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Objectives To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology ( SAVE), to determine its value for genetic analyses. Design Longitudinal, community-based cohort study. Setting The Long Life Family Study ( LLFS) in the United States and Denmark. Participants Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551). Measurements The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models. Results Heritability of the SAVE was 0.23 ( P < .001) overall (n = 3,599), 0.31 ( P < .001) in probands (n = 1,479), and 0.26 ( P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio ( HR) = 2.83, 95% confidence interval ( CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2). Conclusion The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses. [ABSTRACT FROM AUTHOR]

The lack of a formal definition of human longevity continues to generate confusion about its genetic and nongenetic determinants. In order to characterize how differences in birth year cohorts and percentiles of survival are associated with familial contribution to variation in survival, we estimated sibling relative risk of living to increasingly rare percentiles of survival based on a dataset of 1,917 validated sibships each containing at least one individual living to age 90 years. About 1,042 of the sibships included at least one individual who survived to age 100 and 511 included at least one individual who survived to age 105 and older. We show that sibling relative risk increases with older ages, sex, and earlier birth year cohorts of the proband and siblings of male 90-year-olds (5th percentile of survival) have 1.73 (95% CI: 1.5; 2.0) times the chance of living to age 90, while siblings of both male and female probands who survived to age 105 years (~0.01 percentile of survival) have 35.6 (95%CI: 15.1; 67.7) times the chance of living to age 105 compared with population controls. These results emphasize the importance of consistently defining the longevity phenotype in terms of rarity of survival for appropriate comparisons across studies. [ABSTRACT FROM AUTHOR]

Background: The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease?Methods: We used 2008-2010 Beneficiary Annual Summary Files from the Centers for Medicare & Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population. Analyses accounted for nesting within LLFS families.Results: Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure.Conclusions: Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life-limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen. [ABSTRACT FROM AUTHOR]

Background. Given previous evidence of familial predisposition for longevity, we hypothesized that siblings and parents of supercentenarians (age ≥ 110 years) were predisposed to survival to very old age and that, relative to their birth cohorts, their relative survival probabilities (RSPs) are even higher than what has been observed for the siblings of centenarians. Methods. Mean age at death conditional upon survival to ages 20 and 50 and survival probabilities from ages 20 and 50 to higher ages were determined for 50 male and 56 female siblings and 54 parents of 29 supercentenarians. These estimates were contrasted with comparable estimates based on birth cohort-specific mortality experience for the United States and Sweden. Results. Conditional on survival to age 20 years, mean age at death of supercentenarians' siblings was ~81 years for men and women. Compared with respective Swedish and U.S. birth cohorts, these estimates were 17%-20% (12-14 years) higher for the brothers and 11%-14% (8-10 years) higher for the sisters. Sisters had a 2.9 times greater probability and brothers had a 4.3 times greater probability of survival from age 20 to age 90. Mothers of supercentenarians had a 5.8 times greater probability of surviving from age 50 to age 90. Fathers also experienced an increased survival probability from age 50 to age 90 of 2.7, but it failed to attain statistical significance. Conclusions. The RSPs of siblings and mothers of supercentenarians revealed a substantial survival advantage and were most pronounced at the oldest ages. The RSP to age 90 for siblings of supercentenarians was approximately the same as that reported for siblings of centenarians. It is possible that greater RSPs are observed for reaching even higher ages such as 100 years, but a larger sample of supercentenarians and their siblings and parents is needed to investigate this possibility. [ABSTRACT FROM AUTHOR]

Discusses results of a population-based study determining the prevalence of dementia in centenarians in Boston, Massachusetts. Diagnostic criteria; Percent of population with no dementia and with some degree of dementia; Correlation of degree of dementia with activities of daily living abilities.

The authors discuss the illegal distribution of human growth hormones (hGHs). The U.S. Food and Drug Administration (FDA) specifies that anti-aging, bodybuilding, and athletic enhancement are not approved indications for human growth hormone (hGH). Issues surrounding the confusion of age-related diseases with the rare condition of adult growth hormone deficiency (GHD) are examined. They stress that there is no justifiable reason to prescribe hGH for adults who do not meet the criteria for adult GHD.

The author discusses the marketing of the drug procaine hydrochloride (Gerovital H3) in the U.S. as an antiaging and longevity treatment, despite the ban of the 1982 drug by the U.S. Food and Drug Administration (FDA). He notes that the government of Romania under Communist leader Nicolae Ceausescu promoted the drug in the 1950s. He presents several U.S. studies which found no antiaging or cognitive enhancing activities of Gerovital H3, other than a mild inhibition of monoamine oxidase (MAO).

Abstract: Exceptional longevity is associated with substantial heritability. The ɛ4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ɛ2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ɛ4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE ɛ2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ɛ4 allele and increase in the frequency of the ɛ2 allele contribute to longevity. [Copyright &y& Elsevier]

Background: This study compared the mortality risk of long-lived siblings with the U.S. population average and their spouse controls, and investigated the leading causes of death and the familial effect in death pattern., Methods: In the Long Life Family Study (LLFS), 1 264 proband siblings (mean age 90.1, standard deviation [SD] 6.4) and 172 spouses (83.8, 7.2) from 511 U.S.-based families were recruited and followed more than 12 years. Their survival function was compared with a birth cohort-, baseline age-, sex-, and race-matched pseudo sample from U.S. census data. To examine underlying and contributing causes, we examined in detail 338 deaths with complete death adjudication at the University of Pittsburgh Field Center through the year 2018. A familial effect on survival and death patterns was examined using mixed-effect models., Results: The LLFS siblings had better survival than the matched U.S. population average. They also had slightly but not significantly better survival than their spouses' (HR = 1.18 [95%CI 0.94-1.49]) after adjusting for age and sex. Age at death ranged from 75 to 104 years, mean 91.4. The leading causes of death were cardiovascular disease (33.1%), dementia (22.2%), and cancer (10.7%). Mixed effect model shows a significant random effect of family in survival, with adjustment of baseline age and sex. There was no significant familial effect in the underlying cause of death or conditions directly contributing to death among siblings recruited by the University of Pittsburgh Field Center., Conclusions: Our findings demonstrate a higher survival in the LLFS siblings than the U.S. census data, with a familial component of survival. We did not find significant correspondence in causes of death between siblings within families., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.

The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.

Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury., Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease., Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle., Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes., (© 2015 American Heart Association, Inc.)

Objective: This study investigated the association between maternal age at birth of last child and likelihood of survival to advanced age., Methods: This was a nested case-control study using Long Life Family Study data. Three hundred eleven women who survived past the oldest 5th percentile of survival (according to birth cohort-matched life tables) were identified as cases, and 151 women who died at ages younger than the top 5th percentile of survival were identified as controls. A Bayesian mixed-effect logistic regression model was used to estimate the association between maternal age at birth of last child and exceptional longevity among these 462 women., Results: We found a significant association for older maternal age, whereby women who had their last child beyond age 33 years had twice the odds for survival to the top 5th percentile of survival for their birth cohorts compared with women who had their last child by age 29 years (age between 33 and 37 y: odds ratio, 2.08; 95% CI, 1.13 to 3.92; older age: odds ratio, 1.92; 95% CI, 1.03 to 3.68)., Conclusions: This study supports findings from other studies demonstrating a positive association between older maternal age and greater odds for surviving to an unusually old age.

Background: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study., Methods: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model., Results: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring., Conclusion: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.

Objectives: Studies of health and longevity require accurate age reporting. Age misreporting among older adults in the United States is common., Methods: Participants in the Long Life Family Study (LLFS) were matched to early-life census records. Age recorded in the census was used to evaluate age reporting in the LLFS. The study population was 99% non-Hispanic white., Results: About 88% of the participants were matched to 1910, 1920, or 1930 U.S. censuses. Match success depended on the participant's education, place of birth, and the number of censuses available to be searched. Age at the time of the interview based on the reported date of birth and early-life census age were consistent for about 89% of the participants, and age consistency within 1 year was found for about 99% of the participants., Discussion: It is possible to match a high fraction of older study participants to their early-life census records when detailed information is available on participants' family of origin. Such record linkage can provide an important source of information for evaluating age reporting among the oldest old participants. Our results are consistent with recent studies suggesting that age reporting among older whites in the United States appears to be quite good.

Professional Athletes' misuse of anabolic steroids, growth hormone and other drugs are the tip of a very large, mostly ignored iceberg, made up of people who receive these drugs for such non-medical uses as body-building, school sports and "anti-aging". Although these drugs are often used in combination, this article focuses on growth hormone. Fuelling the demand for these drugs are drug manufacturers, pharmacies, websites, clinics and their doctors.

Objectives: To determine whether the offspring of centenarians have personality characteristics that are distinct from the general population., Design: Case-control., Setting: Nationwide U.S. sample., Participants: Unrelated offspring of centenarians (n=246, mean age 75) were compared with published norms., Measurements: Using the NEO-Five-Factor Inventory (NEO-FFI) questionnaire, measures of the personality traits neuroticism, extraversion, openness, agreeableness, and conscientiousness were obtained. T-scores and percentiles were calculated according to sex and used to interpret the results., Results: Male and female offspring of centenarians scored in the low range of published norms for neuroticism and in the high range for extraversion. The women also scored comparatively high in agreeableness. Otherwise, both sexes scored within normal range for conscientiousness and openness, and the men scored within normal range for agreeableness., Conclusion: Specific personality traits may be important to the relative successful aging demonstrated by the offspring of centenarians. Similarities across four of the five domains between male and female offspring is noteworthy and may relate to their successful aging. Measures of personality are an important phenotype to include in studies that assess genetic and environmental influences of longevity and successful aging.

Objectives: To report phenotypic characteristics of 32 age-validated supercentenarians., Design: Case series., Setting: U.S.-based recruitment effort., Participants: Thirty-two supercentenarians., Measurements: Multiple forms of proof were used to validate age claims. Sociodemographic, activities of daily living, and medical history data were collected., Results: Age range was 110 to 119. Fifty-nine percent had Barthel Index scores in the partially to totally dependent range, whereas 41% required minimal assistance or were independent. Few subjects had a history of clinically evident vascular-related diseases, including myocardial infarction (n=2, 6%) and stroke (n=4, 13%). Twenty-two percent (n=7) were taking medications for hypertension. Twenty-five percent (n=8) had a history of cancer (all cured). Diabetes mellitus (n=1, 3%) and Parkinson's disease (n=1, 3%) were rare. Osteoporosis (n=14, 44%) and cataract history (n=28, 88%) were common., Conclusion: Data collected thus far suggest that supercentenarians markedly delay and even escape clinical expression of vascular disease toward the end of their exceptionally long lives. A surprisingly substantial proportion of these individuals were still functionally independent or required minimal assistance.

Objectives: To assess the cause of death for centenarians' offspring and controls., Design: Cross-sectional study., Setting: Community-based, nationwide sample., Participants: Family pedigree information was collected on 295 offspring of centenarians (from 106 families with a parent already enrolled in the nationwide New England Centenarian Study) and on 276 controls (from 82 control families) from 1997 to 2000. Controls were individuals whose parents were born in the same year as the centenarians but at least one of whom died at the average life expectancy., Measurements: Age at death and cause of death., Results: Centenarians' offspring had a 62% lower risk of all-cause mortality (P<.001), a 71% lower risk of cancer-specific mortality (P=.002), and an 85% lower risk of coronary heart disease-specific mortality (P<.001). Significant differences were not found for other causes of death. However of those who died centenarian offsprings dead at a significantly younger age than controls., Conclusion: These findings suggest that centenarians' offspring have lower all-cause mortality rates and cause-specific mortality rates for cancer and coronary heart disease. These results suggest that mechanisms for survival to exceptional old age may go beyond the avoidance or delay of cardiovascular disease and also include the avoidance or delay of cancer. Moreover survival advantage of centenarian offsprings may not be due to factors related to childhood mortality. Ultimately, survival to exceptional old age may involve lower susceptibility to a broad range of age-related diseases, perhaps secondary to inhibition of basic mechanisms of aging.

To assess the presence of quackery in the anti-aging industry, the Internet was surveyed for web sites marketing anti-aging products as well as those providing consumer advice regarding quackery and hucksterism. The United States Federal Food, Drug, and Cosmetic Act and its amendments were reviewed, particularly as they pertain to dietary supplements and human growth hormone. Anti-aging quackery and hucksterism are pervasive on the Internet and in clinics advertising anti-aging treatments. Review of the marketing techniques of the industry revealed 15 common ruses used by many in the industry to market their products. Federal law states that distributing or administering human growth hormone for anti-aging or age-related problems is illegal. Nonetheless, anti-aging clinics thrive, administering human growth hormone to thousands of gullible and oftentimes vulnerable patients. Anti-aging quackery has become a multimillion dollar industry exacting great monetary, health, and social costs. Consumers and health care providers alike are wise to educate themselves on how to recognize quackery. Congress must reassess the wisdom of the 1994 Dietary Supplements Health and Education Act, which facilitates and, in numerous cases, endangers Americans on a grand scale. In the case of some substances such as human growth hormone, adequate legal safeguards are impotent without adequate resources allocated to enforcement agencies.

Although survival to old age is known to have strong environmental and behavioral components, mortality differences between social groups tend to diminish or even disappear at older ages. Hypothesizing that surviving to extreme old age entails a substantial familial predisposition for longevity, we analyzed the pedigrees of 444 centenarian families in the United States. These pedigrees included 2,092 siblings of centenarians, whose survival was compared with 1900 birth cohort survival data from the U.S. Social Security Administration. Siblings of centenarians experienced a mortality advantage throughout their lives relative to the U.S. 1900 cohort. Female siblings had death rates at all ages about one-half the national level; male siblings had a similar advantage at most ages, although diminished somewhat during adolescence and young adulthood. Relative survival probabilities for these siblings increase markedly at older ages, reflecting the cumulative effect of their mortality advantage throughout life. Compared with the U.S. 1900 cohort, male siblings of centenarians were at least 17 times as likely to attain age 100 themselves, while female siblings were at least 8 times as likely.