10-year follow-up of the Super-Seniors Study: compression of morbidity and genetic factors.

BACKGROUND: Super-Seniors are healthy, long-lived individuals who were recruited at age 85 years or older with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease. In a 10-year follow-up, we aimed to determine whether surviving Super-Seniors showed compression of morbidity, and to test whether the allele frequencies of longevity-associated variants in APOE and FOXO3 were more extreme in such long-term survivors. METHODS: Super-Seniors who survived and were contactable were re-interviewed 10 years after initial characterization. Health and lifestyle were characterized via questionnaire. Geriatric tests including the Timed Up and Go (TUG), Geriatric Depression Scale (GDS), Instrumental Activities of Daily Living (IADL) and the Mini-Mental State Exam (MMSE) were administered, and data were compared to results from on average 10 years earlier. As well, genotype and allele frequencies for SNPs rs7412 and rs429358 in APOE, and rs2802292 in FOXO3 were compared to the frequencies in the original collection of Super-Seniors and mid-life controls. RESULTS: Of the 480 Super-Seniors recruited from 2004 to 2007, 13 were alive, contactable, and consented to re-interview (mean age = 100.1 ± 3.3). Eight of these 13 participants (62%) still met Super-Senior health criteria. Diseases that occurred in late life were cardiovascular (5 of 13; 38%) and lung disease (1 of 13; 8%). MMSE and IADL scores declined in the decade between interviews, and GDS and TUG scores increased. The surviving group of centenarians had a higher frequency of APOE and FOXO3 longevity-associated variants even when compared to the original long-lived Super-Senior cohort. CONCLUSIONS: Although physical and mental decline occurred in the decade between interviews, the majority of Super-Seniors re-interviewed still met the original health criteria. These observations are consistent with reports of compression of morbidity at extreme ages, particularly in centenarians. The increased frequency of longevity- associated variants in this small group of survivors is consistent with studies that reported genetics as a larger contributor to longevity in older age groups.

Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers.

BACKGROUND: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease. OBJECTIVE: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals. METHODS: We compared the number of disease-associated alleles, and the proportion of alleles predicted to be functionally damaging, between the centenarian brothers and published population data. Mitochondrial sequence reads were extracted from the exome data in order to analyze mitochondrial variants. RESULTS: The brothers carry a similar number of common disease-associated variants and predicted damaging variants compared to reference groups. They did not carry any high-penetrance clinically actionable variants. They carry mitochondrial haplogroup T, and one brother has a single heteroplasmic variant. CONCLUSION: Although our small sample size does not allow for definitive conclusions, a healthy aging and longevity phenotype is not necessarily due to a decreased burden of common disease-associated variants. Instead, it may be rare 'positive' variants that play a role in this desirable phenotype.

Wearable Biosensors in the Workplace: Perceptions and Perspectives.

Objectives: Wearable body and brain sensors are permeating the consumer market and are increasingly being considered for workplace applications with the goal of promoting safety, productivity, health, and wellness. However, the monitoring of physiologic signals in real-time prompts concerns about benefit and risk, ownership of such digital data, data transfer privacy, and the discovery and disclosure of signals of possible health significance. Here we explore the perceptions and perspectives of employers and employees about key ethical considerations regarding the potential use of sensors in the workplace. Methods: We distributed a survey developed and refined based on key research questions and past literature to a wide range and size of industries in British Columbia, Canada. Both employers (potential Implementers) and employees (potential Users) were invited to participate. Results: We received 344 survey responses. Most responses were from construction, healthcare, education, government, and utilities sectors. Across genders, industries, and workplace sizes, we found a convergence of opinions on perceived benefit and concern between potential Implementers and potential Users regarding the motivation to use biosensors in the workplace. Potential Implementers and Users also agreed on issues pertaining to safety, privacy, disclosure of findings of possible medical significance, risks, data ownership, data sharing, and transfer of data between workplaces. The greatest variability between potential Users and Implementers pertained to data ownership. Conclusion: Strong agreement in the perception of biosensor use in the workplace between potential Implementers and Users reflects shared interest, motivation, and responsibility for their use. The use of sensors is rapidly increasing, and transparency about key use factors-both practical and ethical-is essential to maintain the current and desirable level of solidarity.

Gynecologic Cancer Risk and Genetics: Informing an Ideal Model of Gynecologic Cancer Prevention.

Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit "Gynecologic Cancer Prevention: Thinking Big, Thinking Differently" in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy.

Allele-Specific Transcript Abundance: A Pilot Study in Healthy Centenarians.

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

Influenza Classification Suite: An automated Galaxy workflow for rapid influenza sequence analysis.

Influenza viruses continually evolve to evade population immunity, and the different lineages are assigned into clades based on shared mutations. We have developed a publicly available computational workflow, the Influenza Classification Suite, for rapid clade mapping of sequenced influenza viruses. This suite provides a user-friendly workflow implemented in Galaxy to automate clade calling and antigenic site extraction. Workflow input includes clade definition and amino acid index array files, which can be customized to identify any clades of interest. The Influenza Classification Suite provides rapid, high-resolution understanding of circulating influenza strain evolution to inform influenza vaccine effectiveness and the need for potential vaccine reformulation.

Extraction and Detection of Avian Influenza Virus From Wetland Sediment Using Enrichment-Based Targeted Resequencing.

Early virus detection and characterization is key to successful avian influenza virus (AIV) surveillance for the health of humans as well as domestic poultry. We explored a novel sampling approach and molecular strategy using sediment from wetlands and outdoor waterbodies on poultry farms as a population-level proxy of AIV activity in waterfowls. RNA was extracted using the MoBio RNA PowerSoil Total RNA isolation kit with additional chloroform extraction steps to reduce PCR inhibition. AIV matrix protein (MP) gene was detected in 42/345 (12.2%) samples by RT-qPCR; an additional 64 (18.6%) samples showed evidence of amplification below the threshold and were categorized as "suspect positive." Enrichment-based targeted resequencing (TR) identified AIV sequences in 79/345 (22.9%) samples. TR probes were designed for MP, hemagglutinin (HA), and neuraminidase (NA), however PB2 and PA were also identified. Although RT-qPCR and TR only had fair-moderate agreement, RT-qPCR positivity was predictive of TR-positivity both when using only strictly positive RT-qPCR samples (OR = 11.29) and when coding suspect positives as positive (OR = 7.56). This indicates that RT-qPCR could be used as a screening tool to select samples for virus characterization by TR and that future studies should consider RT-qPCR suspect positives to be positive samples for subsequent resequencing when avoiding false negatives is the priority, for instance in a diagnostic test, and to consider suspect positives to be negative samples when cost efficiency over a large number of samples is the priority, for instance in a surveillance program. A total of 13 HA (H1-7, H9-13, H16) and 9 NA (N1-9) subtypes were identified, with a maximum of 8 HA and 8 NA subtypes detected in a single sample. The optimized RNA extraction and targeted resequencing methods provided increased virus detection and subtyping characterization that could be implemented in an AIV surveillance system.

Evidence for transmission of COVID-19 prior to symptom onset.

We collated contact tracing data from COVID-19 clusters in Singapore and Tianjin, China and estimated the extent of pre-symptomatic transmission by estimating incubation periods and serial intervals. The mean incubation periods accounting for intermediate cases were 4.91 days (95%CI 4.35, 5.69) and 7.54 (95%CI 6.76, 8.56) days for Singapore and Tianjin, respectively. The mean serial interval was 4.17 (95%CI 2.44, 5.89) and 4.31 (95%CI 2.91, 5.72) days (Singapore, Tianjin). The serial intervals are shorter than incubation periods, suggesting that pre-symptomatic transmission may occur in a large proportion of transmission events (0.4-0.5 in Singapore and 0.6-0.8 in Tianjin, in our analysis with intermediate cases, and more without intermediates). Given the evidence for pre-symptomatic transmission, it is vital that even individuals who appear healthy abide by public health measures to control COVID-19.

The first cases of COVID-19 were identified in Wuhan, a city in Central China, in December 2019. The virus quickly spread within the country and then across the globe. By the third week in January, the first cases were confirmed in Tianjin, a city in Northern China, and in Singapore, a city country in Southeast Asia. By late February, Tianjin had 135 cases and Singapore had 93 cases. In both cities, public health officials immediately began identifying and quarantining the contacts of infected people. The information collected in Tianjin and Singapore about COVID-19 is very useful for scientists. It makes it possible to determine the disease's incubation period, which is how long it takes to develop symptoms after virus exposure. It can also show how many days pass between an infected person developing symptoms and a person they infect developing symptoms. This period is called the serial interval. Scientists use this information to determine whether individuals infect others before showing symptoms themselves and how often this occurs. Using data from Tianjin and Singapore, Tindale, Stockdale et al. now estimate the incubation period for COVID-19 is between five and eight days and the serial interval is about four days. About 40% to 80% of the novel coronavirus transmission occurs two to four days before an infected person has symptoms. This transmission from apparently healthy individuals means that staying home when symptomatic is not enough to control the spread of COVID-19. Instead, broad-scale social distancing measures are necessary. Understanding how COVID-19 spreads can help public health officials determine how to best contain the virus and stop the outbreak. The new data suggest that public health measures aimed at preventing asymptomatic transmission are essential. This means that even people who appear healthy need to comply with preventive measures like mask use and social distancing.

The Super-Seniors Study: Phenotypic characterization of a healthy 85+ population.

BACKGROUND: To understand why some people live to advanced age in good health and others do not, it is important to study not only disease, but also long-term good health. The Super-Seniors Study aims to identify factors associated with healthy aging. METHODS: 480 healthy oldest-old 'Super-Seniors' aged 85 to 105 years and never diagnosed with cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease, were compared to 545 mid-life controls aged 41-54, who represent a group that is unselected for survival from late-life diseases. Health and lifestyle information, personal and family medical history, and blood samples were collected from all participants. Super-Seniors also underwent four geriatric tests. RESULTS: Super-Seniors showed high cognitive (Mini-Mental State Exam mean = 28.3) and functional capacity (Instrumental Activities of Daily Living Scale mean = 21.4), as well as high physical function (Timed Up and Go mean = 12.3 seconds) and low levels of depression (Geriatric Depression Scale mean = 1.5). Super-Seniors were less likely to be current smokers than controls, but the frequency of drinking alcohol was the same in both groups. Super-Seniors were more likely to have 4 or more offspring; controls were more likely to have no children. Female Super-Seniors had a mean age of last fertility 1.9 years older than controls, and were 2.3 times more likely to have had a child at ≥ 40 years. The parents of Super-Seniors had mean ages of deaths of 79.3 years for mothers, and 74.5 years for fathers, each exceeding the life expectancy for their era by a decade. CONCLUSIONS: Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age, representing the approximately top 1% for healthspan. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype.

Lipid and Alzheimer's disease genes associated with healthy aging and longevity in healthy oldest-old.

Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.

Rare and common variants in the Apolipoprotein E gene in healthy oldest old.

Apolipoprotein E (APOE) alleles are associated with longevity in genome-wide scans, with ε4 correlated with shorter life, and ε2 with longer life, than ε3. We hypothesized that rare APOE variants with large individual effects might also contribute to long-term good health. The APOE exons and promoter were resequenced in DNA samples from 376 healthy oldest old aged ≥ 85 yrs with no self-reported history of cancer, cardiovascular disease, diabetes, major pulmonary disease or Alzheimer disease ("Super-Seniors") and 376 population-based controls aged 41-54. Forty variants were observed: 32 were rare (minor allele frequency <2%); 9 were nonsynonymous. Controls were more likely to have an ε4 allele (Pearson χ(2) = 6.61, p = 0.04). Among the Super-Seniors, APOE allele status was not associated with body mass index or Mini Mental State Examination score. There was no excess of rare APOE variants in healthy oldest old compared with midlife controls, or vice-versa; however, this does not rule out an effect of some variants on ApoE function. Our findings were consistent with ε4 being a risk factor for early mortality.