Long-term economic growth stimulus of human capital preservation in the elderly.

Health care is a crucial factor in US economic growth, because growing health care costs have made US corporations less competitive than their counterparts in countries where central governments assume most of those costs. In this paper we illustrate a second, possibly more powerful, effect of health care expenditures on the long term pace of US economic growth, i.e., that such investments in aging populations helps preserve human capital to later ages. In addition, as current investment in health care improves health and functional status, the future demand for health care as well as future health care costs will be constrained. These are crucial factors in countries experiencing rapid population aging. US labor force projections do not directly represent the effects of health care investment on the health of the future labor force, and federal health cost projections do not reflect the trajectory of health changes. Health dynamic projections suggest the effects of health care investment are large and growth stimulating. Projections done for the time period used by the Congressional Budget Office in budget mark-ups (2010-2020) are presented in the supporting information.

NIH funding trajectories and their correlations with US health dynamics from 1950 to 2004.

To determine optimal future National Institutes of Health (NIH) funding levels, the longitudinal correlation of the level of investment in NIH research with population changes in the risk of specific diseases should be analyzed. This is because NIH research is the primary source of new therapies and treatments for major chronic diseases, many of which were viewed as relatively untreatable in the 1950s. NIH research is also important in developing preventative and screening strategies to support public health interventions. These correlations are examined 1938 to 2004 for 4 major chronic diseases [cardiovascular disease (CVD), stroke, cancer, and diabetes] and the NIH institutes responsible for research for those diseases. This analysis shows consistent non-linear temporal correlations of funding to mortality rates across diseases. The economic implications of this are discussed assuming that improved health at later ages will allow projected declines in the rate of growth of the US labor force to be partly offset by a higher rate of labor force participation in the US elderly population due to reduced chronic disease risks and functional impairment.

Labor force participation and human capital increases in an aging population and implications for U.S. research investment.

The proportion of the United States labor force >/=65 years of age is projected to increase between 2004 and 2014 by the passing of age 65 of the large post-World War II baby boom cohorts starting in 2010 and their greater longevity, income, education, and health [Toossi M (2005) Mon Labor Rev 128(11):25-44]. The aging of the U.S. labor force will continue to at least 2034, when the largest of the baby boom cohorts reaches age 70. Thus, the average health and functional capacity of persons age 65+ must improve for sufficient numbers of elderly persons to be physically and cognitively capable of work. This will require greater investments in research, public health, and health care. We examine how disability declines and improved health may increase human capital at later ages and stimulate the growth of gross domestic product and national wealth.

Association between APOE epsilon 2/epsilon 3/epsilon 4 polymorphism and disability severity in a national long-term care survey sample.

BACKGROUND: early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability. OBJECTIVE: to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality. DESIGN: population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals. PARTICIPANTS: genetic data are available for 1,805 individuals. METHODS: each of six genotypes of three common alleles of the APOE locus (epsilon 2, epsilon 3 and epsilon 4) was tested on the association with a disability index or mortality. RESULTS: APOE epsilon 3/epsilon 3 genotype significantly decreases odds ratio (OR) for IADL disability in males [OR = 0.48; 95% Confidence Interval (CI) 0.31-0.76] while it exhibits no association in females. The OR for ADL disability is 0.19 (CI 0.04-0.99) for epsilon 4/epsilon 4 female carriers. The epsilon 2/epsilon 3 genotype increases the chances of IADL disability for males (OR = 2.33; CI 1.28-4.25). No significant association between APOE polymorphism and mortality was found. A surprising observation was that epsilon 4/epsilon 4 female carriers have a 5.3 times lower chance of having ADL disability than non-epsilon 4/epsilon 4-carriers. CONCLUSIONS: association of the APOE polymorphism with disability and lack of association with mortality support the view that APOE gene actions may be more significant as modulators of frailty than of longevity.

Cohort changes in active life expectancy in the U.S. elderly population: experience from the 1982-2004 National Long-Term Care Survey.

OBJECTIVES: To understand declines in chronic disability prevalence in the U.S. elderly population, we examined cohort changes in active life expectancy, a health measure relating population disability and longevity dynamics. METHODS: We computed active life expectancy and life expectancy using the six National Long-Term Care Surveys done from 1982 to 2004 and linked to continuous-time Medicare service data for the same time period by using a stochastic process model based on disability scores calculated using grade of membership analyses. We simultaneously estimated continuous-time disability dynamic and mortality functions to calculate life tables for specific disability states and for temporally changing mixtures of disability states. RESULTS: Disability dynamics, measured as changes in grade of membership scores, showed significant variation across two birth cohorts followed for 24 years. Disability dynamics and disability-specific hazard functions were significantly improved in the younger cohort (persons aged 65-74 in 1982). DISCUSSION: Our results, supporting the hypothesis of morbidity compression, indicate that younger cohorts of elderly persons are living longer in better health. The methods describe individual disability transitions and mortality and other factors associated with disability changes, making it possible to better evaluate interventions to promote future declines in disability.

SOD2 polymorphisms: unmasking the effect of polymorphism on splicing.

BACKGROUND: The SOD2 gene encodes an antioxidant enzyme, mitochondrial superoxide dismutase. SOD2 polymorphisms are of interest because of their potential roles in the modulation of free radical-mediated macromolecular damage during aging. RESULTS: We identified a new splice variant of SOD2 in human lymphoblastoid cell lines (LCLs). The alternatively spliced product was originally detected by exon trapping of a minigene in order to examine the consequences of an intronic polymorphism found upstream of exon 4 (nucleotide 8136, 10T vs 9T). Examination of the transcripts derived from the endogenous loci in five LCLs with or without the intron 3 polymorphism revealed low levels of an in-frame deletion of exon 4 that were different from those detected by the exon trap assay. This suggested that exon trapping of the minigene unmasked the effect of the 10T vs 9T polymorphism on the splicing of the adjacent exon. We also determined the frequencies of single nucleotide polymorphisms in a sample of US African-Americans and non-African-Americans ages 65 years and older who participated in the 1999 wave of the National Long Term Care Survey (NLTCS). Particularly striking differences between African-Americans and non-African-Americans were found for the frequencies of genotypes at the 10T/9T intron 3 polymorphism. CONCLUSION: Exon trapping can unmask in vitro splicing differences caused by a 10T/9T intron 3 polymorphism. Given the recent evidence that SOD2 is in a region on chromosome 6 linked to susceptibility to hypertension, it will be of interest to investigate possible associations of this polymorphism with cardiovascular disorders.

Medicare cost effects of recent U.S. disability trends in the elderly: future implications.

OBJECTIVE: The authors examine how trends in disability prevalence and in inflation-adjusted per capita, per annum Medicare costs, 1982 to 1999 and 1989 to 1999, affected total Medicare costs projected to 2004 and 2009. METHOD: To describe disability trends, the authors applied grade of membership analyses to 27 measures of disability from the 1982 to 1999 National Long Term Care Surveys (NLTCS). This identified seven disability profiles for which individual scores were calculated. These were used to calculate sample weighted Medicare costs and cost trends. RESULTS: Significant declines (up to 19%) in Medicare costs were found in 2004 and 2009 assuming continuation of the 1982 to 1999 disability declines and Medicare cost trends. In addition to declines in disability prevalence, inflation-adjusted per capita, per annum Medicare costs declined for nondisabled persons aged 65 to 84. DISCUSSION: Preserving health in the growing nondisabled population did not require increased health care expenditures.

Newborn screening for severe combined immunodeficiency (SCID): a review.

Because prompt intervention may prevent complications, early diagnosis is important in many inherited metabolic diseases. Early diagnosis of Severe Combined Immunodeficiency (SCID) is critical - because chances for successful treatment are highest for infants who have not yet experienced severe opportunistic infections. SCID is a rare disease that can be detected in newborn infants (i.e., those more or equal 1 month of age) by automated blood count and manual differential. Early diagnosis of SCID is rare since, because estimates of the incidence rate range from one in 50,000 to 100,000 births, most pediatricians do not routinely count white blood cells in newborns. Tests for T-cell lymphopenia (TCLP) using dried blood spots (DBS) could be used to identify children with SCID - as well as for other immunodeficiencies that would not be apparent until after the child developed an infection. Screening newborns for SCID would allow early diagnosis and treatment -- as well as genetic counseling for the family.

A three-generation approach in biodemography is based on the developmental profiles and the epigenetics of female gametes.

We suggest that there are three premises underlying the need for biodemographic analyses of three-generations: 1.) To describe the structure of the genome, we need to use (apart from mutations) other kinds of heritable changes such as those mediated by facultative elements (variations) and epigenetic alterations. 2.) There are many reasons to analyze individual development and its deviations, such as the biodemographic perspective of fertilization - but also including all long-term intra-generational events of oogenesis and meiosis (beginning with the embryogenesis of the individual's mother - or during the grandmother's pregnancy). 3.) We need to explore the reality that every fertilized egg links - physically and genetically - three successive generations. We focus on genetic and epigenetic events, which start during egg cell lineage determination in F(n-2) gestation and which influence the developmental profile of F(n) generation cohorts. The three-generation approach in epidemiology and biodemography is important so that we might increase our understanding of the effects of environmental forces, such as viral epidemics, and of catastrophes, such as the Chernobyl accident. It is also important for evaluating the processes of senescence and the determinants of human disease.

Genome organization and three kinds of heritable changes: general description and stochastic factors (a review).

Due to the increased knowledge of genome architecture, topology, and the mechanisms of hereditary variability, the list of genetic components has grown. This review outlines the general features and principles of genome organization in diverse organisms. The genome codes, stores, and transfers information in both structurally and dynamically. The genome includes two subsystems of genetic elements: obligatory (genes and gene families) and various types of facultative elements which are predominant the content of the human genome. The features of three kinds of heritable changes: mutations, variations (changes in the number or topography of facultative elements), and epigenetic alterations are described. Facultative elements are the first to react to environmental challenges. Together with epigenetic changes, they implement the operational genomic memory. This review discusses both the role of stochastic factors and the transient features of DNA components.

The immune system in aging: roles of cytokines, T cells and NK cells.

Aging is characterized by a proinflammatory state that contributes to the onset of disability and age-related diseases. Proinflammatory cytokines play a central role in mediating cellular and physiological responses. The levels of these cytokines may reflect immune system effectiveness. Studies of the effects of aging on inflammatory response show interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) to be important. In this review, age-related changes in inflammatory cytokines, T and NK cells, and the biology of IL-6 and TNF-alpha and their relevance to senescence are considered.

Whether ionizing radiation is a risk factor for schizophrenia spectrum disorders?

The neural diathesis-stressor hypothesis of schizophrenia, where neurobiological genetic predisposition to schizophrenia can be provoked by environmental stressors is considered as a model of the effects of exposure to ionizing radiation. Analysis of information from electronic databases (MEDLINE, PsycINFO, EMBASE, Current Contents, Elsevier BIOBASE) and hand-made search was carried out. There are comparable reports on increases in schizophrenia spectrum disorders following exposure to ionizing radiation as a result of atomic bombing, nuclear weapons testing, the Chernobyl accident, environmental contamination by radioactive waste, radiotherapy, and also in areas with high natural radioactive background. The results of experimental radioneurobiological studies support the hypothesis of schizophrenia as a neurodegenerative disease. Exposure to ionizing radiation causes brain damage with limbic (cortical-limbic) system dysfunction and impairment of informative processes at the molecular level that can trigger schizophrenia in predisposed individuals or cause schizophrenia-like disorders. It is supposed that ionizing radiation can be proposed as a risk factor for schizophrenia spectrum disorders. The hypothesis that ionizing radiation is a risk factor for schizophrenia spectrum disorders can be tested using data from the Chernobyl accident aftermath. Implementation of a study on schizophrenia spectrum disorders in Chernobyl accident victims is of significance for both clinical medicine and neuroscience.

Endothelial progenitor cell therapy for atherosclerosis: the philosopher's stone for an aging population?

Much of the increased risk for atherosclerosis progression with age may be a result of age-related declines in the capacity of precursor cells to repair damage in the arterial endothelium. To estimate the impact of progenitor cell therapy for atherosclerosis on cardiovascular disease (CVD) mortality, life expectancy, and survival, as compared with the lifetime control of conventional risk factors, we modeled the health effects of bone marrow-derived endothelial progenitor cell therapy using data from the 1950 to 1996 follow-up of the Framingham Heart Study. To model cardiovascular disease mortality, we assumed that progenitor cell therapy was applied at age 30, with the effect assumed to be a 10-year delay in atherosclerosis progression. Age projections were constructed analytically using the stochastic process model for risk factor dynamics and mortality and microsimulation techniques. We considered three types of interventions: (i) keeping risk factors within selected limits to model current clinical recommendations; (ii) an age shift of 10 years to model the effects of progenitor cell therapy; and (iii) elimination of a competing risk (such as cancer). Our study suggests that progenitor cell therapy might increase life expectancy in the population as much as the complete elimination of cancer (in females, an additional 3.67 versus 3.37 years; in males, an additional 5.94 versus 2.86 years, respectively).

The role of oxidative damage in mitochondria during aging: a review.

Aging is a complex process (or series of processes). Recent evidence suggests that several of its most important mechanisms are linked by means of cellular damage caused by reactive oxygen species (ROS). Oxidative damage may be a major factor in the loss of physiological functions that occur in degenerative diseases and aging. This is because, in aerobic organisms, the mitochondrial electron transport chain plays an important role in energy production and is a significant source of ROS that damage DNA, RNA, and proteins in cells. While oxidative events in other cell organelles are likely to contribute to the pathobiology of aging, this review highlights alterations in mitochondrial function that, due to accumulated oxidative damage, occur with age.

Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice.

From the age of 3 months until their natural death, female Swiss-derived SHR mice were given melatonin with their drinking water (2 or 20mg/l) for 5 consecutive days every month. Intact mice served as controls. There were 54 mice in each group. The results of this study show that the treatment of melatonin did not significantly influence food consumption, but its administration at lower doses did decrease the body weight of mice; it slowed down the age-related switching-off of estrous function; it did not influence the frequency of chromosome aberrations in bone marrow cells; it did not influence mean life span; and it increased life span of the last 10% of the survivors in comparison to controls. We also found that treatment with low dose melatonin (2mg/l) significantly decreased spontaneous tumor incidence (by 1,9-fold), mainly mammary carcinomas, in mice whereas higher doses (20mg/l) failed to influence tumor incidence as compared to controls. For this reason, we conclude that the effect of melatonin as a geroprotector is dose-dependent.

ROS effects on neurodegeneration in Alzheimer's disease and related disorders: on environmental stresses of ionizing radiation.

Neurodegenerative processes associated with Alzheimer's disease are complex and involve many CNS tissue types, structures and biochemical processes. Factors believed involved in these processes are generation of Reactive Oxygen Species (ROS), associated inflammatory responses, and the bio-molecular and genetic damage they produce. Since oxidative processes are essential to energy production, and to other biological functions, such as cell signaling, the process is not one of risk exposure, as for cigarettes and cancer, but one where normal physiological processes operate out of normal ranges and without adequate control. Thus, it is necessary to study the ambiphilicity that allows the same molecule (e.g., beta amyloid) to behave in contradictory ways depending upon the physiological microenvironment. To determine ways to study this in human populations we review evidence on the effects of an exogenous generator of ROS, ionizing radiation, in major population events with radionuclides (e.g., Hiroshima and Nagasaki; Chernobyl Reactor accident; environmental contamination in Chelyabinsk (South Urals) where plutonium was produced, and in the nuclear weapons test area in Semipalatinsk, Kazakhstan). The age evolution, and traits, of neurodegenerative processes in human populations in these areas, may help us understand how IR affects the CNS. After reviewing human population evidence, we propose a model of neurodegeneration based upon the complexity of CNS functions.

Fuzzy set analyses of genetic determinants of health and disability status.

Analyses of complex genotype-phenotype relations require new statistical procedures because of the potentially high dimensionability of those relations which are expressed with both measurement error and stochasticity in the correlation function. We propose modifying a multivariate procedure called grade of membership (GoM) analysis to deal with the special problems of such analyses. In doing so, we make clear some special features of the GoM model for multivariate analysis of high dimensional, discrete data. This is illustrated for apolipoprotein E (APOE) assessments made on 1805 people in the 1999 National Long Term Care Survey. A number of interesting relations with APOE polymorphism were found where disability profiles were more predictive than specific diagnoses because they implicitly contained information on chronicity and severity of disease processes.

Disability trends in gender and race groups of early retirement ages in the USA.

OBJECTIVES: To analyse disability trends over the 1980s-1990s in gender and race groups of early retirement ages in USA. METHODS: Disability trends for white and black males and females aged 65-69 and 70+ are analysed using the 1982-1999 NLTCS. Disability is analysed at three levels (instrumental activities of daily living (IADL), activities of daily living (ADL), and institutionalisation). RESULTS: 1) A larger increase in proportions of non-disabled blacks aged 65-69 compared with whites and males compared with females. 2) Differences in disability trends among gender and race groups. 3) A faster absolute decline in non-institutionalised disabled aged 65-69. 4) A larger absolute decline and a smaller relative decline in proportions of disabled aged 70+ compared with 65-69. 5) A significant decrease in the proportion of ADL disabled blacks and an increase of ADL disabled white females in the age group 70+. CONCLUSIONS: Americans aged 65-69 years manifest a significant improvement in health over the 1980s-1990s but the dynamics differs in gender and race groups. Possible reasons for these differences are discussed.

Recent declines in chronic disability in the elderly U.S. population: risk factors and future dynamics.

As U.S. life expectancy has increased, questions arise as to how the quality of health and functioning in the elderly population has changed. Data from the 1982-2004 National Long-Term Care Survey (NLTCS) suggested that chronic disability prevalence above age 65 declined at an increasing rate with a 2.2% per annum rate of decline from 1999 to 2004 ( 71 ). Inflation-adjusted per capita Medicare expenditure rates in nondisabled persons also declined, 0.9% per annum from 1982 to 2004, which suggests that declines in disability were driven by improving health -- not by increases in per capita health expenditures. Declines in disability prevalence were found in other U.S. national health surveys. Analyses of U.S. Civil War veterans suggest recent disability declines were continuations of declines in both chronic disease and disability occurring over the past century due to improved nutrition, sanitation, and education. Concerns exist about whether disability declines will continue because of recent increases in obesity prevalence.