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OBJECTIVES: We investigated trends in disability among older Americans from 1988 through 2004 to test the hypothesis that more recent cohorts show increased burdens of disability. METHODS: We used data from 2 National Health and Nutrition Examination Surveys (1988-1994 and 1999-2004) to assess time trends in basic activities of daily living, instrumental activities, mobility, and functional limitations for adults aged 60 years and older. We assessed whether changes could be explained by sociodemographic, body weight, or behavioral factors. RESULTS: With the exception of functional limitations, significant increases in each type of disability were seen over time among respondents aged 60 to 69 years, independent of sociodemographic characteristics, health status, relative weight, and health behaviors. Significantly greater increases occurred among non-Whites and persons who were obese or overweight (2 of the fastest-growing subgroups within this population). We detected no significant trends among respondents aged 70 to 79 years; in the oldest group (aged>or=80 years), time trends suggested lower prevalence of functional limitations among more recent cohorts. CONCLUSIONS: Our results have significant and sobering implications: older Americans face increased disability, and society faces increased costs to meet the health care needs of these disabled Americans. [ABSTRACT FROM AUTHOR]

Objective: This article provides estimates of education differentials in life expectancy with and without cognitive impairment for the noninstitutionalized population aged 70 years and older in the United States. Method: Life expectancy with cognitive impairment was calculated using multistate models, allowing transitions between cognitively intact and cognitively impaired states and from each of these states to death and allowing transition rates to vary across age and education. Four waves of the Assets and Health Dynamics of the Oldest Old survey were used. Results: Those with low levels of education are more likely to become cognitively impaired and do so at an earlier age. After age 70, persons with low educational levels can expect to live 11.6 years, and persons with high education 14.1 years, without cognitive impairment. Length of life with cognitive impairment differs by education (1.6 years and 1.0 years at age 70, respectively) but differs little by age. Discussion: Although those with higher education have lower rates of both cognitive impairment and mortality, those who do become cognitively impaired appear to be in poorer health, leading to a reduced probability of improved cognition and increased probability of mortality relative to those with lower educational levels. [ABSTRACT FROM AUTHOR]

Background: Inflammatory proteins including interleukin-6 (IL-6) and C-reactive protein (CRP) have been associated with incident cognitive impairment, but little research has addressed their effects on the rate of cognitive change, and findings are mixed. The purpose of this study was to examine the relationship between serum levels of IL-6 and CRP and the rate of cognitive change across a range of cognitive domains in a sample of healthy older persons.Methods: Growth curve analysis was performed on data from the MacArthur Study of Successful Aging, a longitudinal cohort study of high-functioning older adults aged 70-79 years at baseline in 1988 and reinterviewed in 1991 and 1995 (N = 851). Individual growth curve parameters were derived from baseline and follow-up performance in abstraction, language, spatial ability, verbal recall, spatial recognition, and global cognitive function based on age, IL-6, CRP, and covariates.Results: Cross-sectionally, there is a generally linear negative relationship between inflammation and cognition, such that higher levels of inflammation are associated with lower levels of baseline cognitive function. After controlling for potential confounders, there was no effect of inflammation on baseline cognitive function or the rate of longitudinal cognitive change. However, persons in the top tertile on IL-6 were at an increased risk of incident declines on the Short Portable Mental Status Questionnaire (SPMSQ).Conclusions: Although high levels of inflammation are associated with incident cognitive impairment, these results do not generalize to the full range of cognitive changes, where the role of inflammation appears to be marginal. [ABSTRACT FROM AUTHOR]

This article uses a demographic approach and data from the Health and Retirement Survey, a nationally representative sample of the U.S. population, to investigate sex differences in the length of life lived with heart disease and after a heart attack for persons in the United States age 50 and older. On average, women live longer than men with heart disease. At age 50 women can expect to live 7.9 years and men 6.7 years with heart disease. The average woman experiences heart disease onset three years older and heart attacks 4.4 years older than men. [ABSTRACT FROM AUTHOR]

Background: Growing evidence from animal studies suggests an interaction between antioxidants and apolipoprotein E (APOE) alleles on cognitive functioning. We used data from a 7-year cohort study of high-functioning older persons to explore whether the associations between serum beta-carotene level and subsequent decline of cognitive function differed by APOE 4 genotype.Methods: Baseline information on sociodemographic characteristics, serum beta-carotene level, inflammation markers, APOE genotype, and cognitive functioning measured by a 9-item Short Portable Mental Status Questionnaire (SPMSQ) was obtained in 455 survivors. Multivariable logistic regression analyses were used to examine the relation between high serum beta-carotene level and risk of SPMSQ score decline in participants with or without APOE 4 alleles, while adjusting for age, sex, race, baseline SPMSQ score, and other covariates.Results: Nine (2%) study participants had homozygous and 97 (21%) had heterozygous APOE 4 alleles. Two hundred forty-nine (55%) had decline of SPMSQ scores during the follow-up. The presence of an APOE 4 allele was associated with higher risk and larger magnitude of SPMSQ score decline. The adjusted odds ratio of high beta-carotene level for cognitive decline was 0.11 (95% confidence interval, 0.02-0.57) in participants with at least one APOE 4 allele and 0.89 (95% confidence interval, 0.54-1.47) among those who were APOE 4 negative.Conclusion: Among high-functioning older persons, antioxidants and beta-carotene in particular may offer protection from cognitive decline in persons with greater genetic susceptibility as evidenced by the presence of the APOE 4 allele. [ABSTRACT FROM AUTHOR]

This paper examines gender differences in life with and without six major diseases, including both mortal and morbid conditions. Disease prevalence and health behavior data are from the 1993-1995 National Health Interview Surveys for the United States. Vital registration data are the source of mortality rates used in computing life expectancy. The Sullivan method is used to estimate life lived with and without disease and risky behavior for men and women at various ages. Women live more years with each of the diseases examined, and, for arthritis, the extended years with disease are greatest. Women also live more years than men free of each of these diseases with the exception of arthritis. Gender differences in life without two health-risk behaviors are also discussed. Men spend more years of their lives overweight and have fewer years during which they see a doctor. [ABSTRACT FROM AUTHOR]

Background: The relationship between change in cognitive and physical performance has yet to be fully understood. Because aging decreases the ability to learn new information while preserving more established knowledge, this article examines whether the association between change in cognitive and physical performance depends on the nature of the physical task.Methods: Data from the MacArthur Research Network on Successful Aging Community Study--a longitudinal three-site, cohort study of high-functioning, disability-free Americans aged 70 to 79 in 1988 (reinterviewed in 1991 and 1995)--are used for this investigation. We examine the association between change in cognitive performance and two categories of physical performance: novel/attentional demanding physical tasks (e.g., standing on a single leg) or routine physical tasks (e.g., walking at a normal pace). Change in physical performance (over 7 years) is regressed on change in cognitive performance (over the same period) controlling for baseline cognitive ability, demographic factors, health status, and behavioral characteristics.Results: The findings suggest that declines in cognitive performance are associated with declines in both novel/attentional demanding and routine physical tasks. In addition to decline in cognition, gender, prevalent health conditions (e.g., cancer, high blood pressure, and the fracture of a hip), and smoking behavior are associated with decline in performance on some physical tasks.Conclusions: The findings suggest that the successful execution of physical tasks demands cognitive processes regardless of the nature of the task. Researchers using performance-based measures of physical functioning should pay particular attention to the cognitive capacities of their subjects and how these might influence their assessment. [ABSTRACT FROM AUTHOR]

The Longitudinal Study on Aging (LSOA) and the National Health Interview Survey (NHIS) are used to examine change in the prevalence of disability from 1982 through 1993 for persons 70 years of age and over. Changes in the likelihood of becoming disabled and the likelihood of recovering from disability also are investigated with the LSOA. There is some evidence for improving disability status among the old. The prevalence of disability is somewhat lower in more recent years in the NHIS; also, the incidence of disability is lower, and the rate of recovery higher during 1988-90 than in the 1984-86 interval. On the other hand, the prevalence of disability increases at some dates after 1984 in the LSOA sample. In both datasets, there is fluctuation rather than a clear trend in the prevalence of disability. Continued steady improvement in rates of onset and recovery and a consistent trend toward improving prevalence is needed before concluding that we are witnessing the beginning of an ongoing trend toward improving health among the older population. [ABSTRACT FROM AUTHOR]

Purpose: To quantify socioeconomic status and ethnic differences in risk for coronary heart disease (CHD) accrued from major risk factors in the United States.Methods: Data came from the National Health and Nutrition Examination Survey 2001-2006. Outcomes examined were (a) 10-year risk for CHD events as predicted by the National Cholesterol Education Program Adult Treatment Panel III 2004 Updated Guidelines; and (b) the prevalence of the metabolic syndrome and overt diabetes mellitus (a CHD risk-equivalent).Results: Strong inverse socioeconomic gradients with risk were present in all race/ethnicity groups except foreign-born Mexican American men, and were attenuated by controls for physical activity, smoking, and abdominal obesity. In contrast, race/ethnicity disparities were seen in some but not all socioeconomic strata, with some non-Hispanic Blacks and US-born Mexican Americans having higher risk and some foreign-born Mexican Americans having lower risk.Conclusions: Disparities in cardiovascular risk in the United States are primarily related to socioeconomic status and less to race/ethnicity. Socioeconomically disadvantaged individuals should be targeted for lifestyle counseling and early screening for risk factors, regardless of race/ethnicity, to reduce social disparities in cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

While racial inequities in dementia risk are well-documented in the United States, research has paid less attention to role of US Southern context in shaping dementia risk through life course exposures. In this study, we examine how Southern birth and Southern residence in adulthood are linked to dementia incidence for Black and White older adults in the United States. Using the Health and Retirement Study (N = 15,613), we estimate a series of hazard models to evaluate how life course risk factors such as childhood health and social disadvantage, education, adult socioeconomic status, health behaviors, and cardiometabolic conditions impact the association between Southern life course residency and dementia risk. We find different patterns in how Southern life course context shapes dementia risk among Black and White adults, with dementia risk among Blacks especially sensitive to combinations of Southern life course context. These findings demonstrate the importance of considering potential heterogenous life course pathways to cognitive aging and health that may be shaped by larger socio-historical experiences., Competing Interests: Declarations Ethic approval and consent to participate The Health and Retirement Study is a publicly available dataset managed by the University of Michigan. The University of Michigan obtains and maintains IRB approval along with acquiring consent from participating respondents. Consent for publication Not applicable. Consent for publication is given at initial enrollment of participants into the Health and Retirement Study. Respondents are informed that their responses may be used in research and will be publicly available. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Chronic low-grade systemic inflammation is a risk factor for chronic diseases and mortality and is an important biomarker in health research. DNA methylation (DNAm) surrogate biomarkers are valuable exposure, risk factor and health outcome predictors in studies where the measures cannot be measured directly and often perform as well or better than direct measure. We generated a DNAm surrogate biomarker for chronic, systemic inflammation from a systemic inflammation latent variable of seven inflammatory markers and evaluated its performance relative to measured inflammatory biomarkers in predicting several age-associated outcomes of interest, including mortality, activities of daily living and multimorbidity in the Health and Retirement Study (HRS). The DNAm surrogate, Inflammation Latent Variable Methylation Surrogate (InfLaMeS), correlated with seven individual inflammation markers (r= -0.2-0.6) and performed as well or better to the systemic inflammation latent variable measure when predicting multimorbidity, disability, and 4-year mortality in HRS. Findings were validated in an external cohort, The Irish Longitudinal Study of Ageing. These results suggest that InfLaMeS provides a robust alternative to measured blood-chemistry measures of inflammation with broad applicability in instances where values of inflammatory markers are not measured but DNAm data is available.

Past research suggests that resilience to health hazards increases with age, potentially because less resilient individuals die at earlier ages, leaving behind their more resilient peers. Using lifetime cigarette smoking as a model health hazard, we examined whether accelerated epigenetic aging (indicating differences in the speed of individuals' underlying aging process) helps explain age-related resilience in a nationally representative sample of 3,783 older U.S. adults from the Health and Retirement Study. Results of mediation moderation analyses indicated that participants aged 86 or older showed a weaker association between lifetime cigarette smoking and mortality relative to participants aged 76-85 and a weaker association between smoking and multimorbidity relative to all younger cohorts. This moderation effect was mediated by a reduced association between smoking pack-years and epigenetic aging. This research helps identify subpopulations of particularly resilient individuals and identifies epigenetic aging as a potential mechanism explaining this process. Interventions in younger adults could utilize epigenetic aging estimates to identify the most vulnerable individuals and intervene before adverse health outcomes, such as chronic disease morbidity or mortality, manifest., (Copyright © 2024 The Authors.)

Objective: Functional limitations are prevalent among aging demographics, especially women. Structural and health factors, which vary worldwide, influence rates of functional limitations. Yet, gender disparities in functional limitation remain unclear in a global context., Methods: We use 2018 data from the Health and Retirement Study (HRS) international family of studies with respondents ages 50-64 and (n = 87,479) and 65-89 (n = 92,145) to investigate gender disparities in large muscle functional limitation (LMFL) across 10 countries/regions using mixed effects logistic regression, with special attention to structural indicators of inequality and health., Results: Among both women and men, LMFL was generally higher in China, India, Mexico, United States, and Baltic States than in England, Scandinavia, Southern Europe, Eastern Europe, and Western Europe. The gender disparity in LMFL gradually declined at older ages in India, China, Mexico, and United States, while this disparity gradually increased at older ages throughout Europe. Among middle age respondents, the greater risk of LMFL for women in countries/regions with a high GII was no longer observed after accounting for comorbidities. Among older respondents, a lower risk of LMFL for women in countries/regions with a high GII was not observed until accounting for comorbidities., Discussion: Our findings suggest that rates of LMFL are higher in middle-income countries than high-income countries, especially among women, and in countries with a higher GII. In addition, consideration of comorbidities was integral to these relationships. Thus, national/regional contexts inform differential rates of functional limitation, particularly as it relates to gender., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: We investigate global differences in psychosocial well-being between older adult age groups., Methods: Using multinomial logistic regression, we analyzed 2018 data ( n = 93,663) from 9 countries/regions in the Health and Retirement Study international family of studies to compare age group differences in depression, loneliness, and happiness., Results: Compared to the young old, the old-old reported more depression in Southern Europe, while the oldest old had higher risk in India and Southern Europe but lower risk in the United States. The old-old reported less loneliness in the United States but more in Southern Europe, while the oldest old had greater risk in Southern Europe. The old-old reported less happiness in Korea, while the oldest old had lower reports in Korea but higher reports in the United States., Discussion: The psychosocial well-being of the oldest old is exceptionally good in the United States but exceptionally poor in Southern Europe., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Low childhood socioeconomic status (SES) is a social hallmark of aging that contributes to adult health disparities and earlier morbidity and mortality. Childhood perceptions of stress are associated with child health outcomes and may contribute to premature biological aging into adulthood., Objective: To describe the association of childhood SES and perceived stress with midlife insulin resistance and epigenetic age and to explore whether late adolescent adiposity mediates the observed associations., Design, Setting, and Participants: The longitudinal cohort National Heart, Lung, and Blood Institute Growth and Health Study enrolled girls aged 10 years from January 1987 to May 1988, and followed them up to 19 years of age. Participants from Richmond, California, were recruited again at midlife in 2016 to assess insulin resistance and epigenetic age. Analyses were conducted from August 2, 2023, to March 18, 2024. A total of 433 participants were eligible and included in the analyses (specific sample sizes ranged across analyses from 303 to 391)., Exposures: Childhood levels of SES at 10 years of age (parental educational level and income) and perceived stress at 11 years of age., Main Outcomes and Measures: The hypotheses tested were formulated after data collection. Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and the GrimAge and DunedinPACE epigenetic clocks. Waist circumference in late adolescence was tested as a mediator., Results: Among the 433 participants, the mean (SD) age was 39.4 (1.2) years; 218 (50.3%) were Black and 215 (49.7%) were White; and 135 (31.2%) had parents with a college degree or higher. Higher parental educational level was associated with lower HOMA-IR (B = -0.22 [95% CI, -0.41 to -0.02]; P = .03), lower midlife GrimAge (B = -1.76 [95% CI, -2.85 to -0.66] years; P = .002), and slower midlife DunedinPACE (B = -0.03 [95% CI, -6.29 to -0.002]; P = .04). Childhood perceived stress was indirectly associated through late adolescent adiposity with midlife HOMA-IR (B = 0.01 [95% CI, 0.001-0.01]; P = .02) and midlife GrimAge (B = 0.02 [95% CI, 0.003-0.04] years; P = .01)., Conclusions and Relevance: In this longitudinal cohort study of midlife health and aging, childhood social hallmarks of aging were associated with midlife insulin resistance and epigenetic age (GrimAge and DunedinPACE). Future studies should identify malleable factors that may slow the impact of social hallmarks of aging.

Background: Cardiometabolic risk (CMR) is associated with cognitive health, but the association can be affected by broader social, economic, and medical contexts. The United States and China have very different developmental and epidemiological histories, and thus CMR among older people could be linked to cognitive function differently in the 2 countries., Methods: Cross-sectional and longitudinal ordinary least squares regression models were estimated for each country using nationally representative samples of populations over age 50: 7 430/4 474 Americans and 6 108/3 655 Chinese in the cross-sectional/longitudinal samples., Results: In the United States, higher CMR is associated with worse cognitive function (b = -0.08, p < .016). Longitudinally, CMR increase is associated with worse cognitive function at a marginally significant level (b = -0.10, p = .055). No relationship between CMR level or change and cognitive function is observed in China. Higher education levels are linked to better cognitive function and slower cognitive decline in both countries. Unlike older Americans, relative to those with very low education levels, among older Chinese with the highest education level, a higher CMR links to better cognitive function (b = 0.63, p = .013) and slower cognitive decline (b = 0.35, p = .062); Nevertheless, a rapid increase in CMR is additionally harmful (b = -0.54, p = .050) for cognitive function and may lead to faster cognitive decline (b = -0.35, p = .079)., Conclusions: The significant relationship between CMR and cognitive function in the United States suggests the importance of monitoring and controlling CMR factors at older ages. The insignificant relationship in China may be explained by the high CMR among those with high education levels, highlighting the need for improving cardiometabolic health through education and promoting healthy lifestyles., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

We examine effects of parental divorce on epigenetic aging in later adulthood for two birth cohorts: one born in the early 20th century and the other born in the later 20th century. Using data from the Health and Retirement Study (n = 1,545), we examine the relationship between parental divorce in childhood and accelerated epigenetic aging in older adulthood as indicated by the Dunedin methylation Pace of Aging score. We assess how this relationship is mediated by chronic depressive symptoms, education, lifetime smoking, body mass index (BMI), and an older adult's own divorce. The mean age of the earlier cohort is 85.8 (SD = 3.9) and that of the later cohort is 60.2 (SD = 2.8). We find that parental divorce was related to faster aging in the later-born cohort, and that 56% of this relationship (b = 0.060) was mediated by chronic depressive symptoms (b = 0.013), lower education levels (b = 0.005), and smoking (b = 0.019). For the earlier cohort, there was no effect of parental divorce on epigenetic aging. Parental divorce in childhood may have lasting effects on later-life health, as reflected in the rate of epigenetic aging. However, the effects and mechanisms of this relationship differ across cohorts living in different social environments., Competing Interests: Conflict of interests The authors declare that there is no conflict of interest.

Objective: Short sleep and insomnia are each associated with a greater risk of age-related disease, which suggests that insufficient sleep may accelerate biological aging. We examine whether short sleep and insomnia alone or together relates to epigenetic age among older adults., Methods: A total of 3795 men (46.3%) and women aged 56 to 100 years from the Health and Retirement Study were included. Insomnia was defined as reporting at least one insomnia symptom (difficulty falling asleep, waking up at night, or waking up too early in the morning) and feeling unrested when waking up most of the time. Those reporting <6 hours of bedtime were categorized as short sleepers. Three second- or third-generation epigenetic age acceleration clocks were derived from the 2016 Health and Retirement Study Venous Blood Study. The linear regression analysis was adjusted for age, sex, race/ethnicity, education, and obesity status., Results: Insomnia and short sleep were associated with acceleration of GrimAge of 0.49 (95% confidence interval [CI] = 0.03-0.94 years; p = .04) and 1.29 (95% CI = 0.52-2.07 years; p = .002) years, respectively, as well as a faster pace of aging (DunedinPACE; 0.018 [95% CI = 0.004-0.033; p = .02] and 0.022 [95% CI = -0.004 to 0.048; p = .11]). Compared with healthy sleepers, individuals with the combination of short sleep and insomnia had an accelerated GrimAge (0.97 years; 95% CI = 0.07-1.87 years, p = .04) and a greater DunedinPACE (0.032; 95% CI = 0.003-0.060, p = .04)., Conclusions: Our findings indicate that short sleep, insomnia, and the combination of the two are linked to epigenetic age acceleration, suggesting that these individuals have an older biological age that may contribute to risk of comorbidity and mortality., (Copyright © 2023 by the American Psychosomatic Society.)

Introduction: A growing number of international population surveys have included measurement of biomarkers, but differ in the type of specimens collected, sample processing procedures, shipment protocols, and laboratory assay platforms. The purpose of this study is to harmonize biomarker data from nine nationally representative studies of people 50 years of age and over by adjusting for assay platforms and type of specimens for total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), and C-reactive protein (CRP)., Methods: Sets of 24 identical serum, plasma, whole blood, and dried blood spot harmonization samples with known analyte levels were generated at a reference laboratory, shipped at -80°C to the respective study laboratories, and subsequently assayed following the study laboratory's protocol. Both original and harmonized study data were used to calculate mean values and at-risk prevalence., Results: The correlation coefficients between the biomarker values of the harmonization samples obtained by the study laboratories and the reference laboratory were 0.99 or above for all analytes and laboratories, indicating the high quality of assays at all laboratories. However, using the harmonized data from each study, there were significant differences in the mean values and country ranking of the prevalence of at-risk levels of these four biomarkers., Conclusions: While the biomarker data from the different study laboratories were highly correlated, indicating very high correlation of rank order of specimens, absolute values did vary significantly. This can have a major impact on assessment of international differences in estimates of risks for chronic morbidity and mortality., (© 2023 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Parental death in early life has been linked to various adverse health outcomes in older adulthood. This study extends prior research to evaluate how parental death in early life is tied to accelerated epigenetic aging, a potentially important biological mechanism from which social and environmental exposures impact age-related health. We used data from the 2016 Venous Blood Study (VBS), a component of the Health and Retirement Study (HRS), to examine the association between parental death in early life and accelerated epigenetic aging as measured by three widely used epigenetic clocks (PCPhenoAge, PCGrimAge, and DunedinPACE). We also assessed whether some of the association is explained by differences in educational attainment, depressive symptoms, and smoking behavior. Methods included a series of linear regression models and formal mediation analysis. Findings indicated that parental death in early life is associated with accelerated epigenetic aging for PCPhenoAge and DunedinPACE. The inclusion of educational attainment, depressive symptoms, and smoking behavior attenuated this association, with formal mediation analysis providing additional support for these observations. Parental death in early life may be one of the most difficult experiences an individual may face. The elevated biological risk associated with parental death in early life may operate through immediate changes but also through more downstream risk factors. This study highlights how early life adversity can set in motion biological changes that have lifelong consequences., Competing Interests: No conflicts of interest to report., (© 2024 The Authors.)

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age., (© 2024. The Author(s).)

Background and Objectives: Previous studies estimated that modifiable risk factors explain up to 40% of the dementia cases in the United States and that this population-attributable fraction (PAF) differs by race and ethnicity-estimates of future impact based on the risk factor prevalence in contemporary surveys. The aim of this study was to determine the race-specific and ethnicity-specific PAF of late-onset Alzheimer disease and related dementias (ADRDs) based on the risk factor prevalence and associations observed on the same individuals within a prospective cohort., Methods: Data were from Multiethnic Cohort Study participants (African American, Japanese American, Latino, Native Hawaiian, and White) enrolled in Medicare Fee-for-Service. We estimated the PAF based on the prevalence of risk factors at cohort baseline and their mutually adjusted association with subsequent ADRD incidence. Risk factors included low educational attainment and midlife exposures to low neighborhood socioeconomic status, unmarried status, history of hypertension, stroke, diabetes or heart disease, smoking, physical inactivity, short or long sleep duration, obesity, and low-quality diet, as well as APOE ε4 for a subset., Results: Among 91,881 participants (mean age 59.3 at baseline, 55.0% female participants), 16,507 incident ADRD cases were identified from Medicare claims (1999-2016, mean follow-up 9.3 years). The PAF for nongenetic factors combined was similar in men (24.0% [95% CI 21.3-26.6]) and women (22.8% [20.3-25.2]) but varied across Japanese American (14.2% [11.1-17.2]), White (21.9% [19.0-24.7]), African American (27.8% [22.3-33.0]), Native Hawaiian (29.3% [21.0-36.7]), and Latino (33.3% [27.5-38.5]) groups. The combined PAF was attenuated when accounting for competing risk of death, in both men (10.4%) and women (13.9%) and across racial and ethnic groups (4.7%-25.5%). The combined PAF was also different by age at diagnosis and ADRD subtypes, higher for younger (65-74 years: 43.2%) than older (75-84 years: 32.4%; ≥85 years: 11.3%) diagnoses and higher for vascular or unspecified ADRD than for AD or Lewy body dementia. An additional PAF of 11.8% (9.9-13.6) was associated with APOE ε4, which together with nongenetic risk factors accounted for 30.6% (25.8-35.1) of ADRD., Discussion: Known risk factors explained about a third of the ADRD cases but with unequal distributions across racial and ethnic groups.

Introduction: The Health and Retirement Study (HRS) has collected biomarker data over multiple waves. Such data can help improve our understanding of health changes in individuals and the causal pathways related to health. There are, however, technical challenges to using the HRS dried blood spots (DBS) biomarker data due to changes over time in assay protocols, platforms, and laboratories. We provide technical and summary information on biological indicators collected as part of the HRS from 2006 to 2016 that should be helpful to users of the data., Methods: We describe the opportunities and challenges provided by the HRS DBS data as well as insights provided by the data. The HRS collected DBS from its nationally representative sample of respondents 51 years of age or older from 2006 to 2016. DBS-based biomarkers were collected from half the sample in 2006, 2010, and 2014, and from the other half of the sample in 2008, 2012, and 2016. These DBS specimens were used to assay total and HDL cholesterol, glycosylated hemoglobin, C-reactive protein, and cystatin C from 2006 to 2016, and Interleukin 6 was added in 2014/2016. Samples included approximately 6000 individuals at each wave, and completion rates ranged from 81% to 90%. HRS transformed DBS values into venous blood equivalents to make them more comparable to those of the whole blood-based assays collected in most other studies and to facilitate longitudinal analysis., Results: Distribution of changes over time by age shows that total cholesterol levels decreased for each age, while HbA1c levels increased. Cystatin C shows a clear age gradient, but a number of other markers do not. Non-Hispanic Black persons and Hispanic respondents have a higher incidence of risk levels of each biomarker except for CRP among non-Hispanic Black older persons., Conclusion: These public-use DBS data provide analysis opportunities that can be used to improve our understanding of health change with age in both populations and among individuals., (© 2023 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD., (© 2023. The Author(s).)

Aim: This is a brief description of links between nine epigenetic clocks related to human aging and socioeconomic and behavioral characteristics as well as health outcomes. Materials & methods: We estimate frequently used and novel clocks from one data source, the Health and Retirement Study. Results: While all of these clocks are thought to reflect "aging," they use different CpG sites and do not strongly relate to each other. First and fourth generation clocks are not as linked to socioeconomic status or health outcomes as second and third generation clocks. Conclusion: Epigenetic clocks reflect exciting new tools and their continued evolution is likely to improve our understanding of how exposures get under the skin to accelerate aging.

Background: Hearing loss has been identified as an independent risk factor for negative health outcomes and mortality. However, whether rehabilitation with hearing aid use is associated with lower mortality is currently unknown. This study aimed to examine the associations of hearing loss, hearing aid use, and mortality in the USA., Methods: In this cross-sectional, follow-up study, we assessed 9885 adults (age 20 years and older) who participated in the National Health and Nutrition Examination Survey between 1999 and 2012 and completed audiometry and hearing aid use questionnaires (1863 adults with hearing loss). Main measures included hearing loss (speech-frequency pure-tone average) and hearing aid use (never users, non-regular users, and regular users). Mortality status of the cohort was linked to the National Death Index up to Dec 31, 2019. Cox proportional regression models were used to examine the association between hearing loss, hearing aid use, and mortality while adjusting for demographics and medical history., Findings: The cohort consisted of 9885 participants, of which 5037 (51·0%) were female and 4848 (49·0%) were male with a mean age of 48·6 years (SD 18·1) at baseline. The weighted prevalence of audiometry-measured hearing loss was 14·7% (95% CI 13·3-16·3%) and the all-cause mortality rate was 13·2% (12·1-14·4) at a median 10·4 years of follow-up (range 0·1-20·8). The rate of regular hearing aid use among adults with hearing loss was 12·7% (95% CI 10·6-15·1). Hearing loss was an independent risk factor associated with higher mortality (adjusted hazard ratio [HR] 1·40 [95% CI 1·21-1·62]). Among individuals with hearing loss, the adjusted mortality risk was lower among regular hearing aid users in comparison with never users (adjusted HR 0·76 [0·60-0·95]) accounting for demographics, hearing levels, and medical history. There was no difference in adjusted mortality between non-regular hearing aid users and never users (adjusted HR 0·93 [0·70-1·24])., Interpretation: Regular hearing aid use was associated with lower risks of mortality than in never users in US adults with hearing loss when accounting for age, hearing loss, and other potential confounders. Future research is needed to investigate the potential protective role of hearing aid use against mortality for adults with hearing loss., Funding: None., Competing Interests: Declaration of interests JSC received a grant from the Lions Hearing Foundation. MEA reports serving on a medical advisory council to Advanced Bionics. FRL reports being a consultant to Frequency Therapeutics and Apple and the Director of a public health research centre funded in part by a philanthropic donation from Cochlear to the Johns Hopkins Bloomberg School of Public Health., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The aging process is accompanied by decline in kidney functioning. It remains unknown to what extent age-related decline in kidney functioning can be attributed to health indicators, and whether rate of decline differs across sociodemographic groups., Methods: Using data from the Health and Retirement Study from 2006/2008 through 2014/2016, we estimated kidney functioning trajectories, determined by cystatin C, among adults aged over 51 over 8 years. We evaluated the role of age, health conditions/behaviors, and genetics in the decline and also examined sociodemographic differentials., Results: Kidney function declined with age and accelerated at older ages, even after adjusting for health conditions/behaviors and genetic differences (eg, 0.019 mg/L annual increase in cystatin C among 70-79 compared to 0.007 mg/L among 52-59 at baseline). Decline occurred faster among those with uncontrolled diabetes (0.008, p = .009), heart conditions (0.007, p < .000), and obesity (0.005, p = .033).Hispanic participants (0.007, p = .039) declined faster than non-Hispanic White persons due to diabetes, heart conditions, and obesity; non-Hispanic Black participants had worse baseline kidney functioning (0.099, p < .000), but only one fourth of this Black-White difference was explained by investigated risk factors. People with higher education experienced slower decline (-0.009, p = .004)., Conclusions: Age was a significant predictor of decline in kidney functioning, and its association was not fully explained by health conditions/behaviors, or genetics. Better management of diabetes, heart conditions, and obesity is effective in slowing this decline. Baseline differences in kidney functioning (eg, between non-Hispanic White and Black persons; those with and without hypertension) suggest disparities occur early in the life course and require early interventions., (© The Author(s) 2023. 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.)

Introduction: Age-related immunosenescence is characterized by changes in immune cell subsets and is associated with mortality. However, since immunosenescence is associated with other concurrent age-related changes such as inflammation and multi-organ dysfunction, it is unclear whether the association between age-related immunosenescence and mortality is independent of other concurrent age-related changes. To address these limitations, we evaluated the independent association between immune cell subsets and mortality after adjustment for age-related inflammation and biologic age., Methods: Data for this study was obtained from the 2016 interview of the Health and Retirement Study (N=6802). Cox proportional hazards regression models were used to estimate the association between 25 immune cell subsets (11 T-cell subsets, 4 B-cell subsets, 3 monocyte subsets, 3 natural killer cell subsets, 3 dendritic cell subsets, and neutrophils) and 4-year mortality adjusting for covariates such as the Klemera-Doubal algorithm biological age, chronological age, gender, race/ethnicity, BMI, smoking status, comorbidity index, CMV seropositivity, and inflammatory latent variable comprising C-reactive protein, and 4 cytokines (interleukin-10, interleukin-1 receptor antagonist, interleukin-6, and soluble tumor necrosis factor)., Results: Four hundred and seventy-six participants died during the study period with an overall median follow up time of 2.5 years. After controlling for covariates and adjustment for sample-weights, total T cells [HR: 0.86, p=0.004], NK CD56LO cells [HR: 0.88, p=0.005], and neutrophils [HR: 1.22, p=0.004] were significantly associated with mortality., Conclusions: These findings support the idea that an aging immune system is associated with short-term mortality independent of age-related inflammation or other age-related measures of physiological dysfunction. If replicated in other external cohorts, these findings could identify novel targets for both monitoring and intervention to reduce the age-related mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seshadri, Vivek, Prizment, Crimmins, Klopack, Faul, Guan, Meier and Thyagarajan.)

Objectives: Age-related changes in adaptive immunity and subclinical inflammation are both important risk factors for diabetes in older adults. We evaluated the independent association between T-cell subsets, subclinical inflammation, and diabetes risk in the Health and Retirement Study (HRS)., Methods: We measured 11 T-cell subsets, 5 pro-inflammatory markers, and 2 anti-inflammatory markers from the 2016 wave of the HRS (baseline). Diabetes/prediabetes status was estimated at the 2016, 2018, and 2020 waves of HRS, based on levels of blood glucose/glycated hemoglobin in plasma or self-reported status. We used survey generalized logit models to evaluate the cross-sectional associations and Cox proportional hazard models to evaluate longitudinal associations., Results: Among 8,540 participants (56 to 107 years of age), 27.6% had prevalent type 2 diabetes and 31.1% had prediabetes in the 2016 survey. After adjusting for age, sex, race/ethnicity, education, obesity, smoking, comorbidity index, and cytomegalovirus seropositivity, individuals with type 2 diabetes had lower naive T cells and higher memory and terminal effector T cells as compared with normoglycemic individuals. Among 3,230 normoglycemic participants in the 2016 survey, the incidence of diabetes was 1.8% over 4 years of follow-up. The baseline percentage of CD4 + effector memory T cells was associated with a lower risk of incident diabetes (hazard ratio [HR]=0.63, 95% confidence interval [CI] 0.49 to 0.80, p=0.0003) after adjustment for covariates. Baseline level of interleukin-6 (IL-6) was associated with risk of incident diabetes (HR=1.52, 95% CI 1.18 to 1.97, p=0.002). The associations between age-related changes in CD4 + effector memory T cells and risk of incident diabetes remained unchanged after adjustment for subclinical inflammation, although adjusting for CD4 + effector memory T cells nullified the association between IL-6 and incident diabetes., Conclusions: This study showed that the baseline percentage of CD4 + effector memory T cells was inversely associated with incident diabetes independent of subclinical inflammation, but CD4 + effector memory T-cell subsets affected the relationship between IL-6 and incident diabetes. Further studies are needed to confirm and investigate mechanisms by which T-cell immunity affects diabetes risk., (Copyright © 2023 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Introduction: There is growing interest in accelerating adoptions of vaccines. This study examined factors that differentiate the acceptance and timing of uptake of the first shingles vaccine, Zostavax, among older adults in the U.S., Methods: Data from Health and Retirement Study respondents who were aged ≥62 years in 2008 were analyzed to determine whether they received a shingles vaccination from 2006 to 2016. Multinomial logistic regression was used to examine the characteristics associated with vaccine uptake and timing., Results: Of those eligible, 15.2% were vaccinated early (between 2006 and 2010), 20.2% were vaccinated later, and 64.6% remained unvaccinated 10 years after the shingles vaccine was introduced. Respondents more likely to be vaccinated were those who had higher education and income, experience with influenza vaccination, more frequent social interaction with friends, or were residing in an area with higher shingles vaccination rates., Conclusions: Shingles vaccination rates vary by social and geographic characteristics. Efforts to improve and expedite vaccination and other new preventive measures should target specific populations and geographic areas., Competing Interests: None., (© 2023 The Author(s).)

Objectives: Individuals with more education are at lower risk of developing multiple, different age-related diseases than their less-educated peers. A reason for this might be that individuals with more education age slower. There are 2 complications in testing this hypothesis. First, there exists no definitive measure of biological aging. Second, shared genetic factors contribute toward both lower educational attainment and the development of age-related diseases. Here, we tested whether the protective effect of educational attainment was associated with the pace of aging after accounting for genetic factors., Methods: We examined data from 5 studies together totaling almost 17,000 individuals with European ancestry born in different countries during different historical periods, ranging in age from 16 to 98 years old. To assess the pace of aging, we used DunedinPACE, a DNA methylation algorithm that reflects an individual's rate of aging and predicts age-related decline and Alzheimer's disease and related disorders. To assess genetic factors related to education, we created a polygenic score based on the results of a genome-wide association study of educational attainment., Results: Across the 5 studies, and across the life span, higher educational attainment was associated with a slower pace of aging even after accounting for genetic factors (meta-analysis effect size = -0.20; 95% confidence interval [CI]: -0.30 to -0.10; p = .006). Further, this effect persisted after taking into account tobacco smoking (meta-analysis effect size = -0.13; 95% CI: -0.21 to -0.05; p = .01)., Discussion: These results indicate that higher levels of education have positive effects on the pace of aging, and that the benefits can be realized irrespective of individuals' genetics., (© The Author(s) 2023. 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: Frailty status has been sparsely studied in some groups including Native Hawaiians and Asian Americans., Methods: We developed a questionnaire-based deficit accumulation frailty index (FI) in the Multiethnic Cohort (MEC) and examined frailty status (robust, FI 0 to <0.2, prefrail, FI 0.2 to <0.35, and frail FI ≥ 0.35) among 29 026 men and 40 756 women., Results: After adjustment for age, demographic, lifestyle factors, and chronic conditions, relative to White men, odds of being frail was significantly higher (34%-54%) among African American, Native Hawaiian, and other Asian American men, whereas odds was significantly lower (36%) in Japanese American men and did not differ in Latino men. However, among men who had high school or less, none of the groups displayed significantly higher odds of prefrail or frail compared with White men. Relative to White women, odds of being frail were significantly higher (14%-33%) in African American and Latino women, did not differ for other Asian American women and lower (14%-36%) in Native Hawaiian and Japanese American women. These racial and ethnic differences in women were observed irrespective of education. Risk of all-cause mortality was higher in prefrail and frail men than robust men (adjusted hazard ratio [HR] = 1.69, 1.59-1.81; HR = 3.27, 3.03-3.53); results were similar in women. All-cause mortality was significantly positively associated with frailty status and frailty score across all sex, race, and ethnic groups., Conclusions: Frailty status differed significantly by race and ethnicity and was consistently associated with all-cause mortality. The FI may be a useful tool for aging studies in this multiethnic population., (© The Author(s) 2022. 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.)

Introduction: Prior estimates of dementia prevalence in India were based on samples from selected communities, inadequately representing the national and state populations., Methods: From the Longitudinal Aging Study in India (LASI) we recruited a sample of adults ages 60+ and administered a rich battery of neuropsychological tests and an informant interview in 2018 through 2020. We obtained a clinical consensus rating of dementia status for a subsample (N = 2528), fitted a logistic model for dementia status on this subsample, and then imputed dementia status for all other LASI respondents aged 60+ (N = 28,949)., Results: The estimated dementia prevalence for adults ages 60+ in India is 7.4%, with significant age and education gradients, sex and urban/rural differences, and cross-state variation., Discussion: An estimated 8.8 million Indians older than 60 years have dementia. The burden of dementia cases is unevenly distributed across states and subpopulations and may therefore require different levels of local planning and support., Highlights: The estimated dementia prevalence for adults ages 60+ in India is 7.4%. About 8.8 million Indians older than 60 years live with dementia. Dementia is more prevalent among females than males and in rural than urban areas. Significant cross-state variation exists in dementia prevalence., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Cognitive status classification (e.g. dementia, cognitive impairment without dementia, and normal) based on cognitive performance questionnaires has been widely used in population-based studies, providing insight into the population dynamics of dementia. However, researchers have raised concerns about the accuracy of cognitive assessments. MRI and CSF biomarkers may provide improved classification, but the potential improvement in classification in population-based studies is relatively unknown., Methods: Data come from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined whether the addition of MRI and CSF biomarkers improved cognitive status classification based on cognitive status questionnaires (MMSE). We estimated several multinomial logistic regression models with different combinations of MMSE and CSF/MRI biomarkers. Based on these models, we also predicted prevalence of each cognitive status category using a model with MMSE only and a model with MMSE + MRI + CSF measures and compared them to diagnosed prevalence., Results: Our analysis showed a slight improvement in variance explained (pseudo-R2) between the model with MMSE only and the model including MMSE and MRI/CSF biomarkers; the pseudo-R2 increased from .401 to .445. Additionally, in evaluating differences in predicted prevalence for each cognitive status, we found a small improvement in the predicted prevalence of cognitively normal individuals between the MMSE only model and the model with MMSE and CSF/MRI biomarkers (3.1% improvement). We found no improvement in the correct prediction of dementia prevalence., Conclusion: MRI and CSF biomarkers, while important for understanding dementia pathology in clinical research, were not found to substantially improve cognitive status classification based on cognitive status performance, which may limit adoption in population-based surveys due to costs, training, and invasiveness associated with their collection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Farina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Shortened lifespans are associated with having Attention Deficit Hyperactivity Disorder (ADHD), which is likely mediated by related behavioral and sociodemographic factors that are also associated with accelerated physiological aging. Such factors include exhibiting more depressive symptoms, more cigarette smoking, higher body mass index, lower educational attainment, lower income in adulthood, and more challenges with cognitive processes compared to the general population. A higher polygenic score for ADHD (ADHD-PGS) is associated with having more characteristic features of ADHD. The degree to which (1) the ADHD-PGS associates with an epigenetic biomarker developed to predict accelerated aging and earlier mortality is unknown, as are whether (2) an association would be mediated by behavioral and sociodemographic correlates of ADHD, or (3) an association would be mediated first by educational attainment, then by behavioral and sociodemographic correlates. We evaluated these relationships in a population-based sample from the US Health and Retirement Study, among N = 2311 adults age 50 and older, of European-ancestry, with blood-based epigenetic and genetic data. The ADHD-PGS was calculated from a prior genomewide meta-analysis. Epigenome-wide DNA methylation levels that index biological aging and earlier age of mortality were quantified by a blood-based biomarker called GrimAge. We used a structural equation modeling approach to test associations with single and multi-mediation effects of behavioral and contextual indicators on GrimAge, adjusted for covariates., Results: The ADHD-PGS was significantly and directly associated with GrimAge when adjusting for covariates. In single mediation models, the effect of the ADHD-PGS on GrimAge was partially mediated via smoking, depressive symptoms, and education. In multi-mediation models, the effect of the ADHD-PGS on GrimAge was mediated first through education, then smoking, depressive symptoms, BMI, and income., Conclusions: Findings have implications for geroscience research in elucidating lifecourse pathways through which ADHD genetic burden and symptoms can alter risks for accelerated aging and shortened lifespans, when indexed by an epigenetic biomarker. More education appears to play a central role in attenuating negative effects on epigenetic aging from behavioral and sociodemographic risk factors related to ADHD. We discuss implications for the potential behavioral and sociodemographic mediators that may attenuate negative biological system effects., (© 2023. The Author(s).)

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)