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This editorial comments on the article by Lu et al [ABSTRACT FROM AUTHOR]

The Trail Making Test (TMT) is a neuropsychological test used to assess cognitive dysfunction. The TMT consists of two parts: TMT‐A requires connecting numbers 1 to 25 sequentially; TMT‐B requires connecting numbers 1 to 12 and letters A to L sequentially, alternating between numbers and letters. We propose using a digitally recorded version of TMT to capture cognitive or physical functions underlying test performance. We analyzed digital versions of TMT‐A and ‐B to derive time metrics and used Bayesian hidden Markov models to extract additional metrics. We correlated these derived metrics with cognitive and physical function scores using regression. On both TMT‐A and ‐B, digital metrics associated with graphomotor processing test scores and gait speed. Digital metrics on TMT‐B were additionally associated with episodic memory test scores and grip strength. These metrics provide additional information of cognitive state and can differentiate cognitive and physical factors affecting test performance. [ABSTRACT FROM AUTHOR]

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' 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 < 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. [ABSTRACT FROM AUTHOR]

The article explores the high number of COVID-19 deaths in long-term care facilities (LTCFs) in the U.S. As of May 28, 2020 26 states reported that 50% or more of their coronavirus deaths occured in long-term care facilities. Topics discussed include the undercounting of deaths in some states, statistics on the COVID-19 pandemic from the Massachusetts Department of Public Health, and the consequences of ongoing isolation and other protective measures for the vulnerable populations of these establishments.

Because people age differently, age is not a sufficient marker of susceptibility to disabilities, morbidities, and mortality. We measured nineteen blood biomarkers that include constituents of standard hematological measures, lipid biomarkers, and markers of inflammation and frailty in 4704 participants of the Long Life Family Study ( LLFS), age range 30-110 years, and used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging. The signatures show that dysregulation of a single biomarker can change with patterns of other biomarkers, and age-related changes of individual biomarkers alone do not necessarily indicate disease or functional decline. [ABSTRACT FROM AUTHOR]

Objectives To determine reference values for laboratory tests in individuals aged 85 and older. Design Cross-sectional cohort study. Setting International. Participants Long Life Family Study (LLFS) participants (N~5,000, age: range 25-110, median 67, 45% male). Measurements Serum biomarkers were selected based on association with aging-related diseases and included complete blood count, lipids (triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol), 25-hydroxyvitamin D2 and D3, vitamin D epi-isomer, diabetes mellitus-related biomarkers (adiponectin, insulin, insulin-like growth factor 1, glucose, glycosylated hemoglobin, soluble receptor for advanced glycation endproduct), kidney disease-related biomarkers (albumin, creatinine, cystatin), endocrine biomarkers (dehydroepiandrosterone, sex-hormone binding globulin, testosterone), markers of inflammation (interleukin 6, high-sensitivity C-reactive protein, N-terminal pro b-type natriuretic peptide), ferritin, and transferrin. Results Of 38 measured biomarkers, 34 were significantly correlated with age. Summary statistics were generated for all biomarkers according to sex and 5-year age increments from 50 and up after excluding participants with diseases and treatments that were associated with biomarkers. A biomarker data set was also generated that will be useful for other investigators seeking to compare biomarker levels between studies. Conclusion Levels of several biomarkers change with older age in healthy individuals. The descriptive statistics identified herein will be useful in future studies and, if replicated in additional studies, might also become useful in clinical practice. The availability of the reference data set will facilitate appropriate calibration of biomarkers measured in different laboratories. [ABSTRACT FROM AUTHOR]

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]

Objectives To determine, in a sample of Ashkenazi Jewish aged 95 and older, whether there is a compression of morbidity similar to what has been reported in other cohorts with exceptional longevity. Design Case-control study. Setting Longevity Genes Project ( LGP) and New England Centenarian Study ( NECS). Participants LGP (n = 439, mean age 97.8 ± 2.8) and NECS (n = 1,498, mean age 101.4 ± 4.0) participants with exceptional longevity and their respective younger referent cohorts ( LGP, n = 696; NECS, n = 302). Measurements Self- and proxy reports of age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension, osteoporosis, and stroke. Results Long-lived individuals from LGP and NECS had later age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension, and osteoporosis than their respective younger reference groups. The risk of overall morbidity was lower in participants with exceptional longevity than in younger participants ( NECS men: relative risk ( RR) = 0.12, women: RR = 0.20; LGP men: RR = 0.18, women: RR = 0.24). The age at which 20% of each of the groups with exceptional longevity experienced specific diseases was between 18 and 24 years later than in the reference groups, stratified according to sex. Conclusion The similar extension of health span and compression of morbidity seen in NECS and LGP participants with exceptional longevity further validates the utility of these rare individuals for the study of factors that delay or prevent a broad spectrum of diseases otherwise associated with mortality and disability. [ABSTRACT FROM AUTHOR]

The author discusses differences between male and female centenarians. Topics include the higher survival rate of women centenarians as compared to men according to the 2005 U.S. Social Security Administration birth cohort life tables, the impact of environment and health-related behaviors such as cigarette use on survival rates, and the tendency for women who naturally bear children in their 40's to be four to five times more likely to live to become centenarians.

Objectives To determine whether oral health is better in centenarians than in a published birth cohort-matched sample and to compare oral health in centenarian offspring with a case-controlled reference sample. Design Observational cross-sectional study. Setting New England Centenarian Study ( NECS). Participants Seventy-three centenarians, 467 offspring, and 251 offspring generation-reference cohort subjects from the NECS. Measurements A self-report questionnaire was administered to measure oral health in all three groups, with edentulous rate as the primary outcome measure. The NECS made information on sociodemographic characteristics and medical history available. Centenarian results were compared with published birth cohort-matched results. Data from offspring and reference cohorts were analyzed to determine differences in oral health and associations between oral health measures and specific medical conditions. Results The edentulous rate of centenarians (36.5%) was lower than that of their birth cohort (46%) when they were aged 65 to 74 in 1971 to 1974 (according to National Center of Health Statistics). Adjusting for confounding factors, the reference cohort was more likely to be edentulous (adjusted odds ratio ( AOR) = 2.78, 95% confidence interval CI = 1.17-6.56), less likely to have all or more than half of their own teeth (AOR = 0.48, 95% CI = 0.3-0.76), and less likely to report excellent or very good oral health (AOR = 0.65, 95% CI = 0.45-0.94) than the centenarian offspring. Conclusion Centenarians and their offspring have better oral health than their respective birth cohorts. Oral health may prove to be a helpful marker for systemic health and healthy aging. [ABSTRACT FROM AUTHOR]

A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N = 873) and genetically matched younger controls ( N = 443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR = 1.56, P = 2.5 × 10−5, multiple-testing-adjusted P = 0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) ( N = 738), (ii) the Southern Italian Centenarian Study (SICS) ( N = 905), (iii) France ( N = 1103), and (iv) the Einstein Ashkenazi Longevity Study ( N = 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, P = 0.0023), but not in the other three samples ( P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, P = 7.5 × 10−4, multiple-testing-adjusted P = 0.037). These results suggest that LMNA variants may play a role in human lifespan. [ABSTRACT FROM AUTHOR]

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. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the relative incidence of age-related diseases in a group of centenarian offspring who have thus far been considered to be predisposed to “healthy” aging. DESIGN: Longitudinal study. SETTING: Nationwide sample. PARTICIPANTS: Four hundred forty centenarian offspring and 192 referent cohort subjects who met inclusion criteria of having initial and follow-up health questionnaire data available. Median age of both cohorts was 72 at the initial health questionnaire. MEASUREMENTS: Initial health questionnaires were collected from 1997 to 2006. Follow-up questionnaires were collected from 2004 to 2007. The mean period of follow-up was 3.5±1.7 years for the centenarian offspring and 3.9±2.2 years for the referent cohort. RESULTS: During the follow-up period, centenarian offspring had a 78% lower risk of myocardial infarction ( P<.04), 83% lower risk of stroke ( P<.004), and 86% lower risk of developing diabetes mellitus ( P<.005) than the referent cohort. There were no significant differences in new onset of other age-related diseases. Additionally, centenarian offspring were 81% less likely to die ( P<.01) than the referent cohort during the follow-up. CONCLUSION: These findings suggest that centenarian offspring retain some important cardiovascular advantages over time over similarly aged referent cohort subjects. These findings reinforce the notion that there may be physiological reasons that longevity runs in families and that centenarian offspring are more likely to age in better cardiovascular health and with a lower mortality than their peers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Attaining age 100 is a rare event in industrialized nations, occurring in 1 person per 10,000 in the population. Becoming a centenarian does not appear to be rare because the individual genetic or behavioral factors (such as specific genetic polymorphisms or lack of specific toxic exposures) that enable such longevity are rare, but rather because having the adequate combination of these factors is rare. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age-matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10-fold lower levels of circulating serum HSP70 compared with spousal controls (P <.001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity. [ABSTRACT FROM AUTHOR]

There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human's ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health. To live beyond the octogenarian years, life-span experiments in lower organisms and mammals and population and molecular genetic studies of centenarian sibships suggest that genetic factors play an important role in exceptional longevity. These factors are likely to influence basic mechanisms of aging, which in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease, and having variations that confer disease resistance (longevity enabling genes), are probably both important to such a remarkable survival advantage. Recent studies indicate the likelihood that such factors will be elucidated in the near future. [ABSTRACT FROM AUTHOR]

The authors reflect on advertising for testosterone products in the U.S. and Canada. They suggest that a combination of direct to consumer product advertising and lax guidelines for testosterone prescribing have led to 10 and 40 fold increases in testosterone prescriptions in the United States and Canada. They argue that the United States Food and Drug Administration and Health Canada should require demonstration of pathology to provide and fill a lawful prescription for testosterone.

Centenarians provide a unique lens through which to study longevity, healthy aging, and resiliency. Moreover, models of human aging and resilience to disease that allow for the testing of potential interventions are virtually non‐existent. We obtained and characterized over 96 centenarian and offspring peripheral blood samples including those connected to functional independence data highlighting resistance to disability and cognitive impairment. Targeted methylation arrays were used in molecular aging clocks to compare and contrast differences between biological and chronological age in these specialized subjects. Isolated peripheral blood mononuclear cells (PBMCs) from 20 of these subjects were then successfully reprogrammed into high‐quality induced pluripotent stem cell (iPSC) lines which were functionally characterized for pluripotency, genomic stability, and the ability to undergo directed differentiation. The result of this work is a one‐of‐a‐kind resource for studies of human longevity and resilience that can fuel the discovery and validation of novel therapeutics for aging‐related disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late‐onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e2 allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOEe2, with aptamer‐based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late‐onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOEe2 molecularly may preserve cognitive function. [ABSTRACT FROM AUTHOR]

To assess the cause of death for centenarians' offspring and controls.Cross-sectional study.Community-based, nationwide sample.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.Age at death and cause of death.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.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. [ABSTRACT FROM AUTHOR]

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).