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Background: Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity., Methods: Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions., Results: Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43-1.86, p = 4.7 × 10-13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30-1.73 per 5 years, p = 3.1 × 10-8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04-1.40 per 5 years, p = .011) decreased the association., Conclusions: PhenoAge measured in 2006-2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes, or coronary heart disease, but whether these comorbidities are true risk factors (ie, more common than in the general older population) is unclear. We estimated associations between preexisting diagnoses and hospitalized COVID-19 alone or with mortality, in a large community cohort., Methods: UK Biobank (England) participants with baseline assessment 2006-2010, followed in hospital discharge records to 2017 and death records to 2020. Demographic and preexisting common diagnoses association tested with hospitalized laboratory-confirmed COVID-19 (March 16 to April 26, 2020), alone or with mortality, in logistic models., Results: Of 269 070 participants aged older than 65, 507 (0.2%) became COVID-19 hospital inpatients, of which 141 (27.8%) died. Common comorbidities in hospitalized inpatients were hypertension (59.6%), history of fall or fragility fractures (29.4%), coronary heart disease (21.5%), type 2 diabetes (type 2, 19. 9%), and asthma (17.6%). However, in models adjusted for comorbidities, age group, sex, ethnicity, and education, preexisting diagnoses of dementia, type 2 diabetes, chronic obstructive pulmonary disease, pneumonia, depression, atrial fibrillation, and hypertension emerged as independent risk factors for COVID-19 hospitalization, the first 5 remaining statistically significant for related mortality. Chronic kidney disease and asthma were risk factors for COVID-19 hospitalization in women but not men., Conclusions: There are specific high-risk preexisting comorbidities for COVID-19 hospitalization and related deaths in community-based older men and women. These results do not support simple age-based targeting of the older population to prevent severe COVID-19 infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people., Methods: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing., Results: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants., Conclusion: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Individuals with low cardiovascular risk factor profiles experience lower rates of cardiovascular diseases, but associations with geriatric syndromes are unclear. We tested whether individuals with low cardiovascular disease risk, aged 60-69 years old at baseline in two large cohorts, were less likely to develop aging-related adverse health outcomes., Methods: Data were from population representative medical records (Clinical Practice Research Datalink [CPRD] England, n = 239,591) and healthy volunteers (UK Biobank [UKB], n = 181,820), followed for ≤10 years. A cardiovascular disease risk score (CRS) summarized smoking status, LDL-cholesterol, blood pressure, body mass index, fasting glucose and physical activity, grouping individuals as low (ie, all factors near ideal), moderate, or high CRS. Logistic regression, Cox models, and Fine and Grey risk models tested the associations between the CRS and health outcomes., Results: Low CRS individuals had less chronic pain (UKB: baseline odds ratio = 0.52, confidence interval [CI] = 0.50-0.54), lower incidence of incontinence (CPRD: subhazard ratio [sub-HR] = 0.75, 0.63-0.91), falls (sub-HR = 0.82, CI = 0.73-0.91), fragility fractures (sub-HR = 0.78, CI = 0.65-0.93), and dementia (vs. high risks; UKB: sub-HR = 0.67, CI = 0.50-0.89; CPRD: sub-HR = 0.79, CI = 0.56-1.12). Only 5.4% in CPRD with low CRS became frail (Rockwood index) versus 24.2% with high CRS. All-cause mortality was markedly lower in the low CRS group (vs. high CRS; HR = 0.40, 95% CI = 0.35-0.47). All associations showed dose-response relationships, and results were similar in both cohorts., Conclusions: Persons aged 60-69 years with near-ideal cardiovascular risk factor profiles have substantially lower incidence of geriatric conditions and frailty. Optimizing cardiovascular disease risk factors may substantially reduce the burden of morbidity in later life., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Iron is essential for life but contributes to oxidative damage. In Northern-European ancestry populations, HFE gene C282Y mutations are relatively common (0.3%-0.6% rare homozygote prevalence) and associated with excessive iron absorption, fatigue, diabetes, arthritis, and liver disease, especially in men. Iron excess can be prevented or treated but diagnosis is often delayed or missed. Data on sarcopenia, pain, and frailty are scarce., Methods: Using 200,975 UK Biobank volunteers aged 60-70 years, we tested associations between C282Y homozygosity with Fried frailty, sarcopenia, and chronic pain using logistic regression adjusted for age and technical genetic covariates. As iron overload is progressive (with menstruation protective), we included specific analyses of older (65-70 years) females and males., Results: One thousand three hundred and twelve (0.65%) participants were C282Y homozygotes; 593 were men (0.62%) and 719 were women (0.68%). C282Y homozygote men had increased likelihoods of reporting chronic pain (odds ratio [OR] 1.23: 95% confidence interval [CI] 1.05-1.45, p = .01) and diagnoses of polymyalgia rheumatica, compared to common "wild-type" genotype. They were also more likely to have sarcopenia (OR 2.38: 1.80-3.13, p = 9.70 × 10-10) and frailty (OR 2.01: 1.45-2.80, p = 3.41 × 10-05). C282Y homozygote women (n = 312, 0.7%) aged 65-70 were more likely to be frail (OR 1.73: 1.05-2.84, p = .032) and have chronic knee, hip, and back pain. Overall, 1.50% of frail men and 1.51% of frail women in the 65-70 age group were C282Y homozygous., Conclusions: HFE C282Y homozygosity is associated with substantial excess sarcopenia, frailty, and chronic pain at older ages. Given the availability of treatment, hereditary hemochromatosis is a strong candidate for precision medicine approaches to improve outcomes in late life., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity., Methods: A genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted., Results: A genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p = .0002)., Conclusions: A promising genetic signal for parental life span was identified but was not replicated in independent samples., (Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Patterns of DNA methylation (DNAm) that track with aging have been identified. However, the relevance of these patterns for aging outcomes remains unclear. Longitudinal epigenome-wide DNAm information was obtained from the InCHIANTI study, a large representative European population. DNAm was evaluated using the Illumina HumanMethylation450 array on blood samples collected at baseline and 9-year follow-up: observations from 499 participants with paired longitudinal blood sample and information on differential blood count were included in analyses. A total of 56,579 markers were significantly associated with age in cross-sectional analysis of DNAm at year 9, 31,252 markers were changed significantly over the 9-year follow-up, and 16,987 markers were both cross-sectionally associated with age and significantly changed over time. Rates of change at 76 markers and year 9 level of DNAm at 88 markers were identified as strongly associated with mortality in Cox proportional hazard models adjusted for age and relevant covariates (mean follow-up time 4.4 years). Less than 0.05% of markers associated with age or that changed over time were also associated with mortality after adjusting for chronological age. Although the influence of DNAm on health and longevity remains unclear, these findings confirm that aging is associated cross-sectionally and longitudinally with robust and consistent patterns of methylation change., (Published by Oxford University Press on behalf of the Gerontological Society of America 2015.)