data indicate that GH/IGF-1 deficiency and resistance do not impair neural function and instead may offer some degree of protection that results in delayed cognitive and motor aging.
PMCID: PMC2464729  PMID: 19943138
aging; cognition; delayed aging; dwarfism; growth hormone; learning and memory
19.  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.
PMCID: PMC2464728  PMID: 19943141
aging; evolutionary conservation; loss-of-heterozygosity; mclk1; mouse models of longevity; ubiquinone
20.  Introduction 
Age  2006;28(2):123-124.
PMCID: PMC2464725  PMID: 19943134
21.  Extension of mouse lifespan by overexpression of catalase 
Age  2006;28(2):209-218.
The free radical theory of aging was originally proposed 50 years ago, and is arguably the most popular mechanism explaining the aging process. According to this theory, aging results from the progressive decline in organ function due to the damage generated by reactive oxygen species (ROS). These chemical species are a normal part of metabolism, and a group of enzymes exists to protect cells against their toxic effects. One of these species is hydrogen peroxide (H2O2), which can be degraded by catalase. To determine the role of hydrogen peroxide in aging and its importance in different subcellular compartments, transgenic mice were developed with increased catalase activities localized to the peroxisome (PCAT), nucleus (NCAT), or mitochondrion (MCAT). The largest effect on lifespan was found in MCAT animals, with a 20% increase in median lifespan and a 10% increase in the maximum lifespan. A more modest effect was seen in PCAT animals, and no significant change was found in NCAT animals. Upon further examination of the MCAT mice, it was found that H2O2 production and H2O2-induced aconitase inactivation were attenuated, oxidative damage and the development of mitochondrial deletions were reduced, and cardiac pathology and cataract development were delayed. These results are consistent with a role of H2O2 in the development of pathology and in the limitation of mouse lifespan. They also demonstrate the importance of mitochondria as a source, and possible target, of ROS.
PMCID: PMC2464724  PMID: 19943142
aconitase; aging; catalase; hydrogen peroxide; lifespan; mitochondria; mitochondrial DNA; reactive oxygen species; superoxide dismutase
22.  Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice 
Age  2006;28(2):125-144.
Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin/IGF-1 signal transduction pathway that regulates lifespan. In C. elegans, Drosophila, and rodents, attenuated insulin/IGF-1 signaling appears to regulate lifespan and enhance resistance to environmental stress. The Ames (Prop1df/df) and Snell (Pit1dw/dw) hypopituitary dwarf mice with growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin deficiencies live 40–60% longer than control mice. Both mutants are resistant to multiple forms of environmental stress in vitro. Taken collectively, these genetic models indicate that diminished insulin/IGF-l signaling may play a central role in the determination of mammalian lifespan by conferring resistance to exogenous and endogenous stressors. These pleiotropic endocrine pathways control diverse programs of gene expression that appear to orchestrate the development of a biological phenotype that promotes longevity. With the ability to investigate thousands of genes simultaneously, several microarray surveys have identified potential longevity assurance genes and provided information on the mechanism(s) by which the dwarf genotypes (dw/dw) and (df/df), and caloric restriction may lead to longevity. We propose that a comparison of specific changes in gene expression shared between Snell and Ames dwarf mice may provide a deeper understanding of the transcriptional mechanisms of longevity determination. Furthermore, we propose that a comparison of the physiological consequences of the Pit1dw and Prop1df mutations may reveal transcriptional profiles similar to those reported for the C. elegans and Drosophila mutants. In this study we have identified classes of genes whose expression is similarly affected in both Snell and Ames dwarf mice. Our comparative microarray data suggest that specific detoxification enzymes of the P450 (CYP) family as well as oxidative and steroid metabolism may play a key role in longevity assurance of the Snell and Ames dwarf mouse mutants. We propose that the altered expression of these genes defines a biochemical phenotype which may promote longevity in Snell and Ames dwarf mice.
PMCID: PMC2464723  PMID: 19943135
Aging; Ames Dwarf; Detoxification; Metabolism; P450; PPAR; ROS; Snell Dwarf; Steriod
23.  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.
PMCID: PMC2464722  PMID: 19943140
aging; gene disruption; growth hormone receptor/binding protein; longevity; mice
24.  Three layer functional model and energy exchange concept of aging process 
Age  2006;28(1):111-121.
Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.
PMCID: PMC2464718  PMID: 23598683
Aging; Bioenergetics; Body; Cell; Death; Degradation; Diseases; Dissipative; Environment; Formation; Fractal; Hierarchy; Hypothesis; Inanimate; Integument; Layer; Life; Living; Longevity; Model; Nourishment; Organism; Oxygen; Radicals; Regeneration; Rejuvenation; System; Skin; Stem; Thermodynamics; Theory; Tissue
25.  You don't need a weatherman: famines, evolution, and intervention into aging 
Age  2006;28(1):93-109.
Calorie restriction (CR) is the most robust available intervention into biological aging. Efforts are underway to develop pharmaceuticals that would replicate CR's anti-aging effects in humans (“CR mimetics”), on the assumption that the life- and healthspan-extending effects of CR in lower organisms will be proportionally extrapolable to humans (the “proportionality principle” (PP)). A recent argument from evolutionary theory (the “weather hypothesis” (WH)) suggests that CR (or its mimetics) will only provide 2–3 years of extended healthy lifespan in humans. The extension of healthy human lifespan that would be afforded by intervention into aging makes it crucial that resources for therapeutic development be optimally allocated; CR mimetics being the main direction being pursued for interventive biogerontology, this paper evaluates the challenge to the potential efficacy of CR mimetics posed by the WH, on a theoretical level and by reference to the available interspecies data on CR. Rodent data suggest that the anti-aging effects of CR continue to increase in inverse proportion to the degree of energy restriction imposed, well below the level that would be expected to be survivable under the conditions under which the mechanisms of CR evolved and are maintained in the wild. Moreover, the same increase in anti-aging effects continues well below the point at which it interferes with reproductive function. Both of these facts are in accordance with the predictions of evolutionary theory. Granted these facts, the interspecies data—including data available in humans—are consistent with the predictions of PP rather than those of the WH. This suggests that humans will respond to a high degree of CR (or its pharmaceutical simulation) with a proportional deceleration of aging, so that CR mimetics should be as effective in humans as CR itself is in the rodent model. Despite this fact, CR mimetics should not be the focus of biomedical gerontology, as strategies based on the direct targeting of the molecular lesions of aging are likely to lead to more rapidly developable and far more effective anti-aging biomedicines.
PMCID: PMC2464717  PMID: 23598682
aging/drug effects; calorie restriction; evolution; longevity/drug effects; models; biological

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