Differences In Aging Trajectories Research Articles

A voxel-level approach to brain age prediction: A method to assess regional brain aging

Brain aging is a regional phenomenon, a facet that remains relatively under-explored within the realm of brain age prediction research using machine learning methods. Voxel-level predictions can provide localized brain age estimates that can provide granular insights into the regional aging processes. This is essential to understand the differences in aging trajectories in healthy versus diseased subjects. In this work, a deep learning-based multitask model is proposed for voxel-level brain age prediction from T1-weighted magnetic resonance images. The proposed model outperforms the models existing in the literature and yields valuable clinical insights when applied to both healthy and diseased populations. Regional analysis is performed on the voxel-level brain age predictions to understand aging trajectories of known anatomical regions in the brain and show that there exist disparities in regional aging trajectories of healthy subjects compared to ones with underlying neurological disorders such as Dementia and more specifically, Alzheimer’s disease. Our code is available at <a href='https://github.com/nehagianchandani/Voxel-level-brain-age-prediction'>https://github.com/nehagianchandani/Voxel-level-brain-age-prediction</a>

Multiomic analyses suggest a divergent aging trajectory in dementia

AbstractBackgroundAging is the main risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD) and other forms of dementia. Both aging and dementia have been shown to leave a molecular signature in the plasma proteome. Understanding how the Dementia Plasma Proteome (DPP) diverges from the Aging Plasma Proteome may provide insights in pathological changes in the brains of dementia patients, or resilience mechanisms in the brain of cognitive healthy individuals. Here, we provide a more detailed overview on the aging trajectories of the DPP across ‘normal agers’ and dementia patients using a multiomic analysis approach.MethodUsing publicly available datasets such as the Human Protein Atlas, GTEx, and the Aging, Dementia and TBI study, we aim to link changes observed in the plasma to age‐associated changes in the brain and AD pathology. For this, we used publicly available databases. Using immunohistochemistry, we attempt to validate our findings in brain tissue.ResultWe show that differences in expression levels of proteins belonging to the DPP (Dementia Proteins) between non‐demented controls and demented cases are positively associated to previously identified aging associations. Furthermore, we show that Dementia Proteins are preferentially expressed in the brain and among multiple brain cell types, such as neurons, oligodendrocyte precursor cells and astrocytes. Expression trajectories during aging of brain‐expressed Dementia Proteins in the healthy brain appear largely similar as identified in the aging plasma proteome. However, we identified several proteins displaying differential aging trajectories in the brain of demented patients. Lastly, we present how these altered aging trajectories associate to several pathological measures, such as levels of Tau and Amyloid beta.ConclusionThese results suggest differences in aging trajectories between non‐demented controls and dementia patients, which may be reflected in both the plasma and in brains of dementia patients. Together, these results may provide novel insights in proteins associated with dementia‐associated pathology and their contributions to the disease progression. Future studies are needed to further validate these findings and to discover the underlying mechanisms.

Education and age trajectories of chronic conditions: Are tests of the cumulative advantage and disadvantage hypothesis biased by underreporting?

ObjectiveThis study examined the impact of underreporting on tests of the cumulative advantage and disadvantage hypothesis (CAD), which predicts age-related increases in health disparities between individuals with higher and lower education. MethodsUsing the English Longitudinal Study of Ageing (ELSA), we identified underreporting by comparing self-reported hypertension and diabetes with biomedically measured hypertension (systolic blood pressure≥140 mm Hg and/or diastolic blood pressure≥90 mm Hg) and diabetes (fasting glucose level≥7 mmol/l and/or HbA1c≥6.5%). In a sample of 11,859 respondents aged 50 to 85 (54% women, 97% White), we assessed the associations between underreporting and the main analytic constructs in tests of the CAD (education, age, sex, and cohort). ResultsThe results showed that self-reported measures underestimated the prevalence of hypertension and diabetes. Underreporting showed weak to moderate associations with the main constructs in tests of the CAD, being more pronounced in individuals with lower education, in older age, in more recent cohorts, and among men. When correcting for underreporting using biomedical measures, the overall prevalence of hypertension and diabetes increased substantially, but education differences in age trajectories of both conditions remained similar. ConclusionsUnderreporting affected conclusions about the prevalence of hypertension and diabetes, but it did not affect conclusions about the CAD hypothesis for either condition.

A healthy mind in a healthy body: Effects of arteriosclerosis and other risk factors on cognitive aging and dementia.

In this review we start from the assumption that, to fully understand cognitive aging, it is important to embrace a holistic view, integrating changes in bodily, brain, and cognitive functions. This broad view can help explain individual differences in aging trajectories and could ultimately enable prevention and remediation strategies. As the title of this review suggests, we claim that there are not only indirect but also direct effects of various organ systems on the brain, creating cascades of phenomena that strongly contribute to age-related cognitive decline. Here we focus primarily on the cerebrovascular system, because of its direct effects on brain health and close connections with the development and progression of Alzheimer's Disease and other types of dementia. We start by reviewing the main cognitive changes that are often observed in normally aging older adults, as well as the brain systems that support them. Second, we provide a brief overview of the cerebrovascular system and its known effects on brain anatomy and function, with a focus on aging. Third, we review genetic and lifestyle risk factors that may affect the cerebrovascular system and ultimately contribute to cognitive decline. Lastly, we discuss this evidence, review limitations, and point out avenues for additional research and clinical intervention.

Reproductive Hormone Concentrations and Associated Anatomical Responses: Does Soy Formula Affect Minipuberty in Boys?

Soy formula feeding is common in infancy and is a source of high exposure to phytoestrogens, documented to influence vaginal cytology in female infants. Its influence on minipuberty in males has not been established. To assess the association between infant feeding practice and longitudinally measured reproductive hormones and hormone-responsive tissues in infant boys. The Infant Feeding and Early Development study was a prospective cohort of maternal-infant dyads requiring exclusive soy formula, cow milk formula, or breast milk feeding during study follow-up. In the 147 infant boy participants, serum testosterone, luteinizing hormone, stretched penile length, anogenital distance, and testis volume were longitudinally assessed from birth to 28 weeks. We examined feeding-group differences in age trajectories for these outcomes using mixed-effects regression splines. Median serum testosterone was at pubertal levels at 2 weeks (176 ng/dL [quartiles: 124, 232]) and remained in this range until 12 weeks in all feeding groups. We did not observe differences in trajectories of hormone concentrations or anatomical measures between boys fed soy formula (n = 55) and boys fed cow milk formula (n = 54). Compared with breastfed boys (n = 38), soy formula-fed boys had a more rapid increase in penile length (P = .004) and slower initial lengthening of anogenital distance (P = .03), but no differences in hormone trajectories. Reproductive hormone concentrations and anatomical responses followed similar trajectories in soy and cow milk formula-fed infant boys. Our findings suggest that these measures of early male reproductive development do not respond to phytoestrogen exposure during infancy.

Inequality in hospitalization due to non-communicable diseases in Sweden: Age-cohort analysis of the Uppsala Birth Cohort Multigenerational Study.

We aimed to investigate cohort differences in age trajectories of hospitalization due to non-communicable conditions, and if these varied by paternal socioeconomic position. We used the Uppsala Birth Cohort Multigenerational Study—including virtually complete information on medical diagnoses.Our sample constituted 28,448 individuals (103,262 observations). The outcome was five-year prevalence of hospitalization due to major non-communicable conditions in 1989–2008. The exposures were age (19–91), year-of-birth (1915–1929; 1938–1972), gender (man vs woman), and parental socioeconomic position (low, medium, and high). We used multilevel logit models to examine associations between exposures and the hospitalization outcome.Younger cohorts had a higher prevalence of hospitalization at overlapping ages than those born earlier, with inter-cohort differences emerging from early-adulthood and increasing with age. For instance, at age 40 predicted probability of hospitalization increased across birth-cohorts—from 1.2% (born in 1948-52) to 2.0% (born in 1963-67)—whereas at age 50 it was 2.9% for those born in 1938-42 compared with 4.6% among participants born in 1953-57. Those with medium and low socioeconomic position had 13.0% and 20.0% higher odds of experiencing hospitalization during the observation period, respectively—when age, year-of-birth and gender were accounted for.We found that no progress was made in reducing the socioeconomic inequalities in hospitalization across cohorts born between 1915 and 1972. Hence, more effective policies and interventions are needed to reduce the overall burden of morbidity—particularly among the most vulnerable.

Historical Changes in Aging Trajectories of Two Aspects of Self-Perceptions of Aging

In recent years many studies have shown that adults with more positive self-perceptions of aging (SPA) increase their likelihood of aging healthily. Other studies have documented historical changes in individual resources and contextual conditions associated with aging. We explored how these historical changes are reflected in birth-cohort differences in aging trajectories of two aspects of SPA – viewing aging as ongoing development or as increasing physical losses. Using large-scale cohort-sequential data assessed across 21 years (N ≈ 19,000), the analyses modeled birth-cohort differences in aging trajectories of SPA from 40 to 85 years of age. The results illustrated differential birth-cohort differences: Later-born cohorts may experience more potential for ongoing development with advancing age than earlier-born cohorts. However, later-born cohorts seem to view their own aging as more negative than earlier-born cohorts during their early forties but may associate their aging less with physical losses after the age of fifty.

Sex-Dimorphism in Aging Gene Regulation: Are We Missing Half of the Picture?

The existence of human supercentenarians reveals a surprising predictor for exceptional longevity: being female. Not only are 33 out of 34 living supercentenarians women, women are also more resistant to most diseases responsible for age-related morbidity in the US. However, because most molecular aging studies generally opt to use only one sex, sex-driven differences in aging remain poorly understood. A key compartment that can actively respond to sex-specific inputs throughout life is the immune system. Indeed, the majority of age-related diseases share common inflammatory mechanisms, a phenomenon described as “inflamm-aging”. Macrophages play an important role in the inflammatory response throughout life, and are considered major mediators of this phenomenon. Thus, to unbiasedly dissect sex differences in immune aging, we generated ‘omics’ data from 4 and 20 months old female and male mice. Intriguingly, we found that transcriptional aging in primary macrophage populations varies strongly between sexes, with up to 20-fold more aging changes in female vs. male cells. Pathways specifically downregulated in females with aging included lysosome, inflammation and phagolysosome. We confirmed experimentally that metabolic preferences of macrophages are indeed directly modulated in this context (e.g. glycolytic preference for male-derived cells). Our results support the notion that there are functional differences in aging trajectories in the immune system of female vs. male mice. Our research could provide new insights into the molecular underpinnings of sex-dimorphism in aging and disease.

Trajectories of rural-urban disparities in biological risks for cardiovascular disease among Chinese middle-aged and older adults.

This study examined rural-urban differences in age trajectories of biological risks for cardiovascular disease (CVD) among Chinese middle-aged and older adults. Data were from the 2011 wave of China Health and Retirement Longitudinal Study, including 11,528 respondents (Mage=59.15) from 440 communities. CVD risk factors included C-reactive protein (CRP), high-density lipoprotein (HDL), body mass index (BMI), and waist circumference (WC). Multilevel models revealed that rural adults had higher levels of HDL and lower levels of CRP and BMI on average, compared to urban adults. We also found significant rural-urban differences in the age trajectories of CVD risks. Rural-urban disparities in CVD risks increased from middle to later life, and converged at later old age. Findings suggest that rural-urban differences in cardiovascular health are not static, but rather vary throughout adulthood.

Sex-dimorphic trajectories in aging macrophage populations

Abstract The existence of human supercentenarians reveals a surprising predictor for exceptional longevity: being female. Not only are 33 out of 34 living supercentenarians women, women are also more resistant to most diseases responsible for age-related morbidity in the US. However, because most molecular aging studies generally opt to use only one sex, sex-driven differences in aging remain poorly understood. A key compartment that can actively respond to sex-specific inputs throughout life is the immune system. Indeed, the majority of age-related diseases share common inflammatory mechanisms, a phenomenon described as “inflamm-aging”. Macrophages play an important role in the inflammatory response throughout life, and are considered major mediators of this phenomenon. Thus, to unbiasedly dissect sex differences in immune aging, we generated ‘omics’ data from 4 and 20 months old female and male mice. Intriguingly, we found that transcriptional aging in primary macrophage populations varies strongly between sexes, with up to 20-fold more aging changes in female vs. male cells. Pathways specifically downregulated in females with aging included lysosome, inflammation and phagolysosome. We confirmed experimentally that metabolic preferences of macrophages are indeed directly modulated in this context (e.g. glycolytic preference for male-derived cells). Our results support the notion that there are functional differences in aging trajectories in the immune system of female vs. male mice. Our research could provide new insights into the molecular underpinnings of sex-dimorphism in aging and disease.

DAILY EMOTIONS AND STRESS: AGE CHANGES AND DIFFERENCES

Developmental processes differ between individuals (interindividual differences), fluctuate within them on a short-term basis (intraindividual variability), and change over time on a longer-term basis (intraindividual change; Nesselroade, 1991). We situate the relationship between stress and emotions in this process-oriented perspective by examining how the daily relationship between stress and negative affect (NA) as well as stress and positive affect (PA) change over time, while considering cross-sectional age and stress differences. Participants (N = 966) completed daily questionnaires assessing stress, NA, and PA. Three-level multi-level models depicted how cross-sectional age, within-person age changes, and global stress differences impact the daily stress-affect relationship. Findings illustrate that cross-sectional age and the aging process uniquely buffer the stress-NA relationship whereas global stress exacerbates it. Furthermore, older adults as well as adults with low global stress experience a weaker relationship between daily stress and PA as they age, but midlife adults and adults with high global stress experience a stronger relationship. These results depict differences in aging trajectories for both midlife and older adults and thus inform intervention and preventative care strategies aimed toward promoting emotional well-being, suggesting that targeting these strategies at the daily level can promote better stress regulation. Furthermore, we see that midlife adults and adults with greater global stress perceptions are most in need of these interventions, and encouraging these adults to maintain PA in the face of daily stress can be particularly beneficial.

RURAL-URBAN DISPARITY IN BIOMARKER RISKS FOR CARDIOVASCULAR DISEASE AMONG CHINESE MIDDLE-AGED AND OLDER ADULTS

Cardiovascular disease (CVD) is a leading cause of adult mortality in China, accounting for 45% of deaths from noncommunicable disease. Moreover, Chinese health status and health services are disproportionately divided between urban and rural areas. This study examined rural-urban differences in age trajectories of CVD risk, measured by C-reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, body mass index (BMI), and waist circumference. This study also investigated whether community factors, including recreational amenities, infrastructure availability, physical environment, public facilities, and health services, may explain such rural-urban disparities. We used data from the baseline data of the China Health and Retirement Longitudinal Study (2011), including 11, 528 respondents from 440 communities, who were aged 45 and older and participated in the biomarker survey. Multilevel models revealed that rural adults had a higher level of HDL and lower levels of CRP, BMI, and waist circumference compared to their urban counterparts. Rural adults also had slower age-related increases in trajectories for CRP, HDL and BMI. Associations of physical environment and public facilities with CVD risks were largely explained by rural-urban disparity. However, the availability of infrastructure explained both between- and within- rural-urban differences in BMI and waist circumference. Models were controlled for previously diagnosed CVD conditions, individual demographic characteristics, self-rated health, activities of daily living, depressive symptoms, physical activity, smoking and drinking behaviors. Findings contribute to the understanding of prevalence and disparities in biomarker risks for CVD among Chinese middle-aged and older adults. Intervention implications are discussed to address the emerging health disparities.

SEX-DIMORPHISM IN THE GENOMIC REGULATION OF AGING

The current cohort of human supercentenarians reveals a surprising predictor for achieving such an exceptional longevity: being female. Indeed, out of 34 living supercentenarians, 33 are women. We obtained samples from 4 and 20 months old female and male mice. Our data indicates that cytokine levels are differentially regulated with age in males vs. females, with pro-inflammatory cytokines specifically upregulated in the serum of old males, but not females. Because of the central role of macrophages in inflammation and their infiltration in tissues with age, we have generated RNA-seq from purified macrophages of aging animals. Female macrophages displayed ~7-20-fold more transcriptional remodeling with aging than males. Pathways specifically downregulated in females with aging included lysosome, inflammation and phagolysosome. Consistently, our data shows that aged female, but not male macrophages, display decreased phagocytic efficiency. Our results support the notion that there are differences in aging trajectories in female vs. male mice.

Early-life DNA methylation profiles are indicative of age-related transcriptome changes

BackgroundAlterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.ResultsPaired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to altered gene expression. A more striking relationship was found between methylation levels at young age and differential gene expression with aging. Highly methylated gene bodies and promoters in early life were associated with age-related increases in gene expression even in the absence of significant methylation changes with aging. As well, low levels of methylation in early life were correlated to decreased expression with aging. This relationship was also observed in genes altered in two mouse Alzheimer’s models.ConclusionDNA methylation patterns established in youth, in combination with other epigenetic marks, were able to accurately predict changes in transcript trajectories with aging. These findings are consistent with the developmental origins of disease hypothesis and indicate that epigenetic variability in early life may explain differences in aging trajectories and age-related disease.

Daily Stress Reactivity Across the Life span: Longitudinal and Cross-Sectional Effects of Age.

Exploration of development requires the use of research designs and process-oriented methodologies that can capture daily fluctuations within individuals, systematic changes within individuals, and differences between individuals. We examine the stress-affect relationship in this way to assess how the relationship between daily stress and negative affect (NA) as well as the relationship between daily stress and positive affect (PA) differs between individuals and changes over time depending on age and stress differences. Participants (N = 966) completed daily "burst" assessments of stress, NA, and PA. Three-level multilevel models depicted how cross-sectional age, within-person age changes, and global stress differences impact the daily stress-affect relationship. Findings illustrate that cross-sectional age and the aging process uniquely buffer the stress-NA relationship whereas global stress exacerbates it. Furthermore, older adults as well as adults with low global stress experience a weaker relationship between daily stress and PA as they age, but midlife adults and adults with high global stress experience a stronger relationship. These results depict differences in aging trajectories for both midlife and older adults and thus inform intervention and preventative care strategies aimed toward promoting stress regulation.

Differences in physical aging measured by walking speed: evidence from the English Longitudinal Study of Ageing.

BackgroundPhysical functioning and mobility of older populations are of increasing interest when populations are aging. Lower body functioning such as walking is a fundamental part of many actions in daily life. Limitations in mobility threaten independent living as well as quality of life in old age. In this study we examine differences in physical aging and convert those differences into the everyday measure of single years of age.MethodsWe use the English Longitudinal Study of Ageing, which was collected biennially between 2002 and 2012. Data on physical performance, health as well as information on economics and demographics of participants were collected. Lower body performance was assessed with two timed walks at normal pace each of 8 ft (2.4 m) of survey participants aged at least 60 years. We employed growth curve models to study differences in physical aging and followed the characteristic-based age approach to illustrate those differences in single years of age.ResultsFirst, we examined walking speed of about 11,700 English individuals, and identified differences in aging trajectories by sex and other characteristics (e.g. education, occupation, regional wealth). Interestingly, higher educated and non-manual workers outperformed their counterparts for both men and women. Moreover, we transformed the differences between subpopulations into single years of age to demonstrate the magnitude of those gaps, which appear particularly high at early older ages.ConclusionsThis paper expands research on aging and physical performance. In conclusion, higher education provides an advantage in walking of up to 15 years for men and 10 years for women. Thus, enhancements in higher education have the potential to ensure better mobility and independent living in old age for a longer period.

Sex differences in normal age trajectories of functional brain networks.

Resting-state functional magnetic resonance image (rs-fMRI) is increasingly used to study functional brain networks. Nevertheless, variability in these networks due to factors such as sex and aging is not fully understood. This study explored sex differences in normal age trajectories of resting-state networks (RSNs) using a novel voxel-wise measure of functional connectivity, the intrinsic connectivity distribution (ICD). Males and females showed differential patterns of changing connectivity in large-scale RSNs during normal aging from early adulthood to late middle-age. In some networks, such as the default-mode network, males and females both showed decreases in connectivity with age, albeit at different rates. In other networks, such as the fronto-parietal network, males and females showed divergent connectivity trajectories with age. Main effects of sex and age were found in many of the same regions showing sex-related differences in aging. Finally, these sex differences in aging trajectories were robust to choice of preprocessing strategy, such as global signal regression. Our findings resolve some discrepancies in the literature, especially with respect to the trajectory of connectivity in the default mode, which can be explained by our observed interactions between sex and aging. Overall, results indicate that RSNs show different aging trajectories for males and females. Characterizing effects of sex and age on RSNs are critical first steps in understanding the functional organization of the human brain.

Race-Ethnicity and Health Trajectories

Racial-ethnic disparities in static levels of health are well documented. Less is known about racial-ethnic differences in age trajectories of health. The few studies on this topic have examined only single health outcomes and focused on black-white disparities. This study extends prior research by using a life course perspective, panel data from the Health and Retirement Study, and multilevel growth curve models to investigate racial-ethnic differences in the trajectories of serious conditions and functional limitations among blacks, Mexican Americans, and whites. We test three hypotheses on the nature of racial-ethnic disparities in health across the life course (aging-as-leveler, persistent inequality, and cumulative disadvantage). Results controlling for mortality selection reveal that support for the hypotheses varies by health outcome, racial-ethnic group, and life stage. Controlling for childhood socioeconomic status, adult social and economic resources, and health behaviors reduces but does not eliminate racial-ethnic disparities in health trajectories.

The Social Structuring of Mental Health over the Adult Life Course: Advancing Theory in the Sociology of Aging

The sociology of aging draws on a broad array of theoretical perspectives from several disciplines, but rarely has it developed its own. We build on past work to advance and empirically test a model of mental health framed in terms of structural theorizing and situated within the life course perspective. Whereas most prior research has been based on cross-sectional data, we utilize four waves of data from a nationally representative sample of American adults (Americans' Changing Lives Study) collected prospectively over a 15-year period and find that education, employment and marital status, as well as their consequences for income and health, effectively explain the increase in depressive symptoms after age 65. We also found significant cohort differences in age trajectories of mental health that were partly explained by historical increases in education. We demonstrate that a purely structural theory can take us far in explaining later life mental health.

Sex Differences in Age Trajectories of Physiological Dysregulation: Inflammation, Metabolic Syndrome, and Allostatic Load

There is a paucity of knowledge from population data about sex differences and their age variation in physiological determinants of longevity. This study fills this gap using nationally representative samples of 38,000 individuals aged 17+ from the National Health and Nutrition Examination Survey (1988-2006). It examines sex differences in the age trajectories of 14 markers of physiological functions across multiple systems and three summary indices including inflammation burden, metabolic syndrome, and allostatic load. Statistical analyses show substantial sex differences, age variations, and sex by age interaction effects for all variables examined. These patterns remain robust after adjustment of risk factors and shed light on the biological base of the reduction of sex difference in mortality in the post-reproductive life span.