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Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD. [ABSTRACT FROM AUTHOR]

Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care. [ABSTRACT FROM AUTHOR]

Estimates are made of active life expectancy for the U.S. Elderly and oldest-old populations using data from the 1982 and 1984 National Long Term Care Surveys. In the calculation of active life expectancy a multivariate analysis of 27 measures of functioning was used to define scores to decompose total life expectancy by type and level of disability. These analyses showed significant differences in active life expectancy for males and females. Though a higher proportion of male life expectancy at age 65 was “active,” females had larger absolute amounts of active life expectancy. By age 85, in contrast, males had a higher absolute amount of active life expectancy. In addition, calculations were performed with the disability associated with cognitive impairment eliminated in order to illustrate the sensitivity of active life expectancy to changes in morbidity [ABSTRACT FROM PUBLISHER]

Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention. We evaluated the associations of common adult infections (herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses), and vaccinations against shingles and pneumonia, with the risks of AD and other dementias in a pseudorandomized sample of the Health and Retirement Study (HRS). Shingles, pneumonia and mycoses, diagnosed between ages 65 and 75, were all associated with significantly increased risk of AD later in life, by 16 %–42 %. Pneumococcal and shingles vaccines administered between ages 65–75 were both associated with a significantly lower risk of AD, by 15 %–21 %. These effects became less pronounced when AD was combined with other dementias. Our findings suggest that both the pneumococcal polysaccharide vaccine and the live attenuated zoster vaccine can offer significant protection against AD. It remains to be determined if non-live shingles vaccine has a similar beneficial effect on AD. This study also found significant associations of various infections with the risk of AD, but not with the risks of other dementias. This indicates that vulnerability to infections may play a more significant role in AD than in other types of dementia, which warrants further investigation. • Shingles, pneumonia, and recurrent mycoses all increased risk of AD after age 75. • Vaccinations against shingles and pneumonia both significantly reduced risk of AD. • The associations with infections and vaccines were stronger for AD than for other dementias. • Results of this study point to a role of compromised immunity in AD. • Pneumococcal and zoster vaccines are promising candidates for repurposing in AD. [ABSTRACT FROM AUTHOR]

Background. In rebalancing from nursing homes (NHs), states are increasing access of NH-certified dually eligible (Medicare/Medicaid) patients to community waiver programs and Programs of All-Inclusive Care for the Elderly (PACE). Prior evaluations suggest Medicaid's PACE capitation exceeds its spending for comparable admissions in alternative care, although the latter may be underestimated. We test whether Medicaid payments to PACE are lower than predicted fee-for-service outlays in a long-term care admission cohort. Methods. Using grade-of-membership methods, we model health deficits for dual eligibles aged 55 or more entering waiver, PACE, and NH in South Carolina (n = 3,988). Clinical types, membership vectors, and program type prevalences are estimated. We calculate a blend, fitting PACE between fee-for-service cohorts, whose postadmission 1-year utilization was converted to attrition-adjusted outlays. PACE's capitation is compared with blend-based expenditure predictions. Results. Four clinical types describe population health deficits/service needs. The waiver cohort is most represented in the least impaired type (1: 47.1%), NH entrants in the most disabled (4: 38.5%). Most prevalent in PACE was a dementia type, 3 (32.7%). PACE's blend was waiver: 0.5602 (95% CI: 0.5472, 0.5732) and NH: 0.4398 (0.4268, 0.4528). Average Medicaid attrition–adjusted 1-year payments for waiver and NH were $4,177 and $77,945. The mean predicted cost for PACE patients in alternative long-term care was $36,620 ($35,662 and $37,580). PACE's Medicaid capitation was $27,648—28% below the lower limit of predicted fee-for-service payments. Conclusions. PACE's capitation was well under outlays for equivalent patients in alternative care—a substantial savings for Medicaid. Our methods provide a rate-setting element for PACE and other managed long-term care. [ABSTRACT FROM PUBLISHER]

Objectives To determine whether insufficient help for activity of daily living ( ADL) disability, a potentially modifiable condition, significantly increases disabled older adults' risk of future hospital admissions. Design Prospective study. Setting Community-living participants with ADL disabilities in the 1994, 1999, and 2004 National Long- Term Care Survey ( NLTCS). Participants Medicare recipients with one or more ADL disabilities completed 5,884 surveys. Measurements Times to hospital admission in the year after the NLTCS community survey were obtained from linked Medicare claims. Insufficient ADL help for each ADL limitation was determined from a series of questions common to the three NLTCS community surveys. Results Insufficient help for one or more ADL limitations was reported in 22% of surveys. Respondents to 3,629 surveys did not experience a hospital admission in the year after the survey. Of the remaining 2,255 surveys, one admission occurred for 382 surveys, two admissions for 525 surveys, three admissions for 193 surveys, and four or more admissions for 155 surveys. Participants reporting insufficient help were 14% (hazard ratio = 1.14, 95% confidence interval = 1.01-1.28) more likely to experience one or more hospitalizations than those who did not report insufficient help after controlling for demographic characteristics, comorbidities, prior hospitalizations, and level of ADL disability. Conclusion Self-reports of insufficient help provide prognostic information beyond what typical health assessments can capture. Greater recognition and referral for insufficient help for ADL disability may result in lower rates of hospitalization in a population that is at high risk of hospitalization. [ABSTRACT FROM AUTHOR]

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection. [ABSTRACT FROM AUTHOR]

Background: Studies of longevity-enriched families are an important tool to gain insight into the mechanisms of exceptionally long and healthy lives. In the Long Life Family Study, the spouses of the members of the longevity-enriched families are often used as a control group. These spouses could be expected to have better health than the background population due to shared family environment with the longevity-enriched family members and due to assortative mating.Methods: A Danish cohort study of 5,363 offspring of long-lived siblings, born 1917-1982, and 4,498 "first spouses" of these offspring. For each offspring and spouse, 10 controls were drawn from a 5% random sample of the Danish population matched on birth year and sex. Mortality was assessed for ages 20-69 years during 1968-2013 based on prospectively collected registry data.Results: During the 45-year follow-up period, 437 offspring deaths and 502 offspring spouse deaths were observed. Compared with the background population, the hazard ratio for male offspring was 0.44 (95% confidence interval [CI]: 0.38-0.50) and for female offspring it was 0.57 (95% CI: 0.49-0.66). For male spouses, the hazard ratio was 0.66 (95% CI: 0.59-0.74), whereas for female spouses it was 0.64 (95% CI: 0.54-0.76). Sensitivity analyses in restricted samples gave similar results.Conclusion: The mortality for ages 20-69 years of spouses marrying into longevity-enriched families is substantially lower than the mortality in the background population, although long-lived siblings participation bias may have contributed to the difference. This finding has implications for the use of spouses as controls in healthy aging and longevity studies, as environmental and/or genetic overmatching may occur. [ABSTRACT FROM AUTHOR]

Background: Unmet need for assistance with activities of daily living (ADLs) disability is associated with increased risk for future hospitalization. To further explore the association between unmet ADL need and future health outcomes, we examined the association between unmet need for ADL assistance and 1-year mortality.Methods: A prospective study of 6,730 community-living Medicare recipients was conducted among respondents to the 1994, 1999, and/or 2004 National Long Term Care Survey. Only those who reported having one or more ADL disabilities were included. Time to death within 1 year after the community survey was determined from Centers for Medicare and Medicaid Services vital statistics records. The community interviews provided demographic, health, and ADL information.Results: Unadjusted 1-year death rates were 8.7%, 10.6%, 11.4%, 19.2%, and 27.3%, respectively, for respondents with disabilities in 1, 2, 3, 4, and 5 ADLs. Overall, 21.3% reported unmet need for assistance for one or more ADL disabilities. After controlling for demographic and health characteristics, we found a significant interaction between unmet ADL need and level of ADL disability (p = .018). Post hoc analyses revealed that unmet ADL need was associated with increased risk for mortality only for those with one (hazard ratio = 1.96; 95% CI = 1.29-2.87) or two ADL disabilities (hazard ratio = 1.37; 95% CI = 1.07-1.75), but not for those with three or more ADL disabilities.Conclusion: Future studies are needed to determine whether these findings are replicable and, if so, whether physiologic or process of care variables explain why ADL is associated with mortality only for those with mild disability. [ABSTRACT FROM AUTHOR]

This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources. [ABSTRACT FROM PUBLISHER]

Background: Use of a claims-based index to identify persons with physical function impairment and at risk for long-term institutionalization would facilitate population health and comparative effectiveness research. The JEN Frailty Index [JFI] is comprised of diagnosis domains representing impairments and multimorbid clusters with high long-term institutionalization [LTI] risk. We test the index's discrimination of activities-of-daily-living [ADL] dependency and 1-year LTI and mortality in a nationally representative sample of over 12,000 Medicare beneficiaries, and compare long-term community survival stratified by ADL and JFI.Methods: 2004 U.S. National Long-Term Care Survey data were linked to Medicare, Minimum Data Set, Veterans Health Administration files and vital statistics. ADL dependencies, JFI score, age and sex were measured at baseline survey. ADL and JFI groups were cross-tabulated generating likelihood ratios and classification statistics. Logistic regression compared discrimination (areas under receiver operating characteristic curves), multivariable calibration and accuracy of the JFI and, separately, ADLs, in predicting 1-year outcomes. Hall-Wellner bands facilitated contrasts of JFI- and ADL-stratified 5-year community survival.Results: Likelihood ratios rose evenly across JFI risk categories. Areas under the curves of functional dependency at ≥3 and ≥ 2 for JFI, age and sex models were 0.807 [95% c.i.: 0.795, 0.819] and 0.812 [0.801, 0.822], respectively. The area under the LTI curve for JFI and age (0.781 [0.747, 0.815]) discriminated less well than the ADL-based model (0.829 [0.799, 0.860]). Community survival separated by JFI strata was comparable to ADL strata.Conclusions: The JEN Frailty Index with demographic covariates is a valid claims-based measure of concurrent activities-of-daily-living impairments and future long-term institutionalization risk in older populations lacking functional information. [ABSTRACT FROM AUTHOR]

Studying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest related to this study.

Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration) in the literature. Here, we tested the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We assessed the impact of interactions between SNPs in such genes on AD onset in the Long Life Family Study and sought to replicate the findings in the Health and Retirement Study. We found significant interactions between SNPs in the UNC5C and CNTN6 , and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Associations with individual SNPs were not statistically significant. Our findings, thus, support a major role of genetic interactions in the heterogeneity of AD and suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arbeev, Ukraintseva, Bagley, Duan, Wu, Akushevich, Stallard, Kulminski, Christensen, Feitosa, O’Connell, Parker, Whitson and Yashin.)

Associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer's (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were examined in two samples of European ancestry from the US (22,712 individuals 587/2,608 AD/CHD cases) and the UK Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures. Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (β IE = 0.015, p IE = 1.9 × 10 -3 ), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (β IE = 0.019, p IE = 8.6 × 10 -4 ). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD.

Background: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD., Objectives: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI)., Methods: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm., Results: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up., Conclusion: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

Introduction: Identifying the course of Alzheimer's disease (AD) for individual patients is important for numerous clinical applications. Ideally, prognostic models should provide information about a range of clinical features across the entire disease process. Previously, we published a new comprehensive longitudinal model of AD progression with inputs/outputs covering 11 interconnected clinical measurement domains., Methods: Here, we (1) validate the model on an independent cohort; and (2) demonstrate the model's utility in clinical applications by projecting changes in 6 of the 11 domains., Results: Survival and prevalence curves for two representative outcomes-mortality and dependency-generated by the model accurately reproduced the observed curves both overall and for patients subdivided according to risk levels using an independent Cox model., Discussion: The new model, validated here, effectively reproduces the observed course of AD from an initial visit assessment, allowing users to project coordinated developments for individual patients of multiple disease features., (© 2021 the Alzheimer's Association.)

Decline in biological resilience (ability to recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age eventually limiting longevity even in people without major chronic diseases. Understanding the mechanisms of this decline is essential for developing efficient anti-aging and pro-longevity interventions. In this paper we discuss: a) mechanisms of the decline in resilience with age, and aging components that contribute to this decline, including depletion of body reserves, imperfect repair mechanisms, and slowdown of physiological processes and responses with age; b) anti-aging interventions that may improve resilience or attenuate its decline; c) biomarkers of resilience available in human and experimental studies; and d) genetic factors that could influence resilience. There are open questions about optimal anti-aging interventions that would oppose the decline in resilience along with extending longevity limits. However, the area develops quickly, and prospects are exciting., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Recently, Mahalanobis distance (D M ) was suggested as a statistical measure of physiological dysregulation in aging individuals. We constructed D M variants using sets of biomarkers collected at the two visits of the Long Life Family Study (LLFS) and performed joint analyses of longitudinal observations of D M and follow-up mortality in LLFS using joint models. We found that D M is significantly associated with mortality (hazard ratio per standard deviation: 1.31 [1.16, 1.48] to 2.22 [1.84, 2.67]) after controlling for age and other covariates. GWAS of random intercepts and slopes of D M estimated from joint models found a genome-wide significant SNP (rs12652543, p=7.2×10 -9 ) in the TRIO gene associated with the slope of D M constructed from biomarkers declining in late life. Review of biological effects of genes corresponding to top SNPs from GWAS of D M slopes revealed that these genes are broadly involved in cancer prognosis and axon guidance/synapse function. Although axon growth is mainly observed during early development, the axon guidance genes can function in adults and contribute to maintenance of neural circuits and synaptic plasticity. Our results indicate that decline in axons' ability to maintain complex regulatory networks may potentially play an important role in the increase in physiological dysregulation during aging.

Biological aging results in changes in an organism that accumulate over age in a complex fashion across different regulatory systems, and their cumulative effect manifests in increased physiological dysregulation (PD) and declining robustness and resilience that increase risks of health disorders and death. Several composite measures involving multiple biomarkers that capture complex effects of aging have been proposed. We applied one such approach, the Mahalanobis distance (D M ), to baseline measurements of various biomarkers (inflammation, hematological, diabetes-associated, lipids, endocrine, renal) in 3,279 participants from the Long Life Family Study (LLFS) with complete biomarker data. We used D M to estimate the level of PD by summarizing information about multiple deviations of biomarkers from specified "norms" in the reference population (here, LLFS participants younger than 60 years at baseline). An increase in D M was associated with significantly higher mortality risk (hazard ratio per standard deviation of D M : 1.42; 95% confidence interval: [1.3, 1.54]), even after adjustment for a composite measure summarizing 85 health-related deficits (disabilities, diseases, less severe symptoms), age, and other covariates. Such composite measures significantly improved mortality predictions especially in the subsample of participants from families enriched for exceptional longevity (the areas under the receiver operating characteristic curves are 0.88 vs. 0.85, in models with and without the composite measures, p = 2.9 × 10 -5 ). Sensitivity analyses confirmed that our conclusions are not sensitive to different aspects of computational procedures. Our findings provide the first evidence of association of PD with mortality and its predictive performance in a unique sample selected for exceptional familial longevity., (Copyright © 2020 Arbeev, Bagley, Ukraintseva, Duan, Kulminski, Stallard, Wu, Christensen, Feitosa, Thyagarajan, Zmuda and Yashin.)

Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age-related processes contributing to a large fraction of specific geriatric conditions, concordantly with geroscience. We performed a genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals. We identified 30 promising disability-associated polymorphisms in 19 loci at p < 10 -4 ; four of them attained suggestive significance, p < 10 -5 . In contrast, polygenic risk scores aggregating effects of minor alleles of independent SNPs that were adversely or beneficially associated with disability showed highly significant associations in meta-analysis, p = 3.13 × 10 -45 and p = 5.60 × 10 -23 , respectively, and were replicated in each study. The analysis of genetic pathways, related diseases, and biological functions supported the connections of genes for the identified SNPs with disabling and age-related conditions primarily through oxidative/nitrosative stress, inflammatory response, and ciliary signaling. We identified musculoskeletal system development, maintenance, and regeneration as important components of gene functions. The beneficial and adverse gene sets may be differently implicated in the development of musculoskeletal-related disability with the beneficial set characterized, e.g., by regulation of chondrocyte proliferation and bone formation, and the adverse set by inflammation and bone loss.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

Background: Correcting for the potential effects of population stratification is an important issue in genome wide association studies (GWAS) of complex traits. Principal component analysis (PCA) of the genetic structure of the population under study with subsequent incorporation of the first several principal components (PCs) in the GWAS regression model is often used for this purpose., Problem: For longevity related traits such a correction may negatively affect the accuracy of genetic analyses. This is because PCs may capture genetic structure induced by mortality selection processes in genetically heterogeneous populations., Data and Methods: We used the Framingham Heart Study data on life span and on individual genetic background to construct two sets of PCs. One was constructed to separate population stratification due to differences in ancestry from that induced by mortality selection. The other was constructed using genetic data on individuals of different ages without attempting to separate the ancestry effects from the mortality selection effects. The GWASs of human life span were performed using the first 20 PCs from each of the selected sets to control for possible population stratification., Results: The results indicated that the GWAS that used the PC set separating population stratification induced by mortality selection from differences in ancestry produced stronger genetic signals than the GWAS that used PCs without such separation., Conclusion: The quality of genetic estimates in GWAS can be improved when changes in genetic structure caused by mortality selection are taken into account in controlling for possible effects of population stratification.

Purpose: The purpose of this article is to describe the projected use for long-term-care services through 2012., Design and Methods: We constructed a static-component projection model using age, function, and other covariates. We obtained enrollee projections from the Veterans Health Administration (VHA) and combined these with nursing home and community long-term-care service use rates from the 1999 National Long-Term Care Survey and the 2000 National Health Interview Survey., Results: Over the next decade, the number of oldest veterans (aged 85+) will double, and VHA-enrolled veterans aged 85 and older will increase sevenfold. This will result in a 20-25% increase in use for both nursing home and home- and community-based services. VHA currently concentrates 90% of its long-term-care resources on nursing home care. However, among those who receive long-term care from all formal sources, 56% receive care in the community. Age and marital status are significant predictors of use of either type of formal long-term-care service for any given level of disability. VHA's experience with the mandatory nursing home benefit suggests that even when the cost to the veteran is near zero, only 60-65% of eligibles will choose VHA-provided care. Assisted living represents nearly 15% of care provided during the past decade to individuals in nursing homes, and approximately 19% of veterans using nursing homes have disability levels comparable to those of men supported in assisted living., Implications: As most of the increased projected use for long-term care will be for home- and community-based services, VHA will need to expand those resources. Use of VHA resources to leverage community services may offer new opportunities to enhance community-based long-term care.