James R Carey, Ph.D. - US grants

The broad goal of this proposed project is to address questions about the nature of morbidity and mortality and their interrelationships using a large scale medfly model system. The proposed project will help frame basic questions about the dynamics of mortality, will serve as a model experimental system around which research on aging and mortality for other non-humans can be patterned and will contribute to knowledge of the biology of mortality and morbidity by gathering, analyzing and publishing data using large fruit fly cohorts raised under controlled conditions. There are four specific aims of prime interest to this program project on oldest-old mortality. 1. To determine the relationship between the age-specific schedules of mortality and morbidity in a minimum of once million medflies of both sexes. This relationship will be examined using both optimal and suboptimal environmental conditions to produce both high and low mortality rates. These results will test the hypothesis that morbidity rates decrease with increases in life expectancy and will provide the first detailed set of biological data on morbidity incidence and prevalence rates in a nonhuman species. 2. To measures and analyze age-specific mortality and reproductive traits of subsamples in the surviving 0.1% of both sexes starting with cohorts totaling 100 million medflies. This will provide a test of the hypotheses that mortality rates of medflies at the most advance ages remain low and that oldest old flies retain reproductive capabilities using a base population two orders of magnitude larger than previously examined. 3. To determine morbidity and mortality sex differentials over the life course of medflies. Specific questions include whether the gender gap increases or decreases with increasing life expectancies in medfly cohorts and whether the prevalence of morbidity is the same between males and females at low and high life expectancies. 4. To assess sex- and age-specific mortality rates in large cohorts (1 million flies) of two tephritid fruit fly species related to the medfly-- the Mexican fruit fly, Anastrepha ludens and the West Indian fruit fly, A. obliqua. Both species are mass-reared at the medfly rearing facility in Tapachula, Mexico and thus readily available in large numbers. The results of these trials will test hypothesis that slowing of mortality rates at advance ages is not unique to the medfly of Drosophila.

We investigate mortality of the oldest-old by means of nonparametric hazard function estimation based on smoothing techniques for lifetables. Two- dimensional smoothing methods for Lexis diagrams will be developed allowing to predict the survival of demographic cohorts, employing kernel and locally weighted least squares smoothers. Male-female comparisons and changes in the level of mortality will be investigated with change-point techniques. Stochastic process models for samples of lifetables and associated inference will be introduced. It is planned to analyze various biological and demographic data sets with these methods, in particular a huge set of data on the survival of medflies. In this interdisciplinary project, newly developed nonparametric statistical techniques will be applied to approach a complex of biological and demographic qu estions about longevity and mortality of the oldest segment of the population. These questions focus on whether mortality is decreasing for the oldest segment or is invariably increasing with age, how sex differences affect changes in mortality, and to what degree one can predict future mortality and life expectation from current trends. The importance of these problems derives from their potential impact on social planning for the future as well as on the biology of aging. Attacking these problems requires the development of new statistical methods and the innovative application of existing statistical methods to analyze current biological experiments and demographic data

reproduction; animal mortality; longitudinal animal study; diet; fertility; longevity; animal old age; Drosophilidae; dietary restriction; physiology; mathematical model; statistics /biometry; species difference; animal population genetics; biological models; mother /embryo /fetus nutrition; nutrition of aging; gender difference; female; nutrition related tag;

Abstract: DESCRIPTION: (adapted from the application): Although humans live some of the absolute longest documented lives of any mammal, they are not unique in having unusually long lives for body size. Humans, as primates, are heirs to long relative life spans (life span exceeding that predicted by body size) and only when human life spans reach 85-100 years do they significantly exceed primate expectations. To understand the evolution of relatively long lives in humans they must be situated in a more general framework of species potentias for prolonged life span. Interspecific comparisons provide a method for observing historical processes influencing life span over an evolutionary time scale. This project has 3 specific aims of database development and descriptive analyses. First, develop a taxonomically broad database including maximum reported life spans, and life history and socioecological characteristics of species. This database also will allow description of the distribution of variability in patterns of life span across broad phylogenetic groups. Second, conduct phylogenetically, sensitive correlational analyses of sociological and ecological characteristics associated with prolonged relative life spans vertebrates. Analyses of the associations of socio-ecological characteristics with relatively long life spans while controlling for phylogenetic relatedness will provide an evolutionary context in which to model the evolution of longevity in Homo sapiens. The size and breadth of the database will facilitate identification of socioecological correlations with relatively small effect sizes. Results using_the broadly available "maximum reported life span" will be compared with results from sub samples of species for which life table quality data is available. Third, place the evolution of prolonged human life span in the context of other species exhibiting prolonged relative life spans. Specifically, estimate the extent to which longevity is "unusually prolonged" relative to phlogenetic relatives (hominids; primates; mammals; homeothermic vertebrates) and determine the extent to which the social and ecological correlates of longevity in other taxa are replicated or differ in the evolution of human longevity.

DESCRIPTION (provided by applicant): This program will bring experimental techniques, biological systems, demographic concepts, statistical methods, and theoretical models to bear on questions concerning the determinants of life span in both humans and in non-human model systems including both vertebrates (comparative demography of mammals; birds) and invertebrates (fruit flies; nematodes; honey bees). The five research projects that form the program are organized around the following crosscutting themes: (1) Life span is adaptive and shaped by nature; (2) Individuals age in the wild; (3) Sociality and life span are mutually affecting; and (4) Superarching principles provide all embracing order to variation in animal life spans. The program will generate new large-scale demographic databases for the honey bee, wild medflies, and C. elegans and life history data from the literature on several dozen vertebrate species, introduce new statistical models for analysis of demographic data on model species, develop a novel methodology for studying aging in the wild, develop more fully the mathematical foundations of biodemography, generate new models and theories concerned with the role of intergenerational transfer and sociality in the evolution of life span, explore questions concerned with the effects of stochastic environments on the evolution life span and hazard rates, and use comparative demography to identify general principles concerning life span evolution.

Abstract Not Provided.

Project 3: Determinants of Exceptional Longevity in Tephritid Fruit Flies This project will examine the determinants of exceptional longevity using both the medfly and the Mexican fruit fly (Mexfly) in evolutionary, nutritional and behavioral contexts. The addition of the Mexfly to the biodemography experimental system is necessary because of the recent decision by Mexico and the U.S. to discontinue rearing adult medflies at the Tapachula laboratory where all previous research has been conducted. The project will involve seven scientists including Project Leader James Carey, co-PLs Lawrence Harshman (Nebraska), Hans Mtiller (UC Davis), Jane-Ling Wang (UC Davis) and collaborators Drs. Pablo Liedo (Mexico), Byron Katsoyannos (Greece) and Nikos Papadopoulos (Greece). The project has four specific aims. Aim 1 is framed around the concept of 'evolutionary biodemography' where we propose to develop sets of eco-gerontological rules that relate evolved life span to the selection environment. We will use medfly 'races' collected from different regions of the world to test the hypothesis that natural selection favors reduced longevity in tropical environments and exceptional longevity in desert and/or Mediterranean climates. Aim 2 involves gathering baseline biodemographic and behavioral data on the Mexican fruit fly (Mexfly)--a species that is exceptionally long-lived. Aim 3 will involve questions concerned with the biodemography of dietary manipulation where we will use the Mexfly model system for gathering data in one of the largest and most comprehensive biodemographic studies ever conducted on the effects of nutrition on mortality, longevity and female reproduction. Aim 4 is concerned with behavioral biodemography--the study of the age-specific patterns of behaviors that both impact and, in turn, are impacted by aging. This aim will lay the groundwork for the development of model systems concerned with morbidity dynamics--an extremely important but poorly understood aspect of aging research on the biology and demography of individuals who have attained exceptional ages.

Abstract Not Provided.

Active Follow-up; Ankle; Apoplexy; Area; Articular Range of Motion; Brain; CRISP; Cell Communication and Signaling; Cell Signaling; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Computer Retrieval of Information on Scientific Projects Database; Computers; Count; Data; Encephalon; Encephalons; FLR; Failure (biologic function); Floor; Foot; Funding; Gait; Grant; Imagery; Institution; Intracellular Communication and Signaling; Investigators; Joint Range of Motion; Magnetic Resonance; Measurement; Measures; Motion; Movement; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Parietal Lobe; Parietal Lobe of the Brain; Patient Self-Report; Pes; Phase; Range of Motion, Articular; Range of motion exercise; Rate; Regio tarsalis; Research; Research Personnel; Research Resources; Researchers; Resources; Self-Report; Signal Transduction; Signal Transduction Systems; Signaling; Source; Standards; Standards of Weights and Measures; Stroke; Tarsal Bone; Tarsus; Testing; Time; Toes; Training; United States National Institutes of Health; Vascular Accident, Brain; Visual; Visualization; Walking; biological signal transduction; body movement; brain attack; cerebral vascular accident; failure; follow-up; foot; improved; indexing; parietal cortex; range of motion; stroke

[unreadable] DESCRIPTION (provided by applicant): The broad objective is to improve ambulation in subjects with stroke through telerehabilitation training in the subject's own home. Stroke can destroy walking ability. Usually, rehabilitation is offered intensively in the acute stage following stroke and then is curtailed or eliminated entirely. But the acute stage of stroke may not be the optimum time for intensive training. An alternative after initial training in the clinic is to train subjects in their own home using telerehabilitation technology. Also, traditional rehabilitation emphasizes much repetition of simple movements but studies now suggest that simple movement may not be the best stimulus to promote the neural changes leading to recovery. Instead, movements that require skillful learning with cognitive processing produce richer neural changes. So, the PIs' aim is to use the advantage of telerehabilitation in comparing the effectiveness of two different training strategies: tracking training, emphasizing accurate movements, versus movement training, involving simple movements. A total of 20 subjects with stroke will be randomly assigned to either the Track group or Move group. Both groups will be issued ankle electrogoniometers, a computer, web camera, and cell phone to be used at home. Both groups will be directed by the computer to perform 30 blocks of 3 trials of ankle training each day for 20 days (4 weeks). For the Track group, the computer screen will show target waveforms for the subject to track as accurately as possible with a displayed cursor that responds to ankle dorsiflexion/plantarflexion movements. For the Move group, no target or response line will be shown; subjects will merely produce simple ankle movements that will be recorded by the computer but not seen on the screen so that there is no cognitive processing. Visual and audio teleconferencing between subjects and a therapist will occur every other day to keep the subjects motivated. Pretests and posttests will measure 1) ankle range of motion, 2) ankle tracking during fMRI, 3) knee tracking (not during fMRI), 4) Berg Balance performance, and 5) gait parameters with infrared cameras. The PIs hypothesize that the Track group will show greater improvements in behavioral measures and greater changes in brain reorganization on fMRI than the Move group. The relevance of this work is that it may demonstrate an innovative training method that not only carries cost and convenience advantages but also the scientific advantage of intensifying treatment at a more optimal time. [unreadable] [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Paralysis following stroke stems not only from the loss of neurons killed by the stroke but also from the loss of neurons lying dormant in the stroke hemisphere. One of the reasons viable neurons become dormant (down-regulated) is because of excessive interhemispheric inhibition imposed on them from the nonstroke hemisphere. The challenge in neurorehabilitation is to restore excitability and voluntary control of these down-regulated neurons in the stroke hemisphere. Suppression of the source of this excessive interhemispheric inhibition can be achieved with the noninvasive method called repetitive transcranial magnetic stimulation (rTMS). It has been shown in healthy subjects that the known depressant effects of low-frequency rTMS can be increased and prolonged by preceding it with 6-Hz priming stimulation. In a recent safety study, we showed that one treatment of 6-Hz primed low-frequency rTMS applied to the nonstroke hemisphere is safe. It is now important to evaluate a series of these treatments and whether their efficacy can be enhanced by combining the rTMS with motor learning training. The specific aims of this study are to determine the efficacy, mechanism, and safety of a series of 5 treatments of 6-Hz primed low- frequency rTMS applied to nonstroke hemisphere and combined with motor learning training to promote recovery of the paretic hand. Forty subjects with stroke will be randomly assigned to one of four treatment groups. The rTMS/only group will receive 20 min. of rTMS per day. The Track/only group will receive 20 min. of finger tracking training per day. The rTMS/combined group will receive alternating days of the rTMS and Track treatments. The rTMS/sham group will receive 20 min. of rTMS using a sham electrode each day. The hypotheses are: 1) the rTMS/combined group will show the greatest improvements in hand function, 2) the rTMS/combined group will show the greatest improvements in cortical excitability using paired-pulse TMS testing and in brain reorganization using fMRI, and 3) the rTMS treatment will be safe. The proposed research is important because it addresses the greatest cause of long-term disability in society, hemiparesis following stroke, and it is innovative because it applies a technique never used before, 6-Hz primed low-frequency rTMS combined with motor learning training. The potential impact of this research is a radical change to rehabilitation that accomplishes a higher quality of life in stroke. [unreadable] [unreadable] [unreadable]

We propose to develop a novel and far-reaching field program that is initially concerned with aging and life span of Mediterranean fruit flies (medflies) in field populations in Greece and will later expand to include nematode worms. This will be the first research program concerned with aging in the field to use a laboratory model system for which a massive amount of baseline demographic data is available. The methodological concept for the program involves development of a new method for assessing the demographic characteristics of field populations that we refer to as the 'captive cohort method' and which relies on the information content of live-captured flies; that the post-capture patterns of reproduction and death will provide information about the age at capture and previous experience in the field. The approach will involve: (i) building upon the experimental and statistical methods developed in the highly successful program on the biodemography of the medfly; (ii)developing new statistical tools that can be brought to bear on the life history data collected on wild-caught medflies; and (iii)gathering baseline biodemographic information on the nematode, Caenorhabditis elegans, that will be used subsequently for expanding the system to include this well-studied invertebrate. We plan to use the approach to test hypotheses concerning the nature of aging, life span, gender differences, and feeding status of field populations. Our studies will provide insights into aging in the Wild that are impossible to obtain using any of the standard approaches in ecology for analyzing field mortality and aging including the use of mark-recapture techniques, individual tracking (e.g. radio collars), techniques for estimating an animal's age, and field cages. All of these conventional techniques have serious limitations regarding their ability to detect nuances in mortality and aging and/or to estimate age in older individuals. The proposed methods and the new assay technique will have broad applications and will thus provide opportunities for research on systems that heretofore were not amenable to field research on aging, particularly for studying aging in invertebrate populations.

Apoplexy; CRISP; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Investigators; Movement; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurologic; Neurological; Research; Research Personnel; Research Resources; Researchers; Resources; Source; Stroke; United States National Institutes of Health; Vascular Accident, Brain; body movement; brain attack; cerebral vascular accident; stroke

Address; Animals; Apoplexy; Area; Brain; CRISP; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Complex; Computer Retrieval of Information on Scientific Projects Database; Deterioration; Digit; Digit structure; Distal; Elbow; Encephalon; Encephalons; Fingers; Forearm; Forelimb; Funding; Grant; Hand; Impairment; In element; Indium; Individual; Institution; Investigators; Learning; Lesion; Maps; Motor Cortex; Movement; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neurologic; Neurological; Performance; Physical Health Services / Rehabilitation; Rehabilitation; Rehabilitation Research; Rehabilitation therapy; Rehabilitation, Medical; Research; Research Personnel; Research Resources; Researchers; Resources; Retrieval; Saimiri; Saimirus; Source; Squirrel Monkey; Stroke; Training; United States National Institutes of Health; Vascular Accident, Brain; Wrist; base; body movement; brain attack; cerebral vascular accident; function improvement; functional improvement; locomotor learning; motor learning; rehabilitative; skill acquisition; skills; stroke

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this proposal is to build upon the current knowledge of rehabilitation and neuroimaging by examining for the first time the relationship between cardiorespiratory fitness and brain activity in traumatically brain injured (TBI) human subjects. The primary objectives of this study are to identify differences in the cortical activity of TBI subjects compared to normal control subjects during a working memory task and to ascertain the effect of participating in a 12 week aerobic exercise program on that cortical activity. There is both theoretical and practical significance for conducting this study. On a theoretical level, this study will integrate exercise science and neuroscience to enhance the understanding of the distant effects of cardiorespiratory fitness beyond the commonly acknowledged physiological effects. From a practical and therapeutic perspective, knowing whether the benefits of aerobic exercise already seen within well and impaired animals and healthy human populations applies to brain-injured adults may eventually lead to the clinical use of aerobic training programs as efficacious adjuncts to cognitive rehabilitation following TBI.

DESCRIPTION (provided by applicant): Our application addresses broad Challenge Area (04): Clinical Research and specific Challenge Topic, 04- HD-102: Development of Pediatric Medical Devices. The severity of hemiplegia due to damage in the brain in both the pediatric and adult populations stems not only from the loss of neurons killed by the vascular insult but also from the loss of function in viable but dormant neurons in the affected hemisphere. The latter problem may be avoidable and, to a certain extent, correctable. The down-regulated excitability in these neurons results from compensatory overuse of cortical motor neurons in the non-stroke hemisphere, which 1) suppresses motor neurons in the stroke hemisphere through inhibitory transcallosal projections, and 2) competes with and suppresses the functional maturation of corticospinal projections from the stroke hemisphere through its ipsilateral projections to the paretic hand. The strategy in rehabilitating pediatric hemiplegia is to overcome this "developmental disuse". Therefore, in pediatrics, where there may be greater potential for neuroplasticity, the challenge is to restore excitability and voluntary control of these down- regulated neurons. Disruption of the excitability in the non-stroke hemisphere, with resultant increased excitability (disinhibition) in the stroke hemisphere, can be achieved with low-frequency repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating targeted areas of the brain. Furthermore, the disruptive effects of low-frequency rTMS can be increased and prolonged by preceding it with 6-Hz priming stimulation. We have recently demonstrated the safety of this priming/low-frequency rTMS in adults with stroke and we are currently engaged in an NIH-funded study exploring the effectiveness, mechanism and safety of serial treatments of rTMS combined with motor learning training. Very little research, however, has been attempted on interventions to promote brain reorganization and recovery in hemiplegia in children. Thus, this study will determine the effectiveness, mechanism, and safety of 5 treatments of 6-Hz primed low- frequency rTMS applied to the non-stroke hemisphere and combined with constraint induced therapy (CIT) to promote recovery of the paretic hand. Fifteen children with pediatric hemiplegia, age 8 -16 years, at each of two pediatric medical facilities (total N = 30), will be randomly assigned to one of two treatment groups that will receive treatment for 2 weeks. The rTMSreal/CIT group will receive alternating days of the real rTMS and CIT for 5 treatments of each. The rTMSsham/CIT group will receive alternating days of sham rTMS with real CIT for 5 treatments of each. Subjects will be tested at pretest and posttest. The hypotheses are: 1) the rTMS treatment will show no serious side effects, 2) both groups will show improvement in hand function but the rTMSsham/CIT group will show significantly greater improvement, 3) the rTMSreal/CIT group will also show significantly greater improvements in brain reorganization measured by paired-pulse TMS testing, cortical silent period testing, and fMRI. The proposed research is important because very little research on rehabilitation-induced brain reorganization has been done in pediatric hemiplegia. It is innovative because it applies a technique never used before, i.e. 6-Hz primed low-frequency rTMS combined with CIT. The potential impact of this research is a radical change to pediatric rehabilitation that accomplishes a higher functional recovery. This project has the potential to discover a new method of promoting brain reorganization and recovery of hand function in children with hemiplegia. Very little research has been done on children with hemiplegia that addresses brain reorganization. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation, when combined with Constraint Induced Therapy, may show a potent synergism that produces unprecedented rehabilitation gains. Pursuing this knowledge will help to promote higher quality of life in thousands of children each year.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Paralysis following stroke stems not only from the loss of neurons killed by the stroke but also from the loss of neurons lying dormant in the stroke hemisphere. One of the reasons viable neurons become dormant (down-regulated) is because of excessive interhemispheric inhibition imposed on them through transcallosal pathways from the nonstroke hemisphere. Our challenge in neurorehabilitation is to restore excitability and voluntary control of these down-regulated neurons in the stroke hemisphere. Supression of the source of this excessive interhemispheric inhibition can be achieved with the noninvasive method called repetitive transcranial magnetic stimulation (rTMS). It is known that low-frequency rTMS has disruptive or depressant effects on the underlying neurons. Furthermore, recent work has shown that the depressant effect of low-frequenycy rTMS can be magnified and prolonged by preceding it with a period of high-frequency (6-Hz) priming rTMS. And so, it is logical to apply 6-Hz primed low-frequency rTMS to the non-stroke primary motor area (M1) to depress excitability in that hemisphere, thereby increasing excitability of M1 in the stroke hemisphere. But there is risk of inducing a seizure in people with stroke with this treatment, which may outweigh the potential goodness of the treatment. Thus, the aims of the proposed study are to determine the efficacy, mechanism, and safety of 5 treatments of 6-Hz primed low-frequency rTMS applied to the non-stroke hemisphere to promote recovery of the paretic hand. Furthermore, we will explore whether efficacy can be enhanced by combining the rTMS with motor learning training.

Project 7: Sex Differences in Fruit Fly Health and Survival This Project has three components, each of which corresponds to a specific Aim. The first component will involve the use of advanced statistical techniques and methods of meta-analysis to analyze and model demographic data on over 5 million deaths collated from 18 years of studies on the Mediterranean fruit fly and the Mexican fruit fly. This database is one of the largest, cleanest, and richest sources of demographic data available for any non-human model species. Although virtually all of the published research papers based on information contained in the database include analyses of male and female differences, the data have never before been analyzed as a meta-dataset or with the express purpose of identifying the principles for sex-mortality differentials. Development of new statistical techniques for analyzing age- and sex-specific mortality data will also be part of this database research component. The second component involves the use of a newly-developed high resolution (fine-grained time scale) electronic monitoring system to record the daily and lifetime behavior and movement of male and female Mexican fruit flies. The raw data that is generated from this system on individual flies will be analyzed in a range of behavioral and "locomotor" contexts such as lifetime patterns, behavioral differences between young and old flies as well as male and female flies, circadian rhythm-based behaviors (including sleep), and changes in age-specific locomotor characteristics such as velocity, meandering indices, and zonal preferences. One of the goals of this component is to record apparent changes in fly health (as interpreted via behavioral changes) throughout their lives including the acquisition of naturally-occurring impairments and disabilities. The third component involves in-depth studies concerned with sex-specific costs of reproduction using mating as the source of the male costs and both mating and egg production as the sources of female costs. This component will also involve experiments designed to disaggregate the costs of the reproduction constituents including courtship in males and copulation and insemination in both sexes, as well as experiments to elucidate the costs of reproduction in both sexes with access to multiple mates at different exposure intervals. RELEVANCE (Seeinstructions): The operational concept of the proposed research is that a set of principles can serve as a basic foundation for advancing research and developing policy concerned with human aging. We will integrate concepts and empirical approaches derived from survival research on humans into survival research on insects to inform research on humans as well as shed important light on sex differences in mortality and morbidity.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In a previous study using positron emission tomography (PET), Sadato N, Pascual-Leone A, Grafman J et al1 revealed that the visual cortex was involved with tactile tasks using the index finger in subjects who were blind, but not those who were sighted. In a similar study measuring spatial resolution limits, Van Boven RW, Hamilton RH, Kaufmann T2 et al found lower spatial acuity threshold in a dominant Braille reading finger tactile task versus the middle finger for those who were blind versus those who were sighted. Using functional Magnetic Resonance Imaging (fMRI) and a tactile discrimination task, we would like to further explore whether the same brain organization found in the first study exists for the adjacent, non-Braille reading finger. This will address specificity in brain organization and how the brain adapts to conditions that influence the senses, such as early blindness.

DESCRIPTION (provided by applicant): The broad aim of this proposal is to develop an evolutionary demography of lifespan in the wild. The proposed program will consist of the following six projects: Project 1 titled Caste demography and aging in honey bees and directed by Robert Page (Arizona) will address questions concerned with how the honeybee ovary is involved in post emergence development, life history development, reproduction, and life span. Project 2 titled Ecology of lifespan and directed by James Carey (UC Davis) will involve field studies on the medfly in Greece and butterflies in Uganda to ask questions about aging, lifespan, and impairment of insects in the wild. New statistical models for estimation of survival and age structure in the wild will also be developed on this project. Project 3 titled The mathematical demography of biodemography and directed by Kenneth Wachter (UC Berkeley). The project will combine models for mutational load with the other two main strands of evolutionary life-course modeling including Markov processes and optimal life history models. Project 4 titled Natural ecology of stress and aging in C. elegans and directed by Thomas Johnson (Colorado) and Patrick Phillips (Oregon) will be investigating the role that variable environmental inputs play in modulating the demography of C. elegans in a strain-specific way. Project 5 titled Evolutionary dynamics of life span and directed by Shripad Tuljapurkar aims to describe variation in life history phenotypes that significantly affect fitness, and to analyze empirically and theoretically the forces that maintain variation and shape life histories and lifespan. Project 6 titled Ecology of the lifespan in subsistence peoples and directed by Hillard Kaplan (New Mexico) and Michael Gurven (UC Santa Barbara) will involve studies on the Tsimane of Bolivia that are concerned with age-specific contributions to fitness among older individuals in traditional societies. The program will involve major synergistic components including biannual meetings, interactions of three focus groups involving researchers from multiple projects, and a series of seven different mini- workshops designed to foster greater communication between members from different projects and to provide a mechanism for engaging researchers from outside the program. Three of these workshops will be held at research field sites including Kibale National Park, Uganda (Project 2), Rum Island, Scotland (Project 5), and Bolivia (Project 6).

PROJECT SUMMARY/ABSTRACT Although there is considerable debate among scientists on both the importance and the generality of different aging mechanisms, in recent years three interrelated perspectives of aging have emerged on which most gerontologists and demographers agree: (1) there are multiple pathways (and thus mechanisms) for attaining exceptional longevity; (2) these pathways have different mortality consequences; and (3) the health of individuals at older ages is conditional on their pathway to these ages. The concept of pathways to old age and their different health costs is foundational to healthy aging outlined in the landmark paper on morbidity compression by Fries (1980) and is also central to this proposed project. One of the fundamental questions that flows from these concepts is whether increasing survival of individuals to advanced ages yields populations that are healthier, or whether these larger fractions arriving at old age means that the average health of the individuals is actually reduced. Whereas this second scenario is referred to as the 'Failure of Success Model', the first scenario is referred to as the 'Success of Success Model'. A less selected group of survivors to old ages may be shaping an older population whole health profile is more diverse relative to earlier populations at the same age. These concepts and models will be used to form the operational framework around which this proposed research project is organized to explore the interplay of geriatric and demography frailty and, in turn, to gain insights into the relationship of health and old-age mortality. Using the Mexican fruit fly (Anastrepha ludens), our broad goal is to bring experimental demography and mathematical models to bear on specific questions concerned with the health and survival of older individuals that experience a wide range of environmental conditions when young. Specific aims include: Aim 1. Identify and calibrate behavioral metrics of health; Aim 2. Health metric measurement and hypothesis testing including assessing health, survival and female reproduction of oldest-old flies maintained different diets (2a) and different reproductive (2b) and stress (2c) conditions; and Aim 3. Statistical modeling and data analysis.