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Despite the economic, medical and demographic importance of understanding the determinants of chronic disability and frailty in particular and morbidity compression in general, the experimental method and model (animal) systems have not been brought to bear on questions related to these areas. Thus the purpose of this paper is to 1) briefly review the basic concepts of disability and impairment as they relate to both humans and non-human animals. 2) present the results of a study of medflies in which individuals can be classified as healthy or unhealthy based on whether they exhibit “supine behavior,” and 3) introduce a general framework for research on morbidity that integrates experimental biology (manipulative experiments, model animals, hypothesis testing) into the current clinically based morbidity research paradigm on humans.

Fertility is not inversely correlated with longevity in social insects. This fact seems contrary to the norm in solitary model organisms, where experimental manipulations that result in longer life spans often act on reproductive pathways and reduce fertility. In social insects, however, reproduction is divided between two female phenotypes: the queens that are locked into a continuous oviposition mode, and the workers that express the remaining range of maternal functions, such as preparation of oviposition sites, nest defense, brood care, hygienic behaviors, and foraging. In the social honey bee, workers show a flexible aging pattern as they shift between behaviors that are associated with different aging rates. The behavioral repertoire of a honey bee worker is usually expressed in a sequence, so that tasks associated with rapid senescence follow tasks associated with slow or negligible senescence. However, when prompted by changes in colony demography, bees can respond with behavioral reversions and acquire physiological states associated with slower aging. This plasticity emerges in part through an interplay between a systemic hormone and a gene normally expressed exclusively by reproductive females. The genetic networks that control aging in sterile worker bees may have evolved through decoupling and subsequent remodeling of regulatory architectures that linked senescence and fertility in their solitary predecessor. The aging machinery of honey bees may, therefore, provide new knowledge about the structure, plasticity and evolvability of pathways that shape the course of aging and frailty.

In the work we have described here (Murphy et al. 2003), an unbiased micro-array analysis was used to identify transcriptional targets of the DAF-2/DAF-16 pathway, and the identified genes were tested for their individual contributions to longevity. Because we applied an unbiased method of gene expression profiling of a combination of multiple mutant alleles as well as a time course of RNAi treatment, resulting in data from over 70 arrays, we were able to significantly reduce the number of false positives. We found not only the very few previously identified DAF-16 targets but also many novel targets, and the previously described DBE and a new motif were overrepresented in the promoters of the genes. The diversity of the core set of downstream targets suggests that the coordination of expression through DAF-16 is critical in the regulation of longevity.

DAF-16, a FOXO-family transcription factor, influences the rate of aging of in response to insulin/IGF-1 signaling. Using DNA microarray analysis, we found that DAF-16 affects the expression of a set of genes during early adulthood, the time at which this pathway is known to influence aging, and we have shown that many of these genes influence the aging process (Murphy et al. 2003). We also identified a DNA motif, in addition to the canonical DAF-16 motif, that is overrepresented in the promoters of the DAF-16-regulated genes. The insulin/IGF-1 pathway functions cell non-autonomously to regulate life span, and our findings suggest that it signals other cells, at least in part, by feedback regulation of two insulin/IGF-1 homologs.

Our findings suggest that the insulin/IGF-1 pathway ultimately exerts its effect on life span by up-regulating a wide variety of genes, including cellular stress response and anti-microbial genes, fat and steroid hormone synthesis genes, and many genes of unknown function, and by down-regulating specific life-shortening genes. Because the genes seem to act in a cumulative manner to affect life span, this study demonstrates the power of functional microarray analysis for dissecting complex regulatory systems.

has proven to be an excellent model system for the study of aging. In addition to its general utility in genetic approaches (Brenner 1974), the worm also displays distinct phenotypes of aging during its short life span, allowing researchers to study long-and short-lived mutants (Johnson 1990; Kenyon et al. 1993; Linet al. 1997; Lakowski and Hekimi 1996; Ewbank et al. 1997; Dillin et al. 2002a) as well as treatments that affect longevity (Lakowski and Hekimi 1998; Melov 2002). Two recent studies (Herndon et al. 2002; Garigan et al. 2002) carefully described the stochastic progression of aging in worms, which is marked by general tissue deterioration and reduction of motility. Age-related changes include sarcopenia, distortion of the cuticle, collapse and bacterial packing of the pharynx, distortion of gonadal nuclei, and the accumulation of fat in droplets in the head (Herndon et al. 2002; Garigan et al. 2002). Many of these phenotypes are reminiscent of human aging, and the fact that the genetic pathways known to affect life span in worms are highly conserved (Kenyon 2001; Guarente and Kenyon 2000) suggests that what we glean through studies of aging will shed light on the mechanisms of aging regulation in humans.

Among the genetic mechanisms known to affect aging in , the DAF-2/Insulin-IGF-like receptor (IIR) pathway (Kenyon et al. 1993) has perhaps the most dramatic effects and is one of the best studied. mutants are not only long-lived, with a life span of two to three times that of wild type worms, but the mutants are also extremely healthy and active much later than wild type (Kenyon et al. 1993). Many of the components of this signaling pathway have been cloned and characterized and include a P13-kinase (; Morris et al. 1996), a PTEN phosphatase (; Ogg and Ruvkun 1998), and additional kinases (, and ; Paradis et al. 1999; Paradis and Ruvkun 1998; Hertwick et al. 2004). The activation of DAF-2/IIR activates this kinase cascade, culminating in the phosphorylation and nuclear exclusion of the DAF-16/FOXO transcription factor (Lin et al. 1997; Ogg et al. 1997; Lee et al. 2001). The activity of DAF-16/FOXO is required for all of the known phenotypes of mutants, including its extended longevity (Kenyon et al. 1993). However, the downstream targets of this transcription factor were largely unknown before the work we will describe here. Additionally, the only mechanism that had been hypothesized to function downstream of DAF-16/FOXO to extend life span involved the mediation of reactive oxygen species (Honda and Honda 1999). This paper will describe the work that we have done to discover these genes and test their roles in longevity. (For additional details and supplementary data, please see Murphy et al. 2003.)

Dietary caloric restriction (CR) is the only intervention repeatedly demonstrated to retard the onset and incidence of age-related diseases, maintain function, and extend both life span and health span in mammals. In 70 years of study, such beneficial effects have been demonstrated in rodents and lower animals but, prior to 1987, had never been examined in primates. To determine whether CR might eventually be applied to humans, the NIA initiated a study of CR and aging in nonhuman primates. After nearly 18 years, male and female rhesus monkeys () of different ages have been involved in the study, including many old monkeys begun on CR (> 15 yrs). Systematic CR studies of older individuals from long-lived species have not been conducted to date. Control monkeys receive two meals per day, sufficient to attain apparent satiety, whereas the CR group receives 30% less, adjusted for age and body weight. The diet is supplemented with extra micronutrients such that the only substantive variable is the amount of calories consumed. Based on results observed to date, rhesus monkeys exhibit many CR-associated beneficial effects that resemble those observed in CR rodents, such as decreased fat, improved glucoregulatory function, and decreased risk factors for cardiovascular disease and diabetes. Results produced thus far demonstrate that older monkeys can respond to a 30% CR in a manner similar to young animals. For some variables, such as loss of fat, older monkeys do not respond as well. For other variables, such as increased production of melatonin, older monkeys respond more robustly than do young monkeys. Current analyses do not indicate any beneficial or detrimental effects of this nutritional regimen on rates of mortality and morbidity among older monkeys. For selected variables, such as bone density, further analyses will be needed to assess whether CR will have detrimental effects on aging. Additional assessment of the patterns of individual aging among the older cohorts of monkeys will also permit characterization of frailty and factors that predispose monkeys to frailty.

In the work we have described here (Murphy et al. 2003), an unbiased micro-array analysis was used to identify transcriptional targets of the DAF-2/DAF-16 pathway, and the identified genes were tested for their individual contributions to longevity. Because we applied an unbiased method of gene expression profiling of a combination of multiple mutant alleles as well as a time course of RNAi treatment, resulting in data from over 70 arrays, we were able to significantly reduce the number of false positives. We found not only the very few previously identified DAF-16 targets but also many novel targets, and the previously described DBE and a new motif were overrepresented in the promoters of the genes. The diversity of the core set of downstream targets suggests that the coordination of expression through DAF-16 is critical in the regulation of longevity.

DAF-16, a FOXO-family transcription factor, influences the rate of aging of in response to insulin/IGF-1 signaling. Using DNA microarray analysis, we found that DAF-16 affects the expression of a set of genes during early adulthood, the time at which this pathway is known to influence aging, and we have shown that many of these genes influence the aging process (Murphy et al. 2003). We also identified a DNA motif, in addition to the canonical DAF-16 motif, that is overrepresented in the promoters of the DAF-16-regulated genes. The insulin/IGF-1 pathway functions cell non-autonomously to regulate life span, and our findings suggest that it signals other cells, at least in part, by feedback regulation of two insulin/IGF-1 homologs.

Our findings suggest that the insulin/IGF-1 pathway ultimately exerts its effect on life span by up-regulating a wide variety of genes, including cellular stress response and anti-microbial genes, fat and steroid hormone synthesis genes, and many genes of unknown function, and by down-regulating specific life-shortening genes. Because the genes seem to act in a cumulative manner to affect life span, this study demonstrates the power of functional microarray analysis for dissecting complex regulatory systems.

has proven to be an excellent model system for the study of aging. In addition to its general utility in genetic approaches (Brenner 1974), the worm also displays distinct phenotypes of aging during its short life span, allowing researchers to study long-and short-lived mutants (Johnson 1990; Kenyon et al. 1993; Linet al. 1997; Lakowski and Hekimi 1996; Ewbank et al. 1997; Dillin et al. 2002a) as well as treatments that affect longevity (Lakowski and Hekimi 1998; Melov 2002). Two recent studies (Herndon et al. 2002; Garigan et al. 2002) carefully described the stochastic progression of aging in worms, which is marked by general tissue deterioration and reduction of motility. Age-related changes include sarcopenia, distortion of the cuticle, collapse and bacterial packing of the pharynx, distortion of gonadal nuclei, and the accumulation of fat in droplets in the head (Herndon et al. 2002; Garigan et al. 2002). Many of these phenotypes are reminiscent of human aging, and the fact that the genetic pathways known to affect life span in worms are highly conserved (Kenyon 2001; Guarente and Kenyon 2000) suggests that what we glean through studies of aging will shed light on the mechanisms of aging regulation in humans.

Among the genetic mechanisms known to affect aging in , the DAF-2/Insulin-IGF-like receptor (IIR) pathway (Kenyon et al. 1993) has perhaps the most dramatic effects and is one of the best studied. mutants are not only long-lived, with a life span of two to three times that of wild type worms, but the mutants are also extremely healthy and active much later than wild type (Kenyon et al. 1993). Many of the components of this signaling pathway have been cloned and characterized and include a P13-kinase (; Morris et al. 1996), a PTEN phosphatase (; Ogg and Ruvkun 1998), and additional kinases (, and ; Paradis et al. 1999; Paradis and Ruvkun 1998; Hertwick et al. 2004). The activation of DAF-2/IIR activates this kinase cascade, culminating in the phosphorylation and nuclear exclusion of the DAF-16/FOXO transcription factor (Lin et al. 1997; Ogg et al. 1997; Lee et al. 2001). The activity of DAF-16/FOXO is required for all of the known phenotypes of mutants, including its extended longevity (Kenyon et al. 1993). However, the downstream targets of this transcription factor were largely unknown before the work we will describe here. Additionally, the only mechanism that had been hypothesized to function downstream of DAF-16/FOXO to extend life span involved the mediation of reactive oxygen species (Honda and Honda 1999). This paper will describe the work that we have done to discover these genes and test their roles in longevity. (For additional details and supplementary data, please see Murphy et al. 2003.)

When peak performance is unnecessary, Dynamic Voltage Scaling (DVS) can be used to reduce the dynamic power consumption of embedded multiprocessors. In future technologies, however, static power consumption is expected to increase significantly. Then it will be more effective to limit the number of employed processors, and use a combination of DVS and processor shutdown. Scheduling heuristics are presented that determine the best trade-off between these three techniques: DVS, processor shutdown, and finding the optimal number of processors. Experimental results show that our approach reduces the total energy consumption by up to 25% for tight deadlines and by up to 57% for loose deadlines compared to DVS. We also compare the energy consumed by our scheduling algorithm to two lower bounds, and show that our best approach leaves little room for improvement.

Fertility is not inversely correlated with longevity in social insects. This fact seems contrary to the norm in solitary model organisms, where experimental manipulations that result in longer life spans often act on reproductive pathways and reduce fertility. In social insects, however, reproduction is divided between two female phenotypes: the queens that are locked into a continuous oviposition mode, and the workers that express the remaining range of maternal functions, such as preparation of oviposition sites, nest defense, brood care, hygienic behaviors, and foraging. In the social honey bee, workers show a flexible aging pattern as they shift between behaviors that are associated with different aging rates. The behavioral repertoire of a honey bee worker is usually expressed in a sequence, so that tasks associated with rapid senescence follow tasks associated with slow or negligible senescence. However, when prompted by changes in colony demography, bees can respond with behavioral reversions and acquire physiological states associated with slower aging. This plasticity emerges in part through an interplay between a systemic hormone and a gene normally expressed exclusively by reproductive females. The genetic networks that control aging in sterile worker bees may have evolved through decoupling and subsequent remodeling of regulatory architectures that linked senescence and fertility in their solitary predecessor. The aging machinery of honey bees may, therefore, provide new knowledge about the structure, plasticity and evolvability of pathways that shape the course of aging and frailty.

In the work we have described here (Murphy et al. 2003), an unbiased micro-array analysis was used to identify transcriptional targets of the DAF-2/DAF-16 pathway, and the identified genes were tested for their individual contributions to longevity. Because we applied an unbiased method of gene expression profiling of a combination of multiple mutant alleles as well as a time course of RNAi treatment, resulting in data from over 70 arrays, we were able to significantly reduce the number of false positives. We found not only the very few previously identified DAF-16 targets but also many novel targets, and the previously described DBE and a new motif were overrepresented in the promoters of the genes. The diversity of the core set of downstream targets suggests that the coordination of expression through DAF-16 is critical in the regulation of longevity.

DAF-16, a FOXO-family transcription factor, influences the rate of aging of in response to insulin/IGF-1 signaling. Using DNA microarray analysis, we found that DAF-16 affects the expression of a set of genes during early adulthood, the time at which this pathway is known to influence aging, and we have shown that many of these genes influence the aging process (Murphy et al. 2003). We also identified a DNA motif, in addition to the canonical DAF-16 motif, that is overrepresented in the promoters of the DAF-16-regulated genes. The insulin/IGF-1 pathway functions cell non-autonomously to regulate life span, and our findings suggest that it signals other cells, at least in part, by feedback regulation of two insulin/IGF-1 homologs.

Our findings suggest that the insulin/IGF-1 pathway ultimately exerts its effect on life span by up-regulating a wide variety of genes, including cellular stress response and anti-microbial genes, fat and steroid hormone synthesis genes, and many genes of unknown function, and by down-regulating specific life-shortening genes. Because the genes seem to act in a cumulative manner to affect life span, this study demonstrates the power of functional microarray analysis for dissecting complex regulatory systems.

has proven to be an excellent model system for the study of aging. In addition to its general utility in genetic approaches (Brenner 1974), the worm also displays distinct phenotypes of aging during its short life span, allowing researchers to study long-and short-lived mutants (Johnson 1990; Kenyon et al. 1993; Linet al. 1997; Lakowski and Hekimi 1996; Ewbank et al. 1997; Dillin et al. 2002a) as well as treatments that affect longevity (Lakowski and Hekimi 1998; Melov 2002). Two recent studies (Herndon et al. 2002; Garigan et al. 2002) carefully described the stochastic progression of aging in worms, which is marked by general tissue deterioration and reduction of motility. Age-related changes include sarcopenia, distortion of the cuticle, collapse and bacterial packing of the pharynx, distortion of gonadal nuclei, and the accumulation of fat in droplets in the head (Herndon et al. 2002; Garigan et al. 2002). Many of these phenotypes are reminiscent of human aging, and the fact that the genetic pathways known to affect life span in worms are highly conserved (Kenyon 2001; Guarente and Kenyon 2000) suggests that what we glean through studies of aging will shed light on the mechanisms of aging regulation in humans.

Among the genetic mechanisms known to affect aging in , the DAF-2/Insulin-IGF-like receptor (IIR) pathway (Kenyon et al. 1993) has perhaps the most dramatic effects and is one of the best studied. mutants are not only long-lived, with a life span of two to three times that of wild type worms, but the mutants are also extremely healthy and active much later than wild type (Kenyon et al. 1993). Many of the components of this signaling pathway have been cloned and characterized and include a P13-kinase (; Morris et al. 1996), a PTEN phosphatase (; Ogg and Ruvkun 1998), and additional kinases (, and ; Paradis et al. 1999; Paradis and Ruvkun 1998; Hertwick et al. 2004). The activation of DAF-2/IIR activates this kinase cascade, culminating in the phosphorylation and nuclear exclusion of the DAF-16/FOXO transcription factor (Lin et al. 1997; Ogg et al. 1997; Lee et al. 2001). The activity of DAF-16/FOXO is required for all of the known phenotypes of mutants, including its extended longevity (Kenyon et al. 1993). However, the downstream targets of this transcription factor were largely unknown before the work we will describe here. Additionally, the only mechanism that had been hypothesized to function downstream of DAF-16/FOXO to extend life span involved the mediation of reactive oxygen species (Honda and Honda 1999). This paper will describe the work that we have done to discover these genes and test their roles in longevity. (For additional details and supplementary data, please see Murphy et al. 2003.)

Adult life expectancy has progressively increased over the past 150 years, equivalent to one year added per four years of historical time in high life-expectancy populations. This amazing decline of mortality at all adult ages is attributed to environmental and technological advances. Explanations of the decline in longter mortality typically are seated in terms of period or historical factors, to the neglect of cohort or life cycle factors. From associations between the early and later age mortality for birth cohorts, we argue that historical reduction in lifetime exposure to infectious diseases and other sources of inflammation is a major cause of the decline in old age mortality.

Frailty, the loss of physiologic organ reserve with age, and chronic illness, which may accelerate the development of frailty in one or more than one body system, become the dominant determinants of ill-health in those who escape the hazards of early and mid-life. The Compression of Morbidity paradigm holds that if the average age at first infirmity, disability, or other morbidity is postponed, and if this postponement is greater than increases in life expectancy, then average cumulative lifetime morbidity will decrease, squeezed between a later onset and the time of death. The National Long-Term Care Survey, the National Health Interview Survey, and other data from the United States and some other developed countries now document declining disability trends beginning around 1982 and accelerating more recently. The decline in disability is about 2% per year, contrasted with a decline in mortality rates of about 1% a year, documenting compression of morbidity in the United States at the population level. Longitudinal studies now link good health risk status with long-term reductions in cumulative lifetime disability; those with few behavioral health risks have only one-fourth the disability of those who have more risk factors, and the onset of disability in those with good health habits is postponed from 7 to 12 years, far more than any increases in longevity. Randomized controlled trials of health enhancement programs in senior populations have shown a reduction in health risks, improved health status, and decreased medical care utilization. Health policy initiatives now being undertaken have the promise of increasing and consolidating health gains for seniors under the umbrella paradigm of the Compression of Morbidity.