Episodic memory and executive function in familial longevity

Successful aging, the ability to resist age-associated illnesses and functional disability, is of increasing importance as the population ages. Studies have shown that exceptionally long-lived individuals fit the successful aging paradigm by compressing disability toward the end of life. This study investigated whether there is evidence of successful cognitive aging in a familial longevity cohort, the Long Life Family Study (LLFS). Part 1 describes the feasibility of conducting a 2.5 hour neuropsychological battery emphasizing episodic memory and executive function, cognitive domains that elicit signs of cognitive dysfunction in relation to normal aging and dementia. The rationale for the selected tests is discussed within the context of minimizing effects from sensory impairments in an aged cohort and optimizing qualitative and quantitative data. In Part 2, the testing of 70 proband generation and 100 offspring generation LLFS participants and 140 generation-matched referent participants without familial longevity is described. Comparison of LLFS proband generation participants with their referent cohort revealed no significant differences in test scores. However, the referent cohort also had more years of education (an important exposure which is discussed in Part 3). LLFS offspring generation participants had borderline significant better performance on a test of executive function (Clock Drawing Test) and attention (Digits Forward) compared with referents. These findings suggest that familial longevity is associated with better cognitive function even at relatively young ages. Continuing to follow these cohorts to older ages may reveal differences in rate of change in cognitive function. Part 3 examines the role of indicators of cognitive reserve. In the proband generation education and participation in mid- and late-life cognitively stimulating activities were found to be higher in the referent cohort. This suggests that people without familial longevity may be more reliant on higher cognitive reserve in order to achieve similar cognitive performance to those from long-lived families. Implications of preserved cognitive function in long-lived families and the effect of cognitive reserve in those without familial longevity are discussed in terms of compression of disability and successful cognitive aging

Burden of disease variants in participants of the Long Life Family Study

Case control studies of nonagenarians and centenarians provide evidence that long-lived individuals do not differ in the rate of disease associated variants compared to population controls. These results suggest that an enrichment of novel protective variants, rather than a lack of disease associated variants, determine the genetic predisposition to exceptionally long lives. Using data from the Long Life Family Study (LLFS), we sought to replicate these findings and extend them to include a larger number of disease-specific risk alleles. To accomplish this goal, we built a genetic risk score for each of four age-related disease groups: Alzheimer's disease, cardiovascular disease and stroke, type 2 diabetes, and various cancers and compared the distribution of these scores between older participants of the LLFS, their offspring and their spouses. The analyses showed no significant differences in distribution of the genetic risk scores for cardiovascular disease and stroke, type 2 diabetes, or cancer between the groups, while participants of the LLFS appeared to carry an average 1% fewer risk alleles for Alzheimer's disease compared to spousal controls and, while the difference may not be clinically relevant, it was statistically significant. However, the statistical significance between familial longevity and the Alzheimer's disease genetic risk score was lost when a more stringent linkage disequilibrium threshold was imposed to select independent genetic variants

Meta-analysis of genetic variants associated with human exceptional longevity

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population

Leukocyte telomere length is unrelated to cognitive performance among non-demented and demented persons: An examination of long life family study participants

OBJECTIVE: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia. METHOD: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage. RESULTS: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p \u3c 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p \u3c 0.005), who scored significantly lower on all cognitive domains (p \u3c 0.005). CONCLUSIONS: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population

Perceived physical fatigability predicts all-cause mortality in older adults

BACKGROUND: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults. METHODS: Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member\u27s annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates. RESULTS: Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4]) overall, as well as across age strata (p \u3c .001), except for those 60-69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65-3.28]) compared with those who had less severe fatigability (PFS Physical scores \u3c 25) after adjustment. CONCLUSIONS: Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death

Burden of disease variants in participants of the long life family study

Case control studies of nonagenarians and centenarians provide evidence that long‐lived individuals do not differ in the rate of disease associated variants compared to population controls. These results suggest that an enrichment of novel protective variants, rather than a lack of disease associated variants, determine the genetic predisposition to exceptionally long lives. Using data from the Long Life Family Study (LLFS), we sought to replicate these findings and extend them to include a larger number of disease‐specific risk alleles. To accomplish this goal, we built a genetic risk score for each of four age‐related disease groups: Alzheimer’s disease, cardiovascular disease and stroke, type 2 diabetes, and various cancers and compared the distribution of these scores between older participants of the LLFS, their offspring and their spouses. The analyses showed no significant differences in distribution of the genetic risk scores for cardiovascular disease and stroke, type 2 diabetes, or cancer between the groups, while participants of the LLFS appeared to carry an average 1% fewer risk alleles for Alzheimer’s disease compared to spousal controls and, while the difference may not be clinically relevant, it was statistically significant. However, the statistical significance between familial longevity and the Alzheimer’s disease genetic risk score was lost when a more stringent linkage disequilibrium threshold was imposed to select independent genetic variants.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Impact Journals, LLC. The published article can be found at: http://www.ncbi.nlm.nih.gov/pmc/journals/1105/.Keywords: Exceptional longevity, Alzheimer’s disease, Disease variants, Genetic risk scor

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians\u27 offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR \u3c 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity

Genome-wide association study of personality traits in the Long Life Family Study

Personality traits have been shown to be associated with longevity and healthy aging. In order to discover novel genetic modifiers associated with personality traits as related with longevity, we performed a genome-wide association study (GWAS) on personality factors assessed by NEO-FFI in individuals enrolled in the Long Life Family Study (LLFS), a study of 583 families (N up to 4595) with clustering for longevity in the United States and Denmark. Three SNPs, in almost perfect LD, associated with agreeableness reached genome-wide significance (p<10-8) and replicated in an additional sample of 1279 LLFS subjects, although one (rs9650241) failed to replicate and the other two were not available in two independent replication cohorts, the Baltimore Longitudinal Study of Aging and the New England Centenarian Study. Based on 10,000,000 permutations, the empirical p-value of 2X10-7 was observed for the genome-wide significant SNPs. Seventeen SNPs that reached marginal statistical significance in the two previous GWASs (p-value < 10-4 and 10-5), were also marginally significantly associated in this study (p-value < 0.05), although none of the associations passed the Bonferroni correction. In addition, we tested age-by-SNP interactions and found some significant associations. Since scores of personality traits in LLFS subjects change in the oldest ages, and genetic factors outweigh environmental factors to achieve extreme ages, these age-by-SNP interactions could be a proxy for complex gene-gene interactions affecting personality traits and longevity

ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups.

BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments

RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans

The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered.Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function.Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan