Longevity Health and Wellness Protocol

Staying Young

Staying Young

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Comparative Life Expectancy

Although data are collected by race and ethnicity, the National Center for Health Statistics does not publish life-expectancy tables for Latinos or Latino subgroup populations. Data, nonetheless, suggest that life expectancy for ethnic-minority groups (71.3 years) is less than for all races (75.0 years). The life-expectancy rate for African Americans (69.4 years) is substantially less (a difference of 6.2 years) than for whites (75.6 years) and, perhaps even more disturbing, has been steadily declining since at least 1984 (69.7 years in 1984, 69.5 years in 1985, 69.4 years in 1986, 69.2 years in 1990) (National Center for Health Statistics, 1997).

Longevity and Aging in Budding Yeast

This chapter presents an overview of the current understanding of how yeast ages and the genes and pathways that play a role in determining yeast chronological and replicative life span. Several genes, as well as calorie restriction, have been found to regulate aging similarly in yeast and multicellular eukaryotes, and these potentially conserved determinants of longevity are emphasized. Descriptions of the chronological and replicative life span assay are provided in enough detail to allow a researcher with common knowledge of yeast methods to carry out his or her own aging studies.

Study of Tradeoffs Between Physical Activities Reproduction and Longevity

The comparative gerontologist often uses a theory which is assumed to explain the different longevities of organisms. This theory known as ''disposable soma theory'' was introduced into the studies of aging by Kirkwood (1977). The central thought is that the life history of a species in general is characterized by limited resources (constraints) of variable nature. That means that trade-offs exist between key life history variables and such trade-offs favor the allocation of energy between reproduction and maintenance of body constituents. Kirkwood argued that this universal theory should also be adaptable to humans. Together with Westendorp he had the opportunity to study the birth and death rates of about 35,000 males and females of the British aristocracy living between 740 and 1875. The main result was a negative correlation between longevity of females and the number of progeny (Westendorp and Kirkwood, 1998). Recent studies do not agree with these data (Lycett et al., 2000)....

The familiality of exceptional longevity

Studying Mormon pedigrees from the Utah Population Database, Kerber and colleagues investigated the impact of family history upon the longevity of 78 994 individuals who achieved at least the age of 65 years (Kerber et al., 2001). The relative risk of survival (1s) calculated for siblings of probands achieving the 97th percentile of ''excess longevity'' (for males this corresponded with an age of 95 years, and for women with an age of 97 years) was 2.30. Recurrence risks among more distant relatives in the Mormon pedigrees remained significantly greater than 1.0 for numerous classes of relatives leading to the conclusion that single-gene effects were at play in this survival advantage. The Mormon study findings closely agree with a study of the Icelandic population in which first degree relatives of those living to the 95th percentile of surviving age were also almost twice as likely to live to the 95th percentile of survival compared with controls (Gudmundsson et al., 2000). Both...

Genes predisposing to exceptional longevity

Decreased susceptibility to age-associated diseases (Cutler, 1975). Our studies and those of others researching the oldest old have noted that persons who achieve extreme old age probably lack many of the variations (the ''disease genes'') that substantially increase risk for premature death by predisposing persons to various fatal diseases, both age-associated and non-age-associated (Schachter, 1998). More controversial is the idea that genetic variations might confer protection against the basic mechanisms of aging or age-related illnesses (the ''longevity-enabling genes'') (Perls et al., 2002a). The progressive selecting out of more and more genetically fit persons of very old age lays the foundation for a simpler model for sorting out the genetics of aging and longevity. The discovery of genetic variations that explain even 5 to 10 of the variation in survival to extreme old age could yield important clues about the cellular and biochemical mechanisms that affect basic mechanisms...

The Three Longevity Phenotypes of Drosophila

One fact that has emerged from the past several decades of aging research is that aging is not simple. The work that my colleagues and I have done on Drosophila longevity bears this out. We reported that aging in our Ra strain of wild-type flies is rather complex, being characterized by at least three different extended longevity phenotypes, each of which was induced by specific stimuli and had different demographic mortality and survival profiles (Arking et al., 2002). As shown in Figure 25.1A, the first longevity phenotype (Type 1) is a delayed onset of senescence that leads to a significant increase in both mean and maximum life span of the experimental strain.

Stress Resistance And Extended Longevity

It has long been observed that mild or nonlethal stress often has the apparently paradoxical effect of benefiting the organism by increasing its longevity (Minois, 2000). Conversely, it has also been suggested that all long-lived strains and mutants exhibit some form of stress resistance (Parsons, 1995 Johnson et al., 1996). This relationship is thought to reflect the fact that their natural environment usually exerts substantial, albeit variable, stresses on organisms. Evolutionary considerations of Darwinian fitness will thus impose a premium on genotypes conferring metabolic efficiency and stress resistance (Parsons, 1997, 2003). The magnitude of the effects of stress resistance on longevity are summarized in Table 25.3. We will examine four complementary lines of evidence bearing on the relationship of stress resistance and extended longevity in Drosophila. The first involves the use of strains selected for extended longevity, followed by an analysis of the mechanisms responsible...

Avian Longevity Is Consistent With Evolutionary Predictions

Why do birds live so long In the past, it was often argued that life spans and aging rates in warm-blooded vertebrates were constrained by the ''rate of living'' (Pearl, 1928 Rose, 1991). This argument was based on a robust, positive correlation between animals' body size and longevity, and an equally strong, inverse association between life spans and basal metabolic rates. This generalization is clearly refuted, however, when the long life spans of birds and bats are compared with those of nonflying relatives of similar size. These disproportionately long-lived animals are particularly interesting to comparative gerontologists, especially considering the higher metabolic rates and lifetime oxygen expenditures

Chaperones Aging and Longevity

To the phenotype of aging, as an involvement in the definition of longevity can be assumed from high levels of chaperone expression as a common denominator in conditions or procedures leading to an increase in cellular and species longevity as well as in the process of cellular immortalization. The inherent immortality of the embryonic stem cells implies that replicative senescence as possibly aging are epigenetic phenomena, possibly influenced by the progressive age-related epigenetic changes in promoter methylation that have the potential to permanently silence gene expression (Krall, 2005).

Aging And Longevity Of Cells

Aging and longevity of differentiated cells in vitro That replicative senescence the model of aging in vitro probably is related to a chaperone deficit can be assumed from the increase in life span obtained by transfection with protein-chaperones, as well as from the attainment of cellular immortalization by heat shock procedures or transfection with RNA-chaperones (Krall, 2004). Aging and longevity of differentiated cells in vivo The great variability in the life span of differentiated cells in the organism shows a direct correlation to the The inducibility of Hsp70 by heat shock is reduced to approximately 50 in old rat hepatocytes, suggesting that a reduced ability to express hsp70 in response to stress may be a common phenomenon underlying the aging process. This age-related decline in the Hsp70 stress response was reversed by caloric restriction (Heydari et al., 1996). There is a functional link between age-related decrements in Hsp70 expression and patho-physiological responses...

Krzisnik Krk Longevity

Bartke, A., and Brown-Borg, H. (2004). Life extension in the dwarf mouse. Curr Top Developmental Biology 63, 189-225. Bartke, A., Peluso, M.R., Moretz, N., Wright, C., Bonkowski, M., Winters, T.A., et al. (2004). Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice. Horm. Metab. Res. 36, 550-558. Berryman, D.E., List, E.O., Coschigano, K.T., Behar, K., Kim, J.K., and Kopchick, J.J. (2004). Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Hormone & IGF Research 14, 309-318. Besson, A., Salemi, S., Gallati, S., Jenal, A., Horn, R., Mullis, P.S., and Mullis, P.E. (2003). Reduced longevity in untreated patients with isolated growth hormone deficiency. J. Clin. Endocrinol. Metab. 88, 3664-3667. Borg, K.E., Brown-Borg, H.M., and Bartke, A. (1995). Assessment of the primary adrenal cortical and pancreatic hormone basal levels in relation to plasma glucose and age in the...

Human Models of Longevity

Centenarians, though rare at a prevalence of approximately one per 10,000 in industrialized countries, are among the fastest growing segment of our population. Familial studies indicate that exceptional longevity runs strongly in families, but as of yet, few genetic variations have been found to account for this survival advantage. It is likely that the prevalence of centenarians is increasing because achieving exceptional old age is multifactorial. A number of factors important to such longevity are becoming more prevalent with modern public health measures and interventions. Such a multiple trait model would predict that the more extreme the phenotype, the more likely discernible environmental and genetic characteristics are to be discovered that are important to achieving very old age, much of it disability-free. Thus studies of families highly clustered for longevity or studies of supercentenarains, people age 110 and older, hold promise of facilitating such discoveries.

Multifactorial Model for Exceptional Longevity

The fact that siblings maintain half the mortality risk of their birth cohort from age 20 to extreme age suggests a multifactorial model for achieving exceptional longevity. For example, socio-demographic advantages may play key roles at younger ages, whereas genetic advantages may distinguish the ability to go from old age to extreme old age. Undoubtedly exceptional longevity is much more complicated, with temporally overlapping roles for major genes, polygenic, environmental, and stochastic components. Such a scenario would be consistent with a threshold model, where predisposition for exceptional longevity can be measured on a quantitative scale. Figure 47.2 illustrates the standard threshold model proposed by Falconer (Falconer, 1965), where it is predicted that the proportion of affected relatives will be highest among the most severely affected individuals. In the case of exceptional longevity, perhaps severity may be measured by additional years beyond a certain age (threshold)...

Experimental Models Linking Diabetes Mellitus to Aging and Longevity

In some species, caloric restriction (CR) is associated with reduction of aging and increased longevity. It was observed that a reduced body size was correlated to an increased life span in mice, dogs, Caenorhabditis elegans, or Drosophila melanogaster. One very recent study could not find a clear general effect of body size on life span (Hafen, 2004 McCulloch et al., 2003). The question has been asked why smaller individuals would live longer. One explanation that has been put forward, mainly in invertebrates, is the homologous insulin IGF signaling (IIS). In C. elegans it was suggested that the IIS can act to limit the body size. However, in some wild-type strains this correlation was much less clear. Moreover, several mutations in C. elegans led to extended longevity phenotype. Among these are the genes involved in the insulin IGF-signaling pathway, such as daf-2 and age-1, or clk mutants related to respiratory metabolism. Similar results were obtained in Drosophila. The study in...

Highthroughput Longevity Phenotyping

Alternatives to standard life-span assays that accelerate the normal aging process can be useful tools for rapidly screening genes and compounds for effects on longevity. These methods suffer, however, from the fact that they are not true aging assays and putative aging effects must be verified in each case. A more satisfying, but also more difficult approach, is the development of automated, high-throughput methods for standard life-span measurements. The system most amenable to high-throughput longevity phenotyping is the chronological life-span assay in budding yeast. Chronological life span'' refers to the length of time a yeast cell is capable of maintaining viability in a nondividing, quiescent state (see Chapter 18 Longevity and Aging in the Budding Yeast). Traditionally, chronological life span has been measured by culturing cells in 5-50 mL volumes and periodically plating onto rich media and counting colonies (Fabrizio and Longo, 2003). A semiautomated method for...

Vitalism Materialism and Spontaneous Generation

A driving philosophical debate also underlay cell genesis and the origins of germs the ongoing contest between materialism and vitalism. That microbes did not arise spontaneously from bad air or from putrefied matter was an issue of profound importance for medical practice and epidemiology. Attempts to prove or disprove it led to innovative experimental designs and important sterilization techniques in the nineteenth century that became the basis of modern microbiology and the germ theory of disease. The same issues about materialism and vitalism underlay the debates over cell generation in Germany. Schleiden and Schwann had placed their theory about cell formation from disorganized organic materials in direct opposition to the vitalism, idealism, and teleology of Naturphilosophie.33 The apparent gap between inorganic and organic form is not unbridgeable, declared Schwann an organized body is not produced by a fundamental power which is guided in its operation by a definite idea, but...

Aging And Longevity Of Species

Reference conditions An involvement of the molecular chaperones in the definition of species longevity can be assumed from the observed influences of genotypes, levels of Hsp expression, and mutational defects. Thus, a modifier of life span linked to chromosome 4 has been identified as a haplotype marker within the microsomal transfer protein complex comprising the chaperone protein disulfide isomerase (PDI). An influence of genotype can be supposed also from the observation that for Hsp70 the TT polymorphic variant was observed to be significantly increased within a healthy aged Irish population, while conversely the TC genotype was significantly decreased. Also correlations have been observed between a polymorphism in the Hsp70-A1 gene promoter and low self-rated health in aged Danish twins (Singh et al., 2004) as well as impaired longevity in women (Altomare et al., 2003). A relationship between the level of chaperone expression and the longevity of species can be assumed from the...

Ginseng And The Ageing Process

Neuronal energy requirements remain high throughout life, the most efficient source of brain energy being aerobic glycolysis during which adenosine triphosphate (ATP) is continuously synthesised. The ageing process alters cerebral metabolism with lowered glucose and oxygen consumption producing reduced ATP synthesis in persons demonstrating senile cerebral insufficiency (Sebban, 1982). Studying the effect of ginseng extract G115 on rabbit brain both in vitro and in vivo, Samira et al. (1985) concluded that there was a significant increase of glucose uptake with a corresponding decrease of lactate, pyruvate and lactate pyruvate ratio, indicating aerobic rather than the less economical anaerobic pathway. Thus G115 can be considered as a metabolic stimulant for brain tissue at doses equivalent to the recommended single human therapeutic dose, suggesting that altered neuronal metabolism rather than impaired cerebral blood flow is the problem in old age. Li et al. (1997), using...

Life Expectancy In Parkinsonism

All of the parkinsonism variants limit mobility, and the increased tendency for falls and dysphagia predisposes these patients to life-threatening complications (33,34). Life expectancy prior to the widespread use of levodopa was significantly reduced. In one hospital based parkinsonism series during the 1950s and 1960s, the mean survival after onset was 10.8 years (35). Excluding postencephalitic parkinsonism, the mean survival was 9.42 years, which is frequently cited as the yardstick for the prelevodopa era life expectancy (35). Mean survival in the contemporary parkinsonism cases cannot be compared with that study. There have been significant social and health care advances leading to longer life in the general population, and one would expect that parkinsonism patients would share these survival gains. Comparisons for survival should be made matching for year of birth, gender, and region country. Kurtzke et al. (36) noted that patients in the 1980s were, on an average, five years...

Life Expectancy

Arguably the ultimate phenotype of premature aging is reduced life expectancy. It is estimated that the onset of diabetes in human subjects reduces the life expectancy by an average of 10 years. The effect of diabetes on life expectancy depends on the age of onset. In general, the older the patient is at the time of diagnosis of diabetes, the lesser its effect is on life expectancy. Nevertheless it appears that diabetes continues to be a major detriment even when the disease onset is in the seventh decade (Songer, 1995). of glycemic control as measured by glycated hemoglobin (HbAlc) levels (Stratton et al., 2000 Mooradian and Chehade, 2000). It is noteworthy that HbAlc appears to be a predictor of mortality even in nondiabetic populations (Khaw, 2001). These latter observations highlight the importance of glycemia and glycation as a predicator of life expectancy. It is also possible that postprandial blood glucose excursions that contribute to the HbAlc measurements to a greater...

Historical Development of Animal Models of Aging

The modern history of the use of animal (at least rodent) models for research on aging begins with the research of Clive McKay, a noted nutritionist in the 1930s. In the course of research on cancer, McKay and his colleagues (McKay et al., 1935) discovered that severe calorie restriction (to 60 of ad libitum levels) resulted in significant increases in the lifespan of rats. Interestingly, since McKay was primarily interested in cancer, the increased longevity effects were not followed up until the work of Morris Ross in the 1960s using Sprague-Dawley rats (Ross, 1961). Ross, too, was primarily interested in the impact of CR on tumor incidence and age of occurrence in his rat models. Ross's very careful studies through the 1960s and early 1970s brought caloric restriction's effects on longevity to the attention of geron-tologists just at the time that gerontological research was receiving an influx of interest and funding in anticipation of the creation of the NIA. the aging...

The Influence Of Body Size

A number of factors correlate with tmax, and while this work is about species selection, not the methodology of comparative biology, there is one factor that must be mentioned body size (Promislow, 1993). Clearly, bigger species, including mammals, live longer, on average, than shorter-lived species (Austad, 2005). Exceptions exist and, for example, gorillas (Gorilla gorilla) are typically bigger than humans and still do not live longer than us. Likewise, bats live longer than predicted from their body size. Nonetheless, when comparing parameters across species it is crucial to take body size into consideration. Otherwise we could make the mistake of correlating some physiological factor with body size, not with longevity or aging. For example, early studies indicated that DNA repair capacity was higher in longer-lived mammals, arguing that DNA repair was a factor in aging (Hart and Setlow, 1974). Yet it has been argued that the correlation between DNA repair and longevity is due to...

In Vivo Immune Effects Of Senescent T Cells

A final aspect of senescent T cells that could have broad physiological consequences relates to the role of stress in the aging process. T cells that undergo replicative senescence in culture show transcriptional down-regulation of the hsp70 gene in response to heat shock (Effros et al., 1994b), and T cells from elderly persons show attenuation in the molecular chaperone system hsp70, in the steroid binding hsp90, and the chaperonin hsp60. These immune cell changes may contribute to the well-documented reduction in ability to respond to stress that characterizes organismic aging.

Physical characteristics

Sylviids are typically dull in color often in shades of brown, green, yellow, and gray. The family includes some of the tiniest songbirds in the world, the kinglets, as well as some small wren-like birds, many small warblers, and the medium-sized marsh warblers and grassbirds. The smallest sylviids, the kinglets, weigh only a few grams. The largest, the marsh warblers Acrocephalus and the grassbirds Megalurus can weigh close to 2 oz (60 g). A comprehensive summary of longevity data is unavailable, but many species live at least 8-12 years.

Incidence Of Parkinsonism

Incidence increases with increasing age. The incidence of parkinsonism was 0.8 105 in those aged 0 to 29 years, 25.6 105 in those 50 to 59 years and, more than 11 times higher (304.8 105) in the 80- to 99-year age group (18). There has been no significant change in the age-specific incidence rates during the 55-year interval of these studies (29). Slightly higher overall incidence of parkinsonism in recent reports likely reflects longer life expectancy in the general population, more frequent use of neuroleptics and improved diagnosis (18,29).

Prevalence Of Parkinsonism

Prevalence rate are the incidence of new cases and life expectancy. Crude prevalence rates are greatly affected by the age distribution of the source population age-adjusted rates are one way to permit comparisons between different populations but crude rates are most often reported. In two Canadian studies using representative samples of residents aged 65 years and older, the prevalence rate in community residents was 3 (57) while in institutionalized persons the rate was 9 (58). Somewhat comparable figures were reported from Australia (51). Including only PD cases in persons aged 55 years and older, the prevalence rate of PD was 3600 105 in the community and 4900 105 in institutionalized persons. As discussed previously, incidence has remained relatively constant but life expectancy has increased one would then expect overall crude prevalence rates to have increased over time.

Neurologic Aspects of Alzheimers Disease

Quoted from Gulliver's Travels by Jonathan Swift, 1726, on learning that although the Struldbruggs (immortals) live forever, they were not a living treasury of knowledge and wisdom . . . and oracle of the nation but became progressively demented with age. As for much of human history, average life expectancy was 20 to 30 but by 1801 reached 35.9 years in England and Wales.

Autonomy and Protection of Older Adults in Research How Much Is Enough

The aging process presents some unique challenges to respect for autonomy among older adults, particularly in relation to obtaining informed consent and in the research environment those challenges are even more exquisitely complex. We will consider three possibilities that correspond roughly to the variations in decision-making capacities of older adults. The first two possibilities address recognizing and supporting the capacity of older adults to consent to research. The third addresses the possible and actual loss of that capacity.

Is Aging Research Anti Aging

Much of aging research involves understanding and addressing the diseases and conditions that occur in an aging population. That sort of aging research is not ethically controversial and clearly not anti-aging words like ''disease'' and ''disability'' already carry with them the implication that they should be controlled, avoided, or eradicated. Other research begins from the belief in an organism-wide process of aging, a unified process of senescence that is distinct from various specific processes of degeneration and must be dealt with as one would deal with disease. Discovering and controlling that process, just as one would research and address a disease, is ''age retardation'' (President's Council on Bioethics, 2003).

Reproductive biology

No more than a centimeter in length, the newborn young crawl into the backward-facing pouch, where they will remain suckling on a choice of eight teats for the next 80 days. Even after leaving the pouch, the young will stay in the burrow for a further fortnight. The mother continues to suckle them, while at the same time making nocturnal sorties into the open for food. Although the young then leave the burrow and begin feeding on solid food, they often continue to share their mother's burrows for a short while after gaining independence. The young females attain sexual maturity at five months. Male maturity is unknown. The longevity record for a captive greater bilby Macrotis lagotis is seven years and two months.

Issues In Diagnosis And Treatment

For unclear reasons, the risk of developing AD is higher in Black and Hispanic compared to White populations. Although the influence of the ApoE4 polymorphism on increased AD risk is apparent in Blacks, it appears to be less potent compared to Whites. Interestingly, although Black populations in Africa and the United States have similar ApoeE4 allele frequencies, the risk of AD is much higher in the age-matched U.S. Black population. This suggests that unknown environmental factors such as diet or resultant comorbidities may be important culprits. Until recently, vascular dementia was the leading cause of dementia in Japan, but this is shifting to AD, despite a low ApoE4 allele frequency, as life expectancy increases and stroke risk factors such as hypertension are better managed.

Great Crested Grebe Podiceps cristatus

Conservation status Although once nearly extinct in Europe, this species has made an impressive comeback thanks to the eutrophica-tion (yoo-troh-fih-KAY-shun), the aging process, of lakes the lakes contain more food for the grebes as they age. Populations are stable in all ranges.

Demography Mortality and Health Statistics

The last century has seen a dramatic longevity rise in the industrialized world. Some Web sites aim to document this phenomenon and to provide information that might lead researchers to the factors that have caused this life-span gain. The Human Mortality Database, a joint effort between researchers at the University of California, Berkeley and the Max Planck Institute for Demographic Research in Rostock, Germany, currently provides detailed mortality and population data for 23 countries. Visitors can download and analyze these statistics to compare mortality trends in different regions over time. The site also provides links to other resources that contain useful information, such as cause of death, that is not included in the Human Mortality Database. The National Center for Health Statistics at the United States Center for Disease Control and Prevention contains a Data Warehouse on Trends in Health and Aging on its aging activities page. Users can view, chart, and download data on...

Longitudinal and Cross Sectional Studies

Study of changes in cognitive abilities during adulthood might involve administering appropriate measures of these abilities to groups of individuals of different ages from 20 to 80. The cross-sectional approach, which was firs used by Adolphe Quetelet in 1838, is less expensive and more efficient than the longitudinal approach but has its own drawbacks. One drawback is that the different age groups must be matched initially on variables that might confound the relationship between age and the variable of interest (the criterion variable). For example, in a study of changes in cognitive abilities over the life span, the investigator should match various age groups on education before comparing them on measures of cognitive abilities. This matching process is not always easy to do, and even so, it may still not be clear whether differences among selected age groups on the criterion variable are a result of the developmental process, cohort (generational, cultural, etc.) differences, or...

From Bench To Bedside

Previous reports on different animal models revealed that IL-2-activated NK cells are able to induce regression of established lung and liver tumors and metastases of different origin (Schwarz et al., 1989 Vujanovic et al., 1995 Whiteside et al., 1998 Yasumura et al., 1994). The control of tumors and metastases corresponded with an extended life expectancy. In contrast, the injection of IL-2 alone was significantly less efficient compared to an adoptive transfer of IL-2-activated NK cells. These data indicated that cytokine-stimulated NK cells exert beneficial effects on the control of tumors and distant metastases in immunocompetent and immunocompromised animals (Basse et al., 2001 Koda et al., 2003 Kondo et al., 2003). We additionally analyzed life expectancy of tumor-bearing mice after a single i.v. injection of pre-activated effector cells. As summarized in Figure 3, immunod-eficient control mice showed first signs of tumor disease from day 18 onwards the maximum survival time was...

Applications Of Microarrays To Agingrelated Research

Comparing young versus old The most common application of microarrays to aging-related research is an experimental design that compares gene expression in young organisms to gene expression in old organisms. Studies of this type have been carried out in all of the major model systems, as well as in humans (Hudson et al., 2005). Most often, the goal of this type of study is to identify genes for which transcription either increases or decreases as a function of age, in other words, biomarkers of age. It is important to recognize that the gene expression changes observed from this type of design don't confer any information about genes that determine longevity or rate of aging. Also, as is true of any microarray experimental design, the observed gene expression changes can be stated to correlate with the condition being studied (biological age, in this case), but no information is obtained regarding whether the gene products themselves play a causal role. In most cases, it will be...

High Throughput Approaches to Measuring Life Span in Simple Eukaryotes

Simple eukaryotic models, such as yeast, worms, and flies, have had a significant impact on aging-related research, largely due to their short life span and genetic tractabi-lity (see Chapters 17-25). Nearly all model-based studies of aging have been driven either by candidate gene approaches, where a particular gene is studied based on its known or assumed function related to aging, or by genetic screens for secondary phenotypes correlated with longevity. These approaches, while often fruitful, are inherently biased. The development of true high-throughput life span assays, where longevity can be measured for thousands of individuals simultaneously, provides the opportunity to identify genetic and environmental regulators of aging in an unbiased, genome-wide manner.

Alternatives To Standard Lifespan Assays

Even in simple eukaryotes, such as yeast, worms, and flies, the length of time that it takes to measure life span can be a rate-limiting step in high-throughput longevity phenotyping. New approaches are being developed that decrease the time and effort necessary to predict whether a particular mutation or environmental intervention is likely to alter aging rate. For example, in C. elegans a high-throughput method has been developed that combines automated worm-handling technology with a fluorescent dye exclusion phenotype to screen for small molecules that impact oxidative stress resistance and aging (Gill et al., 2003). While the utility of this method has yet to be proven, the approach appears promising. A new method has been proposed that shortens the length of time required to carry out life-span analysis in flies by 80 (Bauer et al., 2004). By coupling the expression of a lethal toxin to expression of a putative age-dependent biomarker, flies are prematurely killed. In theory,...

Targeted Screens for Small Molecules that Slow Aging

In addition to Sirtuins, several other genes have been identified that play a role in determining aging rate in multiple eukaryotic models. For example, stress and nutrient responsive kinases, including TOR and Akt homologs increase life span in several different organisms when function is decreased (Fabrizio et al., 2001 Kaeberlein et al., 2005b Kapahi et al., 2004 Vellai et al., 2003), and are likely to represent viable small molecule targets. Indeed, inhibitors of TOR, such as rapamycin and rapamycin analogues, are currently in clinical trials as anticancer agents. In general, genes that function to promote aging (increase longevity when function is reduced) are likely to make better candidates for high-throughput small molecule screening, as it is much easier to identify protein inhibitors rather than activators.

Studies on health effects

Few reported studies analyse the effects ofspecific interventions, and even fewerfocus on transport-related air pollution. They indicate that reducingthis pollution may directly reduce acute asthma attacks in children and the related medical care. Long-term decreases in air-pollution levels are associated with declines in bronchial hyperreactivity, in the average annual trend in deaths from all causes, and in respiratory and cardiovascular diseases. Such decreases are also associated with gains in life expectancy.

Genomewide Screens for Human Aging Genes

One approach toward identifying genes that modify human aging is to restrict the search space to individuals that demonstrate an extreme longevity trait, such as centenarians. Puca and colleagues have carried out a genome-wide linkage screen to identify loci that correlate with extreme longevity in centenarian sibships (Puca et al., 2001). From this screen, a locus on chromosome 4 was identified and was subsequently mapped to micro-somal transfer protein. Alleles of microsomal transfer protein have been associated with abetalipoproteinemia in humans (Geesaman et al., 2003), and it is likely that

Other High Throughput Approaches

New technologies continue to be developed for biomedical research, and application of these methods to aging-related problems will be an important force for advancing our understanding of the aging process. High-throughput proteomic (see Chapter 9 on proteomics) and metabolomic methods, in particular, offer the opportunity to dissect age-associated changes that go beyond mRNA. Protein microarrays, for example, may allow for genome-scale determination of protein levels (rather than mRNA) as a function of age and aging rate. Other high-throughput methods can detect macromolecular damage and modifications, such as glycation, that might play an important role in cellular aging (Schoneich, 2003). A particularly exciting prospect is the development of a noninvasive test for mammalian aging rate (perhaps serum based) that relies on protein or metabolite markers to determine whether a particular intervention alters aging in individual animals or people. The value of such a diagnostic method,...

Minority Aging And Health Problems Ethnic Comparisons

While people in the United States are living longer, life expectancy remains lower for ethnic minorities (C. Lopez & Aguilera, 1991 U.S. Department of Health and Human Services, 1990a). Life expectancy for the general U.S. population increased from 69.7 years in 1960 to 74.9 years in 1988 and is projected to increase to 77.0 years in 2000 (U.S. Bureau of the Census, 1990d, p. 72).

Natural Models Of Alzheimerlike Pathology

In summary, nonhuman primates and canines have been invaluable in illuminating the biochemistry, cytology and genetics of senile plaques, amyloid angiopathy and tau pathology in the aging brain, and they remain useful for testing emerging therapies for neuro-degenerative diseases (Studzinski et al., 2005 Walker et al., 2005). However, for a variety of reasons, a major component of which is their longevity, research with these species is limited in scope. The emergence of genetically engineered rodent models has greatly accelerated the investigation of AD-like pathogenesis in vivo.

Cardiovascular Disease

Post myocardial infarction A dose of 4 g day l-carnitine over 12 months improved quality of life and increased life expectancy in patients who had suffered a Ml, according to a controlled study (Davini et al 1992). This included an improvement in heart rate, systolic arterial pressure, a decrease in anginal attacks, and improve

Statistical Inference Methods

Analysis of Variance (ANOVA) is another parametric statistical method. One-way ANOVA is a popular tool for comparing the means from several samples. For example, Weindruch et al. (1986) collected data from mice on the relationship between caloric intake and life expectancy. They randomly assigned female mice to feeding regimen groups where scientists regulated the caloric intake as well as the composition and quality of the nutrition in the diets of the mice. In this situation, comparisons of mean life expectancy between feeding groups can be made by using ANOVA. Keep in mind, however, that ANOVA is a parametric method and the validity of the assumptions underlying this method must be verified prior to performing this analysis.

Ethnic Differences In Death And Dying

Industrialization and modernization have resulted in remarkable declines in death rates and substantial increases in life expectancy through improvements in food production, public health, and medical care. These improvements have primarily affected infants, who, in premodern times, were the most vulnerable to malnutrition and widespread disease (Goldscheider, 1971). Such progress in life expectancy is mainly the result of reductions in infant and childhood mortality.

Mortality and morbidity considerations

An understanding of the mortality and morbidity patterns in the modern human being is essential to the planning of preventive programs. The great infectious diseases of the past, such as tuberculosis, syphilis, smallpox, influenza, diphtheria and streptococcal infections, have been largely contained but other diseases have become prominent as life expectancy increases. The great modern diseases are atherosclerosis (hardening of the arteries), malignant disease (cancer), HIV infection and iatrogenesis (doctor-induced illness).

Review of evidence for a genetic effect

In practice, heritability estimates often do not reliably identify which phenotypes are influenced by genes with major effects (Weiss and Terwilliger, 2000) and therefore need to be used cautiously in making decisions. In addition, results are specific to a given population with a particular pattern of environmental exposures. Heritabilities may vary with age, showing a steep decline as age of disease-onset rises, implying a generalised aging process that is not influenced by genetic variation. Even if the total genetic variance is constant or actually

Guardians of Our Cities Linda Fried and Jeremy Barron

The percentage of America's population that is age 65 or older will rise from 12 currently to 20 by 2030. Urban populations are similarly aging and will continue to do so in the coming decades. These trends are due to the increasing life expectancy both at younger ages and once people reach 65. Primary, secondary, and tertiary prevention along with medical advances are all contributors to the improved survivorship resulting in the now 76 million strong Baby Boom cohort.

The Universality of Yeast Aging Mechanisms and Future Outlook

Another major advantage of yeast is the rapid phenotypic testing of candidate longevity genes. For example, the ease of gene deletion in yeast means that one can find a gene whose expression is up-regulated in a microarray experiment under one growth condition, and then delete this gene to determine if this up-regulation is actually required for this growth condition. When this experiment was done with all budding yeast genes, it was found that only 7 of yeast genes that were up-regulated were actually required for optimal growth under the test condition (Giaever et al., 2002). This sobering result means that many of the genes identified by microarray approaches in organisms such as humans are probably not the most important genes affecting the aging process, and some sort of validation is required. Since such gene deletion studies and aging experiments are difficult and long in mammalian systems, budding and fission yeast will

Chronological Aging in Yeast

The chronological life span of a yeast cell is defined as the length of time that a cell can maintain viability in a nondividing state. Chronological aging in yeast has been studied using a variety of different methods involving culturing cells into stationary phase, a quiescent state in which cells are metabolically active but nonreplicative. Compared to replicative aging, relatively few genes have been studied with respect to their effect on chronological life span yet, some of the important pathways regulating this process have already emerged. Unlike laboratory growth conditions, the natural environment of a yeast cell is likely to consist of relatively rare periods of exponential growth followed by prolonged periods of starvation-induced quiescence. Chronological aging may, therefore, play an important part in the ecology of wild yeast populations, as well as provide insight into the aging process of nondividing cells in higher eukaryotes.

What Do Chronologically Aged Cells Die From

A third mechanism by which quiescent yeast cells might senesce is due to damage generated by oxidative stress. The free radical theory of aging posits that one cause of aging is the accumulation of macromolecular damage due to oxidative free radicals (Harman, 1956). There are several lines of evidence suggesting that oxidative damage plays a causal role in the chronological aging process of yeast cells. For example, loss of respiratory capacity increases with time spent in stationary phase, suggesting that mitochondrial damage accumulates during chronological aging (Fabrizio and Longo, 2003). Also consistent with the idea that oxidative damage is correlated with chronological longevity, mutation of either mitochondrial superoxide dismutase (Sod2) or cytosolic superoxide dismutase (Sod1) results in a substantial decrease in stationary phase survival (Longo et al., 1996). Finally, overexpression of both Sod2 and Sod1 increases chronological life span by about 30 , suggesting that...

Chronological Aging And Response To Stress

It has been proposed that aging in nondividing yeast cells is largely under the control of the transcription factors Msn2 and Msn4 (Fabrizio et al., 2001). Msn2 and Msn4 bind to stress response elements (STRE) contained in the promoters of many genes coding for proteins involved in adaptation to starvation and stress, such as heat shock proteins, catalase, superoxide dismutase, and glycogen and trehalose biosynthetic enzymes (Smith et al., 1998). Msn2 and Msn4 are repressed by the nutrient responsive kinases TOR, PKA, and Sch9, which promote phosphory-lation and exclusion of Msn2 4 from the nucleus. Mutation of CYR1 or deletion of SCH9 fails to increase chronological life span in an msn2D msn4D double mutant, consistent with the idea the enhanced longevity seen in these mutants is due to activation of Msn2 4-dependent targets (Fabrizio et al., 2001). In many ways the function of Msn2 and Msn4 as transcriptional regulators of the yeast chronological aging program parallels the role of...

Embracing Diversity Understanding Strainspecific Differences

As with other model systems used for aging-related research, strain-specific effects due to genetic diversity can have a large impact on longevity and other age-associated phenotypes in yeast. The importance of strain diversity for studies of aging consists of two distinct components. The first component of strain diversity is the large genetic variation between different laboratory strains commonly used in scientific research. Laboratory strains can have dramatically different life spans, ranging from an average of less than 10 generations to nearly 30 generations, for replicative life span (Kaeberlein et al., 2005a). This type of diversity is analogous to that seen between different inbred strains of mice, which also can have substantially different longevity and aging The second type of diversity relevant to aging-related research is the genetic divergence between domesticated laboratory yeast and wild isolates of S. cerevisiae. This type of diversity and its impact on yeast aging...

Hormone replacement therapy administration and regimens

Hormone users have a lower risk of death (relative risk, 0.63) than nonusers. This reduction is largest in women with cardiac risk factors. The benefit decreases with use of more than 10 years (due to breast cancer deaths) but still remains significant. HRT should increase life expectancy for nearly all women. The risk of HRT outweighs the benefit only in women without risk factors for CHD or hip fracture, but who have two first-degree relatives with breast cancer.

The Chronological Aging Assay

In addition to the composition of the culture media, another important variant in the chronological aging assay is the condition under which cells are maintained during aging. Temperature and oxygenation are two of the most important environmental parameters that can alter the rate at which cells age chronologically. The importance of temperature is demonstrated by the observation that chronological longevity of cells maintained in water is substantially reduced as temperature is increased (MacLean et al., 2001). Survival is also reduced as oxygenation is increased. For example, cells cultured in flasks on a rotating shaker have a chronological life span that is up to 50 shorter than cells cultured in a tube on a rotating drum, while cells maintained under low aeration (no agitation) in 96-well plates have a median life span that is extended.

The Life Span of Yeast

The chronological life span is determined by measuring the survival time of populations of nondividing yeast. Alternatively, yeast life span is measured by monitoring the replicative potential of single mother cells. Each system has led to the identification of genes involved in either chronological or replicative aging (Bitterman et al., 2003). The activity of the products of some of these genes (SCH9, CYR1 see The Genetics of Chronological Aging Yeast Methuselah Genes) consistently affects both replicative and chronological life span (Fabrizio et al., 2004b). Conversely, some genes encoding for stress resistance proteins (MSN2, SOD1 2) promote chronological longevity but negatively affect replicative life span, suggesting that there is only a partial overlap between the mechanisms that regulate replicative potential and survival of postmitotic yeast (Fabrizio et al., 2004b). In the following section we review both paradigms with emphasis on the chronological life span.

Chronological Life Span Survival In The Postdiauxic And Stationary Phases

When yeast grown in SDC are switched to water between days 1 and 5, metabolic rates decrease and survival is extended (Fabrizio et al., 2004a). However, since long-lived mutants isolated by incubation in SDC also live longer when incubated in water, we believe that analogous pathways and mechanisms regulate survival in both paradigms. Yeast grown and incubated in the nutrient-rich YPD medium also survive for months in a low metabolism stationary phase. However, it is not clear whether YPD medium allows some growth to occur during the supposedly stationary phase (see Survival in Water YPD). To understand how yeast age and to identify conserved pathways that regulate longevity in many eukaryotes,

Replicative Life Span

Sir2 is a NAD-dependent histone-deacetylase whose activity is required to promote chromatin silencing at the telomeres, mating type loci, and rDNA (Braunstein et al., 1993 Tanny et al., 1999). Increased dosage of SIR2 delays replicative aging by inhibiting rDNA recombination and consequently the formation of ERCs (Kaeberlein et al., 1999). Although this aging mechanism has not been observed in any other species, Sir2 was shown to play a conserved antiaging role in higher eukaryotes. In fact, increased dosage of the Sir2 homologs extends the life span of both C. elegans and Drosophila by up to 50 , and Sir2 activity has been associated with the longevity extension caused by calorie restriction an intervention known to extend the life span of all model organisms (Rogina and Helfand, 2004 Tissenbaum and Guarente, 2001 Wood et al., 2004). However, despite the extensive experimental effort to link the Sir2 family of proteins (sirtuins) to mammalian longevity, a...

The Genetics of Chronological Aging Yeast Methuselah Genes

Another glucose-sensing pathway known to regulate chronological aging is the Cyr1 Ras PKA pathway. A reduced activity of adenylate cycalse (Cyr1) promotes stress resistance and longevity, and so does the deletion of RAS2, (Fabrizio et al., 2003 Fabrizio et al., 2001). The down-regulation of the Ras PKA pathway promotes chronological survival via the activation of stress resistance transcription factors Msn2 Msn4 (Fabrizio et al., 2001), which in turn activate the expression of the detoxifying enzymes catalase and superoxide dis-mutase and of several heat shock proteins and promote the accumulation of reserve carbohydrate glycogen (Boy-Marcotte et al., 1998 Schmitt, 1996 Smith et al., 1998) (Figure 19.2). The Sch9 and Ras PKA pathways share several gene targets although in some cases their regulation of gene expression is opposite (Roosen et al., 2005). The exact relationship between these two pathways is still unclear mainly because the Sch9 pathway components upstream and downstream...

Evolutionary Conserved Pro Aging Pathways

Research conducted in C. elegans has identified the insulin IGF-1-like pathway as a major pro-aging pathway (Figure 19.2). The similarities between yeast and worm aging pathways are remarkable. Analogously to the yeast Ras PKA pathway, the insulin IGF-1-like pathway senses the presence of nutrients and regulates entry into a hypometabolic stage (dauer larva) (Kimura et al., 1997). Worm life span can be extended up to three times by reducing the activity of some of the components of the insulin IGF-1-like pathway such as the cellular receptor DAF-2 and PI-3 kinase AGE-1 (Kimura et al., 1997 Morris, 1996). Importantly, AGE-1 activates kinase Akt PKB, which was shown to be homolog of yeast Sch9 and can also be activated by PDK-1, homolog of yeast Pkh1 (Figure 19.2) (Paradis et al., 1999). Life-span extension in both daf-2 and age-1 mutants requires the activity of stress resistance transcription factor DAF-16, which belongs to the FOXO family transcription factors, and of the heat-shock...

Strongyloides ratti A Nematode with Extraordinary Plasticity in Aging

Aging has been characterized in detail in relatively few animal species. Here we describe the aging process of a nematode with an unusual life cycle, Strongyloides ratti. This organism has distinct parasitic and free-living reproductive adult forms, which are genetically identical. S. ratti exhibits a remarkably high degree of pheno-typic plasticity of aging the maximum lifespan of parasitic adults is 80 times greater than that of free-living adults (403 and 5 days, respectively). Free-living S. ratti adults are short-lived even by terrestrial nematode standards their lifespan is approximately only 30 of that of the short-lived free-living nematode model species C. elegans. Phenomenologically, aging appears similar in S. ratti free-living adults and C. elegans, except that it unfolds much more rapidly in S. ratti. Demographic senescence (a hallmark of aging) occurs in free-living S. ratti, with a mortality rate doubling time (MRDT) of 0.8 0.1 days (females), compared with 2.0 0.3 in...

Morphological Changes Accompanying Aging In S Ratti

Number increased with age (Figure 20.4C). Most of these resembled lipid droplets (or possibly secondary lysosomes) within which have accumulated electron-opaque particles with a sooty appearance. By contrast, there were very few such inclusions in the intestines of parasitic females and their number did not change with age. These observations suggest that degeneration of the intestine, possibly associated with accumulation of fluorescent electron opaque waste material, represents a pathology of aging that contributes to nematode pathology. This idea was previously put forward based on TEM studies of aging in Caenorhabditis briggsae (Epstein et al., 1972). The fact that this pathology was not detected in the intestine of the parasitic S. ratti adult is consistent with the idea that the absence of this pathology contributes to parasitic longevity. The parasitic and free-living females morphs of S. ratti are genetically identical. Therefore differences between these morphs must be due to...

Learning About Lifespan Evolution From S Ratti

The relationship between extrinsic mortality rate and aging has been supported by numerous comparative studies. For example, bats generally live longer than rodents of a similar size, presumably since flight aids predator evasion, reducing extrinsic mortality (Wilkinson and South, 2002). Evolution results in intraspecific as well as interspecific differences in lifespan. For example, in social insect species there are intercaste differences in lifespan which may reflect the evolutionary effects of different levels of extrinsic mortality on rates of aging (Page and Peng, 2001 Chapuisat and Keller, 2002). However, the extent to which these lifespan differences are the result of differences in the rate of aging remains unclear. For example, Chapuisat and Keller (2002) compared survival in large and small worker ants, and found that the smaller workers lived significantly longer, which they hypothesized was because the larger morphs were fighting and getting killed more quickly.

Between The Genetics And Evolution Of Lifespan

In C. elegans, DAF-16, a FOXO-family transcription factor, controls the rate of aging in response to insulin IGF-1 signalling. Recently, microarray studies have begun to identify the transcriptional targets of DAF-16, which are predicted to include the ultimate genetic determinants of longevity and aging in C. elegans (Murphy et al., 2003 McElwee et al., 2004). DAF-16 alters the expression of a wide range of genes, involved in many life processes, including defenses against stress,

Learning About Aging From Comparative Studies

A hypothetical scheme for the mechanism of lifespan regulation and evolution. (A) Evolved intraspecific differences in lifespan between parasitic and free-living adults are generated by differences in gene expression, regulated by endocrine and cellular signalling systems via regulated transcription factors. We propose that, as in C. elegans (Murphy et al., 2003), parasitic adult longevity in S. ratti results from up-regulation of longevity assurance genes and down-regulation of genes which promote aging. A arrows stimulation, and T bars inhibition. (B) Potentially, differences in aging rate between species may evolve via similar mechanisms. Here, the environment of an ancestral species changes, such that the extrinsic mortality rate is lowered, and selection against deleterious late-life effects is increased. This leads to the evolution of slower aging and increased longevity, which might occur via alterations in regulation of longevity assurance and aging genes. This...

Life Span Characteristics and Factors Which Are Responsible for Modifying an Insects Life Span

Although the aging pattern of insects, like that of other organisms, is doubtless under genetic control, it is extremely flexible, depending on several biotic and abiotic factors. Life span includes the longevity of all developmental stages an individual passes through during its life cycle. Individuals of insect species (as well as those of other species) experience a number of critical points in time during their life cycles, which influence the life span from eggs over larvae up to pupae and adult stages. Without knowledge of such modifying factors the life span of an insect species is unpredictable. Insects are ectothermic organisms. The ambient temperature is therefore a key life-span modifying factor. It is easy to manipulate the metabolic rate simply by changing ambient temperature. The mentioned work of Loeb and Northrop used this regimen as an experimental tool. The light regime also acts as a prominent abiotic stimulus together with the temperature. Both factors are...

The Possibility of Continuously Measuring Energy Metabolism

Different light regimes influence the adult life span. At least in Drosophila, constant light has a life-shortening effect (Sheeba et al., 2000). Under such conditions, a very high egg production rate can be observed, which might be responsible for the early death. After results from Pittendrigh (1972), the light-dark cycle under which larvae of Drosophila were reared had strong influence on the longevity of the adults. It is generally known that a desynchronization of endogenous rhythms affects many physiological parameters and is therefore of major

Macroevolution and Paleontology

Simpson's works made him the father of the taxic approach to paleontology, a field that employs changes in taxon richness and longevity to understand major patterns in the history of life (see chapter 7). This approach occupies a major part of the efforts of paleontologists today (e.g., Flessa and Imbrie 1973 Raup 1976a, 1976b Sepkoski 1981, 1984, 1993 Valentine 1969 Van Valen 1973b, 1984). Simpson contrasted longevities within major taxonomic groups. The variations and general correlations of taxonomic longevity, speciation, and extinction rates have been used extensively to draw inferences about the tempo and mode of evolution (e.g., Sepkoski 1984 Stanley 1979), although many criticisms have been leveled concerning the potential of taxonomic bias generated by differences in morphological description, systematic practice, and so on, among taxonomic groups (e.g., Levinton and Simon 1980 Patterson and Smith 1987 Schopf, Raup, Gould, and Simberloff 1975 Van Valen 1973a). An article by...

Power Of Decision Making

Callahan (1995) agrees with a position that states that the ''self'' continues to exist even in a demented state. It is possible that we may find acceptance of a life we earlier thought unacceptable. He proposed three contextual and background considerations (1) No one should live longer in the advanced stages of dementia than he or she would have in a pretechnological era (2) the likely deterioration in a late-stage demented patient should lead to a shift in the usual

Neurophysiological Factors

Many supporters of a neurological explanation of age-related declines in intelligence view it as the result of small changes in the brain produced by high blood pressure, alcoholism, and other pathological conditions (Rinn, 1988). It is certainly true that intellectual functioning is affected by health status and that people with higher intellectual abilities are healthier and live longer than those with lower abilities. Self-reports of physical and mental health confirm the results of medical diagnoses in this regard (Perlmutter &

Factors That Affect Lifespan

Intrinsic genetic factors Genetic background plays a major role in lifespan. It is important that the effects of mutant gene actions or any experimental manipulations be studied on a standard genetic background with an appropriate control group. However, because genetic influences on longevity are described in detail in Chapter 25 of this volume, no more will be said here.

Selection And Demographic Experiments

It is a testament to the strength of the Drosophila model that most of the above studies, especially the detailed demographic explorations of mortality, have been done only in Drosophila. However, this also produces the caveat that the results may apply only to Drosophila, or at least may apply less broadly than some of the genetic mechanisms of aging described below. For example, while there do appear to be trade-offs between reproduction and longevity in mammals, the correlation is much less tight than in Drosophila and the mechanisms may be indirect (Cohen, 2004).

Search For Evolutionarily Conserved Genetic Mechanisms Affecting Lifespan

Codes for a G-coupled membrane receptor-like protein, reported in 1998 (Lin et al., 1998) by longevity screens. Since then almost 50 additional genes have been identified. Whether these genes also affect lifespan in other species is yet to be determined, but just as Drosophila has served as a test species for genes identified in other organisms, others may serve to explore patterns initially found in Drosophila.

Is achieving extreme old age worthwhile the centenarian phenotype

Average life expectancy has markedly increased over the past century. In 1900 average life expectancy was 46 years and in the United States it is currently almost 79 years. The age 85+ group is the fastest growing segment of our population and within that group, the number of centenarians is growing even faster. Whether mortality declines have been accompanied by health improvements among the elderly has been a matter of debate. Some authors have suggested that mortality declines have led to increased prevalence of frailty among older survivors because treatment of existing diseases simply postpones death to older ages (Gruenberg, 1977 Kramer, 1983 Olshansky and Ault, 1986), while others suggest that mortality declines have led to a compression of morbidity (Fries, 1980). Early US evidence from the 1970s was generally consistent with the idea that health among the elderly had deteriorated (Crimmins and Ingegneri, 1993 Verbrugge, 1984), while more recent evidence provides a somewhat...

Substantive Issues Demographic Determinants of Population Aging

Using the stable population model, the effect of a change in fertility on the age composition of a population is found to be straightforward. A permanent shift to a lower fertility level, with no change in mortality rates, leads to an aging of the population. This result is not surprising, because it seems obvious that under similar mortality conditions, a population with lower fertility will have proportionately fewer children, and hence an older population, than one with higher fertility. Comparing stable populations with different fertility levels and similar levels of life expectancy shows the magnitude of the effect of a fertility decline. For example, in a stable population with life expectancy of 80 years, 11.9 of the population will be over age 65 if the gross reproduction rate (GRR) is 1.5, but 25.9 if the GRR is 0.8. Other comparisons of stable population age composition under differing fertility and mortality conditions can be made from data in Table 5.1. The effect of...

The relative contributions of genes environment and luck to how we age

The relative contribution of environmental and genetic influences to life expectancy has been a source of debate. Assessing heritability in 10 505 Swedish twin pairs reared together and apart, Ljungquist and colleagues attributed 35 of the variance in longevity to genetic influences and 65 of the variance to non-shared environmental effects (Ljungquist et al., 1998). Other twin studies indicate heritability estimates of life expectancy between 25 and 30 (Herskind et al., 1996 McGue et al., 1993). A study of 1655 old order Amish subjects born between 1749 and 1890 and surviving beyond age 30 years resulted in a heritability calculation for life span of 0.25 (Mitchell et al., 2001). These studies support the contention that the life spans of average humans with their average set of genetic polymorphisms are differentiated primarily by their habits and environments. Supporting this idea is a study of Seventh Day Adventists. In contrast to the American average life expectancy of 78 years,...

Recommendations To Improve Policy Practice And Research

Resist the urge of pursuing, with no limits, medical goals that combine the following beneficiaries are primarily the elderly indefinite life extension is sought, costs are high, and the population-wide benefits are slight. Instead, we should seek to advance research and health care that focus on quality, not quantity, of life. In terms of the individual's responsibility, Callahan claims that a person who cares about his or her society should value more than just medical progress. Each element of progress can bring expenditure of resources. Thus medical progress and increased life expectancy have both good and bad elements.

Physiological Signatures And Patterns Of Lifespan

Stage (up to 280 days reviewed by Omholt and Amdam, 2004). Consequently, the transitions among those three distinct life history states are key determinants of the lifespan of any individual worker (reviewed by Amdam and Page, 2005). Within each temporal caste, however, longevity is further conditional on physiological factors (Maurizio, 1950) (see below). Metabolic Rate (MR) MR is one physiological factor that may underlie the temporal, caste-associated mortality rates of honeybee workers. Forager MR is significantly higher than the MR of hive bees (for a discussion see Suarez et al., 1996), and the MR of a foraging bee constitutes one of the highest known mass-specific aerobe MRs among animals (approximately 3-fold higher than hummingbird flight muscle). Such intense activity is a major source of mechanical senescence in insects and causes mortality to increase as a function of age (reviewed by Finch, 1990). In accordance with their longevity, diutinus bees periodically exhibit low...

The Lifespan of Queens and Drones

No significant demographic data exist on queens for three reasons. Large data sets require a disproportionate experimental effort since only one queen exists in each colony. Moreover, queens are long-lived. Finally, the lifespan of queens may be socially controlled (reviewed by Page and Peng, 2001), and it is difficult to distinguish a swarming event from replacement of the old queen by a daughter (supersedure). Longevity records demonstrate a much higher potential lifespan for queens than for either workers or drones. Their lifespan regularly exceeds one year, and maximal reported queen longevity is above

Practical Aspects of Honeybee Research

There are several excellent sources for information on how to establish and maintain an apiary or a honeybee breeding program (e.g., Atkins et al., 1975). Moreover, there are special resources available that describe experimental handling procedures and protocols for behavioral (Frisch, 1967 Seeley, 1995) and physiological (Snodgrass, 1956) data collection. Yet, we will provide a brief overview of tools, protocols and experimental considerations that are of specific relevance for research on aging and longevity.

Trajectories of Population Aging

The first comparison in Table 5.4 is between the more developed regions (Europe, Northern America, Japan, and Australia and New Zealand) and the less developed regions (Africa, Latin America, and Asia excluding Japan). In general, countries included in the more developed'' regions have had higher levels of income, higher life expectancy, and lower birth rates since 1950 than countries in the less developed'' category. Although this is a crude division of world societies, it is clear that it captures large differences in population aging. Between 1950 and 2000, population aging progressed much more rapidly in more developed areas, and the difference between more and less developed was marked in 2000 (14.3 over age 65 years in more developed, compared to 5.1 in less developed). Between 2000 and 2050 it is anticipated that the proportion of old will nearly double in developed regions (to 26.8 ) and triple in less developed regions (to 14.0 ). In 2050 the less developed regions will have...

Biodemographic Research

The seasonality of worker lifespan is one of the most striking features of the honeybee aging model system (see Temporal Cessation of Behavioral Development). The few studies addressing seasonality from a comparative demographic perspective reveal that not only the average life expectancy, but also the variation in life expectancy (Sakagami and Fukuda, 1968) and life history trade-offs that determine life expectancy vary seasonally (Neukirch, 1982). In general, the diutinus phase over the winter period seems to slow aging effectively without any adverse, compensatory effects before or after this stage (Omholt and Amdam, 2004), but more work on the mechanistic and demographic aspects of this retardation of aging remains to be done. One further interesting aspect, which is unique to the honeybee model, is the connection between social structure and individual life history and aging. Isolated studies have indicated that the caregiver-to-dependent (worker-to-brood) ratio is of crucial...

The Ant Model Systems

Sociality causes an increase in longevity. Redrawing of Figure 2 from Keller and Genoud 1997 showing how extreme life spans evolved multiple times in association with the evolution of sociality. Figure 24.1. Sociality causes an increase in longevity. Redrawing of Figure 2 from Keller and Genoud 1997 showing how extreme life spans evolved multiple times in association with the evolution of sociality.

Public Pension Programs

Two basically different approaches to reforming public pensions are being debated (Disney 2000). The less radical approach, referred to as ''parametric'' reform (Chand and Jaeger 1996), argues that unfunded PAYG schemes can be brought into equilibrium by making changes in a few parameters. More money available for paying pension benefits could come from either increasing taxes on the workers or by increasing the proportion of the working age population that participates in the labor force. Pension expenditures could be reduced by decreasing benefits, either by directly cutting benefits or by increasing age for pension eligibility. The approach of increasing normal retirement age has received support from some demographers who point out that that increasing life expectancy and improving health of cohorts entering old age make a fixed retirement age (such as 60 or 65) increasingly obsolete (Chen 1994 Uhlenberg 1988). The general view of those favoring parametric reform is that by making...

Patterns Of Metastases

The lungs are the next most common site of spread of metastatic disease. This is often asymptomatic and found on routine imaging, but patients can present with symptoms of local pain or cough, or with haemoptysis and dyspnoea due to localized lesions, or, less commonly, with dyspnoea resulting from lymphangitis. Spread to other distant sites occurs less commonly, but as patients live longer following chemotherapy, bone, and, less frequently, brain, adrenals, skin, and other sites may be involved.

Systematics and Macroevolutionary Hypotheses

Although there have been some heartening changes since the first edition of this book, a few paleontologists have avoided the obvious need to define the meanings of taxonomic levels, genealogical reconstruction, and systematics (e.g., Gould 1989). Genealogical aspects of systematics have been largely ignored in studies of taxonomic longevity, diversity, and rates of taxon turnover (e.g., Sepkoski 1981 Van Valen 1973b Valentine 1969). This omission weakens the clarity of macroevolu-tionary hypotheses, which often involve explanations of change between sets of character states in different taxa. A now celebrated example is the so-called extinction of the dinosaurs, whose characters did not become extinct if you accept the idea that birds descended from one dinosaur group. Genealogical considerations therefore muddy up the waters of what extinction really means.

Patterns of Senescence

Do all tissues of the fly age together and at the same rate Our early work suggested that both normal- and long-lived animals undergo the same sort of senescent process, losing different traits in the same sequence and at the same stage (Arking and Wells, 1992). Since the animals do not lose all functions at the same time, it also implies that different tissues age at different rates. Is there any data to support this implication The fact that there is a defined spatio-temporal pattern of gene expression during the aging process (Seyroude et al., 2002), coupled with the fact that at least 9 of the genes are known to undergo transcriptional changes during aging (Pletcher et al., 2002), suggests that it is unlikely that all tissues of the fly age together and at the same rate. Some data to support this supposition were presented by Cook-Wiens and Grotewiel (2002). They showed that different behaviors of the fly, utilizing different sensory systems, age at different rates. For example,...

The Role Of The Spleen In Red Cell Membrane Disorders

The spleen plays a vital role in red cell health and longevity. Because 5 of cardiac output per minute is filtered through the spleen, this organ has ample opportunity to survey red blood cells for imperfections. Only those red cells that are deemed flawless are conducted through the rest of the red cell journey. The four functions of the spleen have been explained in Chapter 2, but when considering red cell membrane defects, it is the splenic filtration function that is the most relevant. As each red cell passes through the spleen, the cell is inspected for imperfections. Now imperfections may take many forms from inclusions to parasites to abnormal hemoglobin products or an abnormal membrane. Inclusions may be removed from the cell, leaving the membrane intact and allowing the red cells to pass through the rest of circulation unharmed. But if the red cell has abnormal hemoglobin (such as seen in thalassemia) or abnormal membrane components, then red cell elasticity and deformability...

How Do Different Pathways Yield a Common Type I Phenotype

Longevity-extending mechanisms known to be operative in flies, which we have discussed above. The schematic is somewhat speculative in detail, but its tying together of the several known methods of inducing stress resistance with the expression of extended longevity as described in the foregoing text is most likely correct in concept. The important point to note is that all the interventions listed are known to induce the Type 1 longevity phenotype (i.e., delayed onset of senescence) (see Figure 25.1A). The ISS pathway, certainly, and the JNK pathway, probably, are involved in producing this phenotype. The details of the CR pathway are still being worked out. Even given our incomplete knowledge, it seems as if all inducers of the Type 1 phenotype work by effecting some common regulatory nexus, probably the dFOXO3 transcription factor that is known to activate or repress various stress resistance genes. The interesting thing about the Type 1 phenotype is that delaying the onset of...

Annual Fish as Models for Aging

We believe that Nothobranchius rachovvi, a killifish, is a better vertebrate model for longevity genetics because their maximum lifespan is about ten months (Herrera and Jagadeeswaran, 2004). Nothobranchius rachovvi are tele-ostei like zebrafish and have already been used in aging studies. They have been shown to begin senescent changes at approximately four months of age. They are relatively easy to breed and are approximately 2 inches in size. The females lay approximately 20 eggs per day. Nothobranchius rachovvi can breed even at an old age until the very end of their lives. This occurs because the natural habitat of these fish dries out seasonally. In order to preserve their species, these annual fish developed schemes to lay eggs up to the time of death. In the laboratory, eggs are collected in peat moss and then stored in a dry container for four months. The eggs hatch when placed in water, and they grow at 28-30 C. The larvae mature by the age of 3-4 weeks when males develop...

Advantages of the Genealogical Approach

Genealogies and character transitions. A framework established from a genealogical algorithm permits a useful analysis of character variation in the context of macro-evolutionary hypotheses. Many macroevolutionary hypotheses attempt to provide mechanisms to explain differential taxon longevity. Claims that taxon longevity depends on biogeographic range (e.g., Boucot 1978 Jackson 1974 Levinton 1974) or that taxon longevity is the result of differential speciation rate or survival of species (e.g., Stanley 1975 Vrba 1983) may depend partially on the nature of character variation within the clades under consideration. In many cases, adaptations of individuals influence the susceptibility to extinction of species and larger taxa. Although speciation rate may ensure survival of a taxon, the possession of certain characters may permit an entire clade to outlast others or might permit descendants of a given clade to invade a new habitat. The testing of such ideas requires a mapping of...

Insertional Mutagenesis

The insertional inactivation of genes by retroviral mutagenesis has been successfully employed in zebrafish as described above. How will this be useful in longevity selection The underlying rationale for insertional muta-genesis in aging studies is that the inactivation of genes that have negative influence on the lifespan might increase the lifespan. Since it is easy to detect dominant genes, first dominant screens should be conducted by simply injecting the retroviruses into the Nothobranchius embryos and then the fish should be selected that are long lived and should be used further to identify the genes that are affected. This concept could also be extended further for recessive screens either by diploidization or by three-generation screens to identify the long-lived Nothobranchius. The methods that are used in zebrafish for insertional mutagenesis should be applicable for the annual fish.

Transgenesis and Overexpression of Genes in Annual Fish

Activator line, the GAL4 (yeast transcriptional activator) gene is placed under the control of a tissue cell specific promoter, while in the effector line the gene of interest is fused UAS (Upstream Activating Sequences, the DNA-binding motif of GAL4). Once the effector line is crossed to the activator line, the effector gene is expressed in a specific tissue because the GAL4 is supplied by the tissue specific promoter and will bind to the UAS and drive the effector gene transcription. Recently, the utility of the Cre lox system has been demonstrated in the zebrafish model by developing a conditional myc-induced T cell acute lymphoblastic leukemia (Langenau et al., 2005). Thus, in addition to GAL4-UAS system, this technology is available for fish. Depending upon the strength of the promoter and taking into account the positional effects, the gene expression could be modulated and the effects on longevity could be studied. Thus, it is conceivable that one could express genes that...

Annual Fish as a Tool for Screening for Antiaging Drugs

In 1999, we suggested that zebrafish could be used as a model for drug discovery (Jagadeeswaran et al., 1999). Due to the availability of a large number of chemical compounds and the ease of screening the larvae, a number of mutants are being investigated to reverse the phenotype with these chemicals. Such reversal of phenotypes has been applied to aortic coarctation (Peterson et al., 2004). This phenotypic reversal is feasible because the larvae are small and it is possible to accommodate screening in a 96-well format in tiny volumes such that only small amounts of chemical are used. However, in longevity studies such screening depends on the availability of compounds on a large scale and continuous replacement of the chemicals to accommodate for their half-lives. Interestingly, there are several naturally occurring compounds that are either antioxidants or participate in metabolic pathways that affect aging. Thus, in the future, it is anticipated that large-scale screens could be...

The Use of Mature Zebrafish Danio rerio as a Model for Human Aging and Disease

Zebrafish (Danio rerio) have been extensively utilized for understanding mechanisms of development. These studies have led to a wealth of resources including genetic tools, informational databases, and husbandry methods. In spite of all these resources, zebrafish have been underutilized for exploring the pathophysiology of disease and the aging process. Zebrafish offer several advantages over mammalian models for these studies, including the ability to perform saturation mutagenesis and the capability to contain thousands of animals in a small space. In this review, we will discuss the use of mature zebrafish as an animal model. The challenges of developing and maintaining a colony of aging zebrafish will be addressed. Specific examples to support the use of mature zebrafish as an animal model will be provided, including the demonstration of clinical pathology and that age-associated changes in various phenotypes can be observed in aging zebrafish.

Identification of Biomarkers of Zebrafish Aging and Senescence

As has already been mentioned, compared with other model organisms, the aging process of zebrafish is in a very early stage of investigation, and we are currently unable to tell precisely how the fish age physiologically, and what the pathophysiological symptoms and lesions are, in zebrafish aging and in their age-associated diseases, respectively. Therefore, first and foremost, it is important to set forth some principles for evaluating the functional aging process in zebrafish.

Senescenceassociated Sa0galactosidase As An Enzymatic Aging Marker

Keyes et al., 2005 Varela et al., 2005). We previously reported on SA-J-gal induction during the aging process in zebrafish in vivo (Kishi, 2004 Kishi et al., 2003). We demonstrated significant increases of SA-J-gal activity in skin from aged (more than 31 months) versus young (less than 17 months) zebrafish (Kishi et al., 2003) (Figure 28.1).

Possible Involvement Of Tumor Suppressor Gene Products P53 And Prb In Zebrafish Aging

The tumor suppressor proteins p53 and pRB regulate cellular replicative senescence and organismal aging. Tumor suppressor mechanisms may represent evolutionary antagonistic pleiotropy because tumor suppressor genes benefit organisms early in life due to suppression of cancer. However, these genes may become harmful later during the aging process, compromising tissue functions. Importantly, telomere attrition in cells induces replicative senescence accompanied by activation of the p53 and pRB pathways. In zebrafish, the p53 pathway is known to exist with relevant functional conservation (Cheng et al., 1997 Langheinrich et al., 2002), but zebrafish pRB pathway has not been reported. Recent studies demonstrated that zebrafish p53 is involved in the tumor suppressor mechanism in vivo (Berghmans et al., 2005 Patton et al., 2005).