Longevity Health and Wellness Protocol

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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...

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...

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...

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...

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...

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 (Kroll, 2005).

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...

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 offamilies 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)...

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.

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 (Kroll, 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...

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...


A schematic diagram integrating all the pathways empirically known to yield a Type 1 (delayed onset of senescence) longevity phenotype in Drosophila melanogaster (after Arking, 2005a). A cautionary note is in order here not all flies react to CR in the same manner as described above. Our selected La and Ra strains have a different response pattern (Arking, unpublished data). Mediterranean fruit flies (Ceratitis capitata) are distantly related to Drosophila and might reasonably be expected to react to CR in the same manner if one assumes that the CR mechanism is highly conserved and public. However, a recent study reported that the Mediterranean fruit fly shows a more or less constant longevity at various levels of diet restriction with a sharp decrease in mortality once the diet falls below 50 of the ad libitum level (Carey et al., 2002). There is no evidence for an increase in longevity at some consistent level of dietary restriction. Reproduction occurred across the...

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 (HbA1c) levels (Stratton et al., 2000 Mooradian and Chehade, 2000). It is noteworthy that HbA1c 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 HbA1c measurements to a greater...

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...

Mammalian Examples Of Lifeextension

It is well-established that longevity increased in the lineage leading to humans, yet the evolution of longevity occurred in other mammalian lineages as well (Figure 2.3). There are no confirmed birds with negligible senescence, though fulmars and the Andean condor age very slowly, if they age at all. The northern fulmar (Fulmarus glacialis), for example, likely ages more slowly than humans (Gosden, 1996). The longest-lived bird, however, is reported to be the Andean condor (Vultur gryphus), which can live up to 75 years. Senescence has not been described in these animals, though detailed studies are lacking (Finch, 1990). In the arctic tern (Sterna para-disaea) too no senescence has been demonstrated so far (Gosden, 1996). The record longevity for this species is only 34 years, but this particular 34-year-old individual appeared in excellent health and was actually released in the wild (Terres, 1980). Such cases again suggest that there may be many species aging more slowly than...

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.

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.

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).

Introduction of Jennerian Vaccination

7 Lee, Wang, and Campbell claim that child mortality of the Machu nobility fell from 400 hundred per 1,000 during the early eighteenth century, to 100 and below by the late eighteenth century, at the same time, life expectancy at birth doubled from the low twenties to the high forties. They suspect that variolation could have contributed to this change.

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.

The Simplest Reliability Model Of Aging

Note also that the identical parallel systems in this example do not die simultaneously when their elements fail by chance. A common view in biology is the idea that all the members of homogeneous population in a hypothetical constant environment should die simultaneously so that the survival curve of such a population would look like a rectangle. This idea stems from the basic principles of quantitative genetics, which assume implicitly that every animal of a given genotype has the same genetically determined lifespan so that all variation of survival time around a genotype mean results from the environmental variance. George Sacher (1977) pointed out that this concept is not applicable to longevity and used an analogy with radioactive decay in his arguments. Even the simplest parallel system has a specific lifespan distribution determined entirely by a stochastic nature of the aging process. In order to account for this stochasticity it was proposed to use a stochastic variance...

Gender And Parkinsonism

The available evidence indicates that men have a slightly higher risk of parkinson-ism than women, with the exception of drug-induced parkinsonism (59,60). According to a meta-analysis, relative risk of parkinsonism for men compared to women is 1.5 (61). Suggested reasons for this risk included differential exposure to external risk factors, an X-linked genetic factor, and mitochondrial dysfunction. The lifetime risk of parkinsonism is greater in men than in women (4.4 vs. 3.7 ) (32). In older patients, 65 to 84 years, the male to female incidence ratio was 1.66 for parkinsonism and 2.13 for PD (19). Interestingly, although women have a longer life expectancy than men, women with PD have the same mortality rates as men with PD (60). Although several studies have suggested that those with darker skin have a reduced risk of PD compared to lighter skin individuals (25,63), a review of 20 studies of PD in African-Americans found no consistent evidence to support this theory (64). The...

Measurements in Dysmorphology and Clinical Genetics

There is a tendency to neglect the observation and description of the adult patient with malformations, in specific syndromes or even isolated mental retardation. As a consequence, we have limited knowledge of physical changes in syndromes with dysmorphic features as related to the aging process. Study of the natural history of these relationships may lead to a better understanding of the underlying pathophysiology and natural history of the disorders.

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.

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...

Project Title Ace Inhibition In Single Ventriclepulmon Hypertension

The beneficial effect of ACE inhibition is expected to occur prior to and following volume unloading surgery with the bidirectional Glenn shunt or hemi-Fontan. The primary hypothesis of the study in congenital heart disease associated with pulmonary hypertension is that the effect of long-term treatment with an oral prostacyclin analogue or an oral endothelin receptor blocker has a salutory effect on exercise capacity, longevity, and quality of life. It will also be determined whether any of these patients carry a defect of the primary pulmonary hypertension-1 gene. Each of these studies could potentially lead to a significant improvement in prognosis in the single ventricle group by preventing a long-term deterioration in ventricular function and in the pulmonary hypertension patients by improving quality of life and survival without transplantation.

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...

General Health Benefits

Studies examining the benefits of sexual activity on physical health have suggested sexual activity improves physical and psychological health in a number of domains. Sexual activity (1) Increases longevity Men with increased orgasmic frequency (i.e., had sex at least two times per week) had a 50 lower risk of mortality at a 10-year follow-up (Davey Smith et al, 1997) (2) Lowers the risk of chronic disease (e.g., heart disease and cancer) Among men, frequency of sex was associated with a lower risk of fatal coronary heart disease (Ebrahim et al, 2002). Furthermore, a national survey of US men found high ejaculation frequency (i.e., > 21 ejaculations per month) was associated with decreased risk of total prostate cancer (Leitzmann et al,

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...

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).

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.

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,...

Racial Mortality Crossover Phenomenon

There is a notable exception to lower life expectancy for African Americans compared to whites 75 to 80 years of age. At this point, a convergence occurs whereby African Americans have more expected years remaining than whites (Wing, Manton, Stallard, Harnes, & Tyroler, 1985 Manton, 1980). We call this the racial mortality crossover phenomenon. There are also racial crossover patterns in death from heart disease and certain types of cancer (National Center for Health Statistics, 1980). The crossover phenomenon exists also for American Indians. There are 1.4 million American Indians and Alaska Natives who identify themselves as Indians. Life expectancy of American Indians and Alaska Natives was 50 in 1940 and approximately 70 in 1980. Once they reach their 55th birthday, however, they die at a slower rate than all other U.S. ethnic groups. Almost half of the Indian elderly living alone live in poverty (U.S. Department of Health and Human Services, 1990a). Among those 75 and older,...

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.

Telomeres and Cell Division

Certain types of cells can be removed from the body and grown in nutrient solutions (outside the body, or in vitro). Under these artificial conditions, the potential longevity of different cell lines can be studied. For unknown reasons, normal connective tissue cells (called fibroblasts) stop dividing in vitro after a certain number of population doublings. Cells from a newborn will divide 80 to 90 times, while those from a 70-year-old will stop after 20 to 30 divisions. The decreased ability to divide is thus an indicator of senescence (aging). Cells that become transformed into cancer, however, apparently do not age and continue dividing indefinitely in culture.

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.

Significance to humans

Young are occasionally removed from the nest and tamed by locals for their fly- and spider-catching abilities. Reported to live 25-30 years in captivity, but more commonly 15. There are no longevity records for wild birds. Hunting has been reported, but is not thought to constitute a threat due to the difficulty in finding the species and the abundance of more common game birds.

Description and Prediction in Cross Sectional and Longitudinal Studies

Our preference is to conceptualize treatment representations using the same framework as illness representations and adapting instruments such as the IPQ for assessment. A treatment would have an identity (e.g., label, how to use take it), time-lines (e.g., when and for how long to take), causal factors (e.g., works by removing, killing, neutralizing pathogenic material), control (e.g., cure and control of symptoms and objective indicators of disease), and consequences or costs (e.g., symptoms or side effects, physical damage, addiction, financial costs, etc.) and benefits (e.g., life extension, improved quality of life). Some of the factors assess the initiation of the treatment, others its expected and or experienced outcomes. Although the experiential base of representations is more readily specified for the treatment of ongoing, symptomatic conditions than for asymptomatic conditions or prevention, people may find or create symptoms to provide a match between a condition and an...

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

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

Conserved Nutrient Sensing Pathways As A Mediator Of Cr In Yeast

The dissociation of Sir2 from CR in yeast has profound implications for the likelihood that downstream molecular events associated with CR are conserved across evolutionarily divergent organisms. It seems certain that ERCs are a mechanism of aging private to yeast, as there is no evidence that ERCs accumulate with age or cause senescence in the cells of multicellular eukaryotes. CR, on the other hand, slows aging in nearly every organism studied. If CR is not regulating yeast longevity by altering ERC levels through up-regulation of Sir2, this raises the possibility that the downstream effectors of CR might also be conserved (Kaeberlein and Kennedy, 2005). At this point it remains unclear which of the downstream targets shared by these nutrient sensing pathways are ultimately responsible for enhanced longevity in response to CR. The Msn2 Msn4-mediated stress response can be ruled out as necessary for increased replicative life span, since deletion of both MSN2 and MSN4 fails to...

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...

Developing Highthroughput Methodologies For Lifespan Analysis

Until recently, discovery of genetic and environmental determinants of longevity in any organism has been driven largely by gene-specific studies based on prior knowledge or hypotheses. The development of new methods and technologies for moderate to high-throughput longevity phenotyping in yeast offers the promise of analyzing the replicative and chronological aging

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...

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...

Spiritual Needs Of Older Adults Versus Younger Adults

In the second half of life, persons experience role transformations, the loss of friends and loved ones, physical change and decline, and other inevitable outcomes of the aging process. These experiences often oblige older adults to reorder their priorities. This reordering is more likely to occur in the older years because by this time persons have grown cognitively and emotionally. This growth helps them think abstractly, tolerate ambiguity and paradox, experience emotional flexibility, and commit themselves to a value system that is bigger than the conventional one (Labouvie-Vief, DeVoe, & Bulka, 1989). All changes, particularly the losses, produce opportunities for the deepening and widening of spiritual integration in the second half of life.

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

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

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.

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 &

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).

Western Heads East a tangible example of what is possible

To date, this project has impacted the lives of over 150 people through intake of the yogurt. It has been awarded the 2006 AUCC Scotiabank Prize for Excellence in Internationalization, and has been funded by the Canada Corps. Cows have been purchased and processes are underway to ensure sustainability and longevity of the project. The long-term goal is to

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.

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.

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,...

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

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.

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,...

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...

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.

Zebrafish as a Model for Aging

Many species of fish have been used as an experimental model for aging (Woodhead 1978 Patnaik et al., 1994 Woodhead 1998) thus in addition to defining mechanisms of disease, zebrafish may be useful for exploring the process of aging. Recent studies have provided initial evidence that zebrafish have a median lifespan of approximately 36 to 42 months with a maximum lifespan of up to 66 months (Gerhard et al., 2002b), indicating that zebrafish undergo an age-related increase in mortality rate. More recently, a shorter median and maximum lifespan was reported for zebrafish, with 31 and 45 months, respectively (Herrera et al., 2004). The different results in these two studies may be a reflection of strain variation and differences in housing and environmental parameters. These findings, however, set the groundwork for identification of genes that control longevity. Aging zebrafish have been demonstrated to develop several phenotypes similar to aging mammals (Table 27.1), including the...

Zebrafish as Aging Models

Zebrafish (Danio rerio) are well recognized as a powerful model for genetic studies in developmental biology. The zebrafish system has also given insights into several human diseases such as neurodegenerative, hematopoietic and cardiovascular diseases and cancer. The aging process affects these and various other human disorders, and it is important to compare age-related disfunctions at the organismal levels among vertebrates. From the point of view in comparative and evolutionary biology of aging, the aging process of zebrafish remains largely unexplored, and little is known about functional aging and senescence, compared with higher vertebrates including mammals. In our recent studies to assess aging phenotypes in zebrafish, we identified several potential biomarkers of zebrafish aging. In aging zebrafish, we have detected senescence-associated fi-galactosidase activity in skin and oxidized protein accumulation in muscle. In contrast, our initial study showed that lipofuscin...

Senescenceassociated Sagalactosidase As An Enzymatic Aging Marker

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

Prospective Basic Studies of Aging and Senescence in Zebrafish

However, humans possess only a limited capacity to restore their missing or injured body parts. Therefore, stimulating regenerative capability may circumvent some tissue deterioration in aging humans. Adult zebrafish have been shown to possess a remarkable capacity for regeneration. Zebrafish regenerate almost all tissues and organs such as fins, spinal cord, retina, and heart. By dissecting molecular mechanisms of zebrafish regeneration, it may be possible to illuminate novel factors that can stimulate a regenerative response in higher vertebrates. Thus, research of regeneration in zebrafish during the aging process will contribute to aging medicine as well as to regenerative medicine in humans.

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).

Zebrafish Aging and Senescence Research for Drug Discovery and Geriatric Medicine

Many genetic or environmental manipulations that alter lifespan in model organisms also alter survival following acute stresses such as oxidative damage, genotoxic stress, and thermal stress. Thus, in flies and worms, mutations that enhance lifespan also increase resistance to oxidative stress. This is also true for most of the small number of mutations that increase lifespan in mice. In lower organisms, this coupling of stress responses and aging mechanisms has proved a useful tool in identifying new genes that affect the aging process without the need for performing lengthy lifespan analyses. Therefore, it is quite possible that this approach may also be applied to the identification of zebrafish aging mutants and pharmacological agents that slow the aging process or extend lifespan through enhanced resistance to oxygen radicals or other stresses. To facilitate high-throughput mutant and drug screens in zebrafish aging, we have developed SA- -gal-based colormetric and fluorometric...

The Significance of Race and Ethnicity for Health

For example, for the 15 leading causes of death in the USA, blacks have higher death rates than whites for nine causes including heart disease, stroke, flu pneumonia, septicemia, homicide, cancer, diabetes, kidney diseases, and hypertension (National Center for Health Statistics, 2009). Moreover, the white-black gap in life expectancy in the USA has widened over the past 25 years due to slower improvements in black health status compared to the overall population (Mensah et al, 2005). American Indians also have markedly poorer health than whites for a number of outcomes including infant mortality, diabetes and injury related mortality, activity limitation, and self-assessed fair poor health (National Center for Health Statistics, 2009). Although the health of US Hispanic and Asian immigrants, as reflected in overall mortality rates, tends to be comparable or better than that of whites, research suggests that their health In contrast, data from the Canadian National Population Health...

Prolong Life Or Forgo Lifesustaining Treatments

The confluence of the factors of greater life expectancy, causes of death precipitating longer periods of disability and dying, and removal of death and dying from the home and the care of families to institutions have produced an unprecedented need to rebuke the unbridled use of life-sustaining technologies. As ethical debate has arisen over the last three decades, two opposing approaches have been used to treat dying patients either to prolong life or allow patients to die by refusing life-sustaining treatments. A significant reason for the latter was a realization that treatment to prolong life was standard and virtually always utilized and that death was even considered to be the enemy of medicine. Of course, prior to this century, physicians had fewer therapies from which to choose in their efforts to prolong life. As more options became available and technologies, such as respirators and dialysis machines, became widespread, health care professionals, as well as patients and...

Aging and Replicative Senescence

Cellular or replicative senescence (in vitro) is often utilized as a model for the aging process (in vivo) due to the hypothesis that cellular aging recapitulates organismal aging (Wadhwa et al., 2005). The central dogma of repli-cative senescence holds that cultures of vertebrate fibroblasts have a limited capacity for proliferation. After a finite number of cell divisions, proliferation slows and culture arrest ensues. The barrier represented by culture arrest, termed the Hayflick Limit, is accompanied by a number of morphological changes including increased cell size, increased nuclear and nucleolar sizes, increased vacuolation of the cytoplasm and endo-plasmic reticulum, expression of senescence-associated markers such as beta-galactosidase, and other changes in morphology and gene expression (Cristafalo et al., 2004 and references therein).

The Chicken as a Paradigm for Aging Research

Organisms frequently used in aging studies include yeast, Drosophila, C. elegans, and M. musculus, the laboratory mouse. With all of these well-characterized models available, particularly a mammalian vertebrate as well-studied as the lab mouse, why use an avian model The advantages of using a vertebrate are obvious, and the mouse would at first glance appear to be a better choice than the chicken except for shortcomings of the mouse vis-a-vis the study of aging and oncogenesis. For example, mice have a very short lifespan. In contrast, maximum life expectancies of many species of birds approach the human life expectancy (Forsyth et al., 2002 Austad, 1997). Lifespan is significant, as cellular and genetic mechanisms governing cell proliferation are likely conserved in longer-lived species.

Surgical Treatment of Heart Failure in the Elderly501

Heart failure (HF) in elderly patients who may benefit from surgical therapy is usually secondary to ischemic or valvular heart disease. When referring such patients for surgery, life expectancy, along with the expectations of the patient and family with regard to the surgical treatment, must be considered. The goals of cardiac surgery in this patient population are to maintain or improve cardiac function, decrease HF episodes, reduce hospital admissions, and improve functional class. Safer surgical techniques developed during the last two decades have allowed high-risk patients well into their 80s to undergo complex cardiac operations with decreasing morbidity and mortality. Successful surgical intervention often leads to a more productive and independent life for elderly patients who have HF.

Avian Models Of Extremely Slow To Negligible Reproductive Aging

Patterns of reproductive aging vary even more widely among birds than among mammals studied to date. As predicted by evolutionary aging and life-history theory, the slower aging of birds relative to mammals is generally reflected in slower reproductive aging in birds of both sexes (for reviews, see Holmes et al., 2003 Holmes and Ottinger, 2003 2004). Bird species that mature and reproduce extremely slowly, including seabirds (e.g., albatrosses, terns, and gulls) and large raptors (e.g., condors), tend also to be among the longest-lived, with some species holding longevity records of 50 years or more. Long-lived animals with exceptionally slow reproductive aging likely have physiological or molecular mechanisms for prolonging fertility, and basic reproductive aging processes may differ significantly between long- and short-lived species (Finch, 1990 Austad, 1993 Martin et al., 1996 Austad and Holmes, 1999 vom Saal et al., 1994). With the exception of primates, however, few long-lived...

Transgenic Mini Rat Strain as a Tool for Studying Aging and Calorie Restriction

Mini rats, a transgenic strain of rats whose somatotropic axis was suppressed by overexpression of the antisense growth hormone gene, were shown to live longer than nontransgenic wild-type rats ( ), when heterozygous for the transgene (tg ) homozygous (tg tg) rats died slightly earlier due to neoplastic causes. As observed in (tg ) rats, moderate suppression of the somatotropic axis produced some phenotypes similar to those in ( ) rats subjected to calorie restriction (CR), a well-known experimental intervention favoring longevity in animals. Thus, comparative studies using (tg ) rats with the CR paradigm will help us understand the role of the somatotropic axis in regulation of lifespan and aging. Furthermore, the level of suppression of the somato-tropic axis in (tg ) rats was not as severe as in other mice models, and thus, experiments can be performed within physiological ranges. In the last decade, since Ames dwarf mice with spontaneous mutation of the prop-1 gene were reported...

Comparability To Human Agerelated Cognitive Decline

Finally, as discussed in more detail below, the absence of frank neural loss among aged rats with memory impairment has now been replicated in aged monkeys and humans. It should be emphasized that although parallels exist between behavioral deficits observed in the rat models of aging discussed here and both rodent experimentally induced brain lesions and human age-related disease, the models we employ are not intended to represent human neurodegenerative disease such as Alzheimer's or Parkinson's disease. Rather, we consider these naturally occurring rat models a tool for understanding the normal aging process in the absence of disease. Some have suggested that the cognitive decline seen in these rat models is akin to what is referred to as nonprogressive mild cognitive impairment in humans, although additional research on neuronal atrophy and other defining characteristics in both rats and humans are needed to support the use of this terminology (Gallagher et al., 2003).

Extension in the Dwarf

Dwarf mice are remarkably long-lived. Congenital deficiency of growth hormone (GH), prolactin, and thyroid-stimulating hormone (TSH) due to mutations at the Pit1 or Prop1 loci, as well as GH resistance due to targeted disruption of the GH receptor gene lead to major increase in both average and maximal lifespan. Prolonged longevity of Snell dwarf (Pit1dw), Ames dwarf (Prop1df), and GHRKO mice is associated with a major extension of ''health span'' and multiple symptoms of delayed aging. Suspected mechanisms of prolonged longevity of hypopituitary and GH resistant mice include reduced peripheral levels of IGF-1 and insulin, enhanced sensitivity to insulin actions, reduced generation of reactive oxygen species, enhanced anti-oxidant defenses and stress resistance, and delayed onset of fatal neoplastic and nonneoplastic disease. Although negative correlation of body size and longevity applies to genetically normal mice and to other species, it remains to be determined whether reduced GH...

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