bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic Bioenergetic Capacity Changes with Cognitive Status and Insulin Sensitivity in Older Adults
Authors: Mahapatra Gargi , Gao Zhengrong , Bateman James , Gonzalez-Armenta Jenny L , Amick Allison , Casanova Ramon , Craft Suzanne , Molina Anthony J A
Published: December 2021

Systemic mitochondrial dysfunction is reported with AD progression, suggesting that peripheral blood cells may be used to investigate systemic mitochondrial alterations related to cognitive decline. We aimed to identify bioenergetic signatures associated with AD-related dementia and differences in insulin sensitivity associated with AD risk. We analyzed mitochondrial bioenergetics in peripheral blood cells collected from 365 older adults with varying cognitive status (normal, mild cognitive impairment, and AD) and insulin sensitivity. Normoglycemic individuals exhibited lower maximal bioenergetic capacity with AD (PBMCs: 239.6 pmol·min−1, p = 0.02; Platelets: 151.7 pmol·min−1, p = 0.06) compared to normal cognition (PBMCs: 271.5 pmol·min−1; Platelets: 171.7 pmol·min−1). Individuals with impaired insulin sensitivity exhibited lower maximal bioenergetic capacity in platelets with AD (171.6 pmol·min−1, p = 0.008) compared to normal cognition (210.6 pmol.min−1). Participants with impaired insulin sensitivity also exhibited unique bioenergetic profiles exemplified by overall higher levels of mitochondrial respiration, indicating that comorbidities such as diabetes can significantly influence bioenergetic capacity. We observed strong positive associations between maximal respiration in normoglycemic individuals with cognitive function, as measured by Modified Preclinical Alzheimer’s Cognitive Composite (mPACC5) (p = 0.06), and fatty acid oxidation in individuals with impaired insulin sensitivity with cortical thickness (p = 0.05). This study demonstrates that circulating cells may provide a cost-effective and minimally invasive way to monitor systemic bioenergetic changes associated with AD risk, progression, and insulin sensitivity. These findings also suggest that blood-based bioenergetics are related to key features of AD development and progression and should be further developed as a potential biomarker.
Using Drosophila to Identify Naturally-Occurring Modifiers of Alzheimer's Disease
Authors: Wang Adrienne , Yang Ming , Fitzgerald-Cook Cecilia , Harrison Ben , Green Akimi , Hartman Kensington , Zinkgraf Matthew , Promislow Daniel
Published: December 2021

Despite significant progress in identifying risk factors for late-onset Alzheimer’s Disease (LOAD), much of the variance in disease pathogenesis remains unexplained, likely due to the contribution of many genes of small effect size. Model organisms such as Drosophila Melanogaster exhibit conservation in both disease-causing genes and cellular processes implicated in Alzheimer’s Disease (AD), offering a genetically tractable model that can be statistically leveraged to identify causal variants. Here, we combine a Drosophila model of AD with the Drosophila Genetic Reference Panel (DGRP), a model of natural variation consisting of over 200 fully sequenced, isogenic lines derived from a wild-caught population. Expression of two proteins closely associated with AD pathogenesis, A□42 and Tau, in the Drosophila eye results in a “rough eye” phenotype, an easily quantifiable phenotype caused by degeneration of the ommatidial array. By quantifying the degree of A□42- and Tau-mediated degeneration across 164 lines of the DGRP and using a gene-based approach to map associations, we have identified and validated a subset of naturally occurring modifiers of degeneration in Drosophila. Enrichment analysis reveals that the set of genes identified in our screen show significant enrichment for genes identified as significant or suggestive (4x10-6>p>2x10-11) in human GWAS studies. The results presented here provide proof-of-principal for an approach that combines the strengths of forward genetic screens in model organisms with the power of human GWAS studies to identify and validate potential risk factors that have been difficult to detect in human studies alone.
Analysis of Survival Data with Competing Risks in ADRD (Alzheimer's Disease and Related Dementias) Research
Authors: Ren Dianxu , Lopez Oscar , Lingler Jennifer
Published: December 2021

Competing risk is an event that precludes the occurrence of the primary event of interest. For example, when studying risk factors associated with dementia, death before the onset of dementia serve as a competing event. A subject who dies is no longer at risk of dementia. This issue play more important role in ADRD research given the elderly population. Conventional methods for survival analysis assume independent censoring and ignore the competing events. However, there are some challenge issues using those conventional methods in the presence of competing risks. First, no one-to-one link between hazard function and cumulative incidence function (CIF), and Kaplan-Meier approach overestimates the cumulative incidence of the event of interest. Second, the effect of covariates on hazard rate cannot be directly linked to the effect of cumulative incidence (the risk). We will discuss two types of analyses in the presence of competing risk: Cause-specific hazard model and Fine-Gray subdistribution hazard model. Cause-specific hazard model directly quantify the cause-specific hazard among subjects who are at risk of developing the event of interest, while Fine-Gray subdistribution hazard model directly model the effects of covariates on the cumulative incidence function. The type of research questions (Association vs. Prediction) may guide the choice of different statistical approaches. We will illustrate those two competing risk analyses using the large national dataset from National Alzheimer’s Coordinating Center (NACC). We will analyze the association between baseline diabetes status and the incidence of dementia, in which death before the onset of dementia is a competing event.
Association Between Body Weight Change In Late Life And Risk Of Dementia: A Population-based Cohort Study
Authors: Guo Jie , Marseglia Anna , Shang Ying , Dove Abigail , Grande Giulia , Fratiglioni Laura , Xu Weili
Published: December 2021

Background. Adiposity in midlife is a modifiable risk factor for dementia. However, the effect of adiposity in late-life on dementia remains unclear. We investigated the association of body mass index (BMI) and weight changes after age 60 with the incident dementia. Methods. Within the Swedish National Study on Aging and Care-Kungsholmen, 1,673 dementia-free participants with data on BMI/weight both at baseline and the 6-year follow-up were followed to detect subsequent incident dementia cases. BMI change was assessed as the percentage of the difference between BMI at baseline and the initial 6-year follow-up and categorized into large (>10%) or moderate (5–10%) loss, stable (≤5%), and moderate (5–10%) or large (>10%) gain. Weight change (difference between weight at baseline and the 6-year follow-up) was categorized into large (>7.5 kg) or moderate (2.5–7.5 kg) loss, stable (≤2.5 kg), and moderate (2.5–7.5 kg) or large (> 7.5 kg) gain. Dementia was diagnosed following the DSM-IV criteria. Data were analyzed using Cox regression models. Results. During the follow-up (median 5.78 years), 102 incident dementia cases developed. BMI/weight change showed U-shaped associations with dementia. Compared with stable BMI, the hazard ratios (95% confidence intervals) of dementia were 2.93 (1.72−4.91) for large BMI loss and 2.61 (1.09−5.54) for large BMI gain. Similar results were observed for a large weight loss (2.92 [1.67−5.07]) or gain (2.95 [1.16−6.53]). These associations became stronger among participants carrying an ApoE ɛ4 allele. Conclusion. Both large bodyweight loss and gain are associated with a higher risk of dementia, especially among ApoE ɛ4 carriers.
Activities Under the RAISE Family Caregiving Act: Developing a National Strategy to Support Family Caregivers
Authors: Fox-Grage Wendy
Published: December 2021

This presentation describes the unique collaboration between The John A. Hartford Foundation, the Administration or Community Living (ACL), and the National Academy for State Health Policy (NASHP) in supporting the RAISE Act Family Caregiver Resource and Dissemination Center, and the goals and activities of the RAISE Act Family Caregiving Advisory Council. Most importantly, she will present the the development of recommendations for a national strategy to support family caregivers involving all levels of government as well as private-sector actors. These recommendations fall into five primary areas, which Fox-Grage will discuss in detail. She will also discuss the Center’s development of family caregiving resources for state and federal policymakers and other stakeholders as well as next steps in turning the Council’s recommendations into concrete action.
Incidence of Mild Cognitive Impairment, Conversion to Probable Dementia, and Mortality
Authors: Zhang Yun , Natale Ginny , Clouston Sean
Published: December 2021

Background: Few studies have jointly estimated incidence of MCI, conversion to probable dementia, and mortality. Methods: We used data from six waves of the National Health and Aging Trends Study (2011-2016). Multivariable-adjusted multi-state survival models (MSMs) were used to model incidence upon accounting for misclassification. Results: A total of 6,078 eligible NHATS participants 65 years of age and older were included (average age: 77.49 ±7.79 years; 58.42% females; 68.99% non-Hispanic White). Incidence of MCI was estimated to be 41.0 [35.5, 47.3]/1,000 person-years (PY). Participants converted to probable dementia at a high rate of 241.3 [189.6, 307.0]/1,000 PY, though a small number also reverted from MCI to cognitively normal. Education was associated with lower incidence of MCI and probable dementia, but increased mortality in those with MCI. There were also substantial racial and ethnic disparities in the incidence of MCI and dementia. Conclusions: Our results underscore the relatively common incidence of and conversions between MCI and dementia in community-dwelling older Americans and uncover the beneficial impact of education to withstand cognitive impairment before death.
Modifiable Risk Factors of Behavioral and Psychological Symptoms in People with Dementia
Authors: Seo Shinae , Mattos Meghan
Published: December 2021

Over ninety percent of people with dementia (PWD) experience behavioral and psychological symptoms, known to increase burden on care providers and healthcare systems. The purpose of this integrative review was to examine the modifiable risk factors of behavioral and psychological symptoms of dementia (BPSD) at the individual, caregiver, and environmental levels. An electronic database search was performed using PubMed, CINAHL[EBSCO], Web of Science, and PsycINFO from 2010-2020. Search terms included “dementia” AND (“Behavioral” OR “Behavioural” OR “Psychological” OR “Neuropsychiatric”) AND “symptoms” AND (“Independent Living” OR “Community Dwelling” OR “Community Living” OR “Living at Home” OR “Ageing in Place.” The search yielded 1,121 articles, and 14 articles were included in this review. Among the 14 articles, there were 11 modifiable risk factors presented across the individual, caregiver, and environmental levels. Individual-level factors included the presence of affective disorder, low quality of life, and leisure dysfunction. The modifiable caregiver-level factors included relationship with PWD, frequency of contact, caregiver burden, distress, frustration level, caregiver as a resource for PWD, and quality of dyadic relationship. One environmental factor, the presence of pandemic disease (e.g., COVID 19), was identified. This review presents the modifiable factors that contribute to the varied symptoms and multi domains of BPSD. Further research is necessary to determine whether, and to what degree, interventions targeting individual, caregiver, or environmental risk factors may reduce BPSD for PWD, caregivers, and providers within the community setting.
Cardiometabolic risk factors predict executive function scores in high-risk individuals
Authors: Gills Joshua , Jones Megan , Campitelli Anthony , Paulson Sally , Madero Erica , Myers Jennifer , Glenn Jordan , Gray Michelle
Published: December 2021

Alzheimer’s disease (AD) is expected to triple by 2050, affecting 16 million Americans. As a result, it is essential to combat this alarming increase in cognitive impairment through early detection. Cardiometabolic risk factors have shown to be associated with higher risk of AD. The purpose of this study was to determine if cardiometabolic risk factors could predict executive function scores in a high-risk population. Fifty (60.9±8.8 years) high-risk adults (classified by the Australian National University Alzheimer’s Disease Risk Index) were enrolled in this study. Participants completed a 6-minute walking test, venous blood draw, blood pressure measurement, and the digit coding symbol test (DCS). Results were examined through a multiple linear regression with DCS as the dependent variable and age, sex, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose, 6-minute walking test, systolic blood pressure (SBP), and diastolic blood pressure (DBP) as predictor variables. The model explained 42% of the variance of DCS (p = .04) with SBP (45%; p = .003) as a significant predictor. LDL (p = .087) and DBP (p = .123) accounted for 24% and 22% of the variance for this model, respectively. These results suggest cardiometabolic risk factors predict executive function values in high-risk individuals. Higher SBP was significantly associated with lower DCS scores indicating SBP as a valuable tool for practitioners when evaluating cognitive decline. Further research should expand sample size and track values longitudinally to substantiate these claims.
Sources of Positivity in the Daily Life of Family Caregivers of Persons with Dementia
Authors: Lee Kyungmi , Archer Breannlyn , Cox Kaitlyn , Pickering Carolyn
Published: December 2021

Family caregivers often experience fatigue, burnout, and health complications yet also enjoy many aspects of caregiving that may benefit their well-being. This study identifies positive aspects of caregiving in the daily life experiences of dementia family caregivers in order to inform interventions to support caregivers’ well-being. This case study entails a secondary analysis of open-ended question data obtained from 165 family caregivers who answered daily diaries over 21 days (n = 2841 responses). We used content analysis to organize and elicit thematic categories from the data collected in response to the question “what was the best part of your day.” A final 762 responses were selected as meeting the “care” criteria for the study, with an inter-rater reliability of 91.6%. Data analysis revealed three major sources of daily positive aspects including: caregiver-focused, patient-oriented, and support-system based. The analysis also revealed seven different kinds of daily positive aspects, such as getting to enjoy time with the care recipient or getting to accomplish other non-caregiving tasks. Many of the positive aspects of caregiving reported were enabled by social support, but they were ultimately from how they utilized that support (e.g., getting alone time) that provided the positivity. The findings of this study demonstrate the important role social support plays in caregiving, as well as highlights other possible intervention targets to create easier, more positive days for family caregivers.
Cognitive Status & Dementia Severity in CVLT-II-SF Forced Choice Recognition: Implications for Effort Assessment
Authors: Grewal Karl , Trites Michaella , O'Connell Megan , Kirk Andrew , MacDonald Stuart , Morgan Debra
Published: December 2021

Effort testing is critical to neuropsychological practice, including dementia assessment. Questions exist around whether cognitive status or impairment severity impacts effort test performance in this population. Presently, we examined whether scores on an embedded effort test - the California Verbal Learning Test II Short Form (CVLT-II-SF) Forced Choice Recognition (FCR) - differed across diagnostic cognitive status groups and how severity of impairment modulated test performance. In a sample of memory clinic patients, three cognitive status groups were identified: subjective cognitive impairment (SCI; n = 92), amnestic mild cognitive impairment (a-MCI; n = 18), and dementia due to Alzheimer’s Disease (AD; n = 70). Significant group differences in FCR performance were observed using one-way ANOVA (p < .001), with post-hoc analysis indicating the AD group performed significantly worse scores than the other groups. Using multiple regression, FCR performance was modelled as a function of cognitive status, impairment severity indexed MMSE, and their interaction, with a parallel analysis for the Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores as an alternate severity measure. Results yielded significant main effects for MMSE (p = 0.019) and cognitive status (p = 0.026), as well as a significant interaction (p = 0.021). Thus, increases in impairment severity disproportionately impaired FCR performance for persons with AD, calling into question research-based cut scores for effort determination in dementia contexts. Corresponding CDR-SOB analyses were non-significant. Future research should examine whether CVLT-II-SF-FCR is an appropriately specific inclusion in a best-practice testing battery for evaluating effort in dementia populations.
Examining Stereotype Threat in Neuropsychological Testing: A Usability and User Experience Pilot Study
Authors: Armendariz Jazlyn , Hwang Sarah , Blanco Giovanna Garrido , Pena Maria , Chan Thomas
Published: December 2021

Stereotype threat is defined as the situational predicament when people feel at risk of conforming to social stereotypes. Correspondingly, stereotype threat may negatively impair a persons’ working memory and cognitive abilities during neuropsychological tests due to hyper awareness of negative stereotypes. Moreover, it is critical to test the usability and the user experience of application-based neuropsychological assessments within diverse aging adult populations. In this pilot study, verbal expressions of feeling pressure to succeed, within a diverse population of young adults, were examined while taking an application-based neuropsychological assessment. Data was collected from 15 self-identified respondents (i.e., 7 Latinx, 5 Asian, 3 Bi-racial). Before beginning the assessment, 8 out of 15 participants exhibited self-handicapping behaviors such as offering explanations of mental exhaustion due to work and lack of sleep. Literature suggests these expressions are related to the onset of anxiety prior to taking cognitive tests, and contribute to potentially offering an excuse in anticipation of poor performance. Additionally, 3 out of 15 participants noted that even though the tasks were simple, they felt unintelligent because they did not complete the tasks to their best abilities (e.g., “I felt stupid. It was simple”). Findings from this pilot support the negative impact stereotype threats have on feelings of inadequacy and increase of anxiety levels among ethnic minorities in testing settings. Further emphases on examining the usability and user experience of application-based tests are needed, particularly within a diverse population of aging adults to facilitate more culturally competent neuropsychological testing experiences.
Gender Differences in Online Health-Related Search Behaviors Among Older Adults
Authors: Picchiello Matthew , Rule Payton , Lu Tina , Carpenter Brian
Published: December 2021

Nearly 60% of older adults use the internet for health-related reasons. Some studies have demonstrated differences in the frequency at which men and women perform various online activities. However, few studies have investigated gender differences in health-related search behaviors (HRSB). The purpose of this study was to examine differences in self-reported HRSB between older men and women. A total of 47 older adults (M age = 66.6, 55% female, 87% White) completed a survey assessing perceived usefulness and trust in the internet for health-care information, types of websites used, and reasons for looking up health information. Independent samples t-tests revealed that, compared to women, men regard the internet as more useful in helping them make health care decisions (t (45) = 2.715) and as a more trustworthy source (t (45) = 2.24, p's < 0.05). Men were more likely to get health information through sources affiliated with educational institutions (χ2(1) = 3.9) and government agencies (χ2(1) = 8.8), whereas women were more likely to use social media, (χ2(1) = 4.3, p's < 0.05). Lastly, men were more likely to use the internet to learn about information on medical procedures (χ2(1) = 5.1), while women were more likely to learn about alternative treatments (χ2(1) = 4.9, p 's < 0.05) online. As 72.3% of participants indicated the internet as their first source for health information, interventions geared towards enhancing HRSB for older adults are needed, especially for older women whose HRSB may make them particularly vulnerable to misinformation.
Interaction Effect of Subjective Health and Attitude about Aging on Gerontechnology Acceptance
Authors: Park Hayoung , Joo Susanna , Kim Kwang Joon , Kim Chang Oh , Lim Yun Mook , Jun Hey Jung
Published: December 2021

This study examined the interaction effect of subjective health and attitude about aging on gerontechnology acceptance among Korean older adults. The sample was 310 Korean older adults aged 65 and above without cognitive impairment who completed an online survey. The dependent variable was the attitude about gerontechnology, especially an exoskeleton robot for exercise. The independent variable was subjective health measured by the questions about self-reported health conditions. The moderating variable was the attitude about aging, which was measured by asking how much they feel less useful as they age. Covariates were age, gender, education level, employment status, income, and marital status. The results from the regression analyses using PROCESS macro and bootstrapping showed that the interaction effect of subjective health and attitude about aging is significant for gerontechnology acceptance; when older adults consider themselves less useful as they age, they tend to have positive attitudes about gerontechnology despite their subjective health. However, of those who consider that they are not less useful as they age, they tend to have positive attitudes about gerontechnology only when they consider themselves unhealthy. Thus, they tend to have negative attitudes about gerontechnology when they consider themselves healthy and useful. The findings imply that gerontechnology-based exercise programs or interventions could be welcomed by those who consider themselves unhealthy and think they are useless as they age. Also, the findings suggest that when applying an intervention program using gerontechnology, health status and self-assessment of aging should be considered in advance.
Older Koreans' Information Support and Internet Use: Internet Skills and Technology Attitudes
Authors: Lee Hye Soo
Published: December 2021

While older Koreans have growing access to Internet, they still lag in actual utilization. This study examined effects of different information support sources on Internet utilization and whether these were mediated by Internet skills and technology attitudes among older men and women. This study used secondary data from 2019 Digital Divide Survey conducted by National Information Society Agency of Korea. The sample consisted of 1,031 Korean Internet users aged 60+, including 495 men and 536 women. Support sources included personal and professional. Skills were measured by ability to use specific features of mobile devices such as smartphones (seven items), while utilization was measured by the use of mobile devices for specific reasons (25 items). Serial mediation analyses using both skills and attitudes were conducted separately according to gender and support sources, covarying for demographics and health. In general, information support was positively associated with utilization. For men, personal informational support was mediated by technology attitudes only. For women, professional informational support was mediated by both Internet skills and technology attitudes, but the serial indirect effect was not significant for this model. The other two models showed significant serial mediation effects through Internet skills and technology attitudes, in this order. Only women had significant direct associations between information support and Internet utilization. Regardless of the source, informational support is positively associated with older Koreans’ Internet utilization. Professional support for men and personal support for women may be most beneficial for greater Internet utilization.
Privacy and Usability in COVID Enrollment Apps
Authors: Calloway Laura , Huber Lesa , Camp L Jean
Published: December 2021

Enrollment apps for COVID-19 vaccinations are meant to be privacy-enhancing, but poor design puts privacy at risk. We report on a qualitative exploration of the experiences of older adults attempting to register for vaccination. We engaged in a think-aloud protocol with six participants over age 65 over Zoom as they used the New York state vaccination portal. Authentication requirements were: Medicare ID, DOB, address, and phone (optional). For this cohort, Social Security numbers were the default Medicare ID. We found that a privacy-enhanced authentication option exists, but efforts to use privacy-preserving enrollment were confounded by security-enhancing timeouts. Choosing to use the time-consuming privacy-preserving authentication increased the risk that available vaccines were taken. As a result, older adults reliant on volunteers to enroll revealed sensitive information and risked identity theft. A design that was meant to be privacy-enhancing by offering multiple avenues for authentication and ensuring logout via timeouts created a system where the more secure option was not effectively available due to a competing security mechanism. This was exacerbated by a counter counting down the number of vaccine sites available, similar to a well-known stress condition used to create cognitive load in laboratory experiments. All six participants used privacy-sensitive information to enroll; provided adequate information for identity theft; and all six encountered stop points. The countdown of available vaccination sites, the time required for insurance validation as an alternative to Medicare ID, and logging off after inactivity to prevent session theft each are good practices; but fail together.
BDNF SNP C270T Modifies the Association Between History of Head Injury and Cognitive Status in Older Adults
Authors: Drewel Mikaela , Gonzalez Hector , Rattinger Gail , Matyi Joshua , Hammond Alexandra , Kauzor Kaitlyn , Buhusi Mona , Tschanz JoAnn
Published: December 2021

Brain derived neurotrophic factor (BDNF), is a neurotrophin involved in neurogenesis and neuroplasticity. Several BDNF genes have been associated with cognitive function. Studies suggest head injury (HI) alters BDNF levels, and activities enhancing BDNF signaling promote better cognitive outcomes. We investigated the relationship between HI and BDNF single-nucleotide polymorphisms (SNPs) in predicting cognitive performance in a population-based sample of older adults. 4165 participants (56.7% female), dementia-free at baseline, were assessed triennially [follow-up years: mean (SD) = 5.85 (4.20), median = 7.33, maximum = 11.39]. Mean (SD) age was 75.36 (6.84). Cognition was assessed using the Modified Mini-Mental State Exam (3MS) and HI history from self-report. We examined interactions between BDNF SNPs [rs56164415 (BDNF C270T), rs6265 (Val66Met), rs2289656 (BDNF receptor trkB), and rs2072446 (NGF/BDNF receptor p75)] and history of HI (none, one, or multiple) in predicting cognitive decline. Covariates included age, education, sex, and apolipoprotein (APOE) E4 allele presence. Linear mixed-effect models indicated BDNF C270T significantly modified the association between HI and cognitive status (p < .006). Specifically, minor T allele carriers with single or multiple HI scored on average 2.08 and 3.21 points lower on the 3MS, respectively, than non-T carriers with no HI. Unexpectedly, there was a trend for APOE4*HI (p = .078) in that APOE E4 carriers with multiple HI scored higher than those lacking APOE E4 and HI. In this population-based sample, rs56164415 predicted cognitive outcomes that varied by history of HI. Factors influencing BDNF signaling may provide a potential avenue for intervention in recovery from HI.
Sirtuin-1 isoforms differentially regulate mitochondrial function
Authors: Zhang Xiaomin , Ameer Fathima , Crane Jasmine , Azhar Gohar , Wei Jeanne
Published: December 2021

Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. Alternatively spliced isoforms may lose part of the protein domain and have different intracellular localization as well as distinct functions. The main form of the SIRT1 (SIRT1v1) protein contains 11 exons. We have identified two new isoforms, SIRT1v2 (lost 2 exons), and SIRT1v3 (lost 3 exons), but their effect on mitochondrial gene expression has not been reported. To study the effect of the three SIRT1 isoforms on mitochondrial gene expression and function, neuronal cells were transfected with SIRT1 isoforms v1, v2 or v3 plasmids, respectively. Gene expression was measured by quantitative reverse transcription PCR (RT-qPCR). Our data showed SIRT1 isoforms v1, v2 and v3 differentially regulated PCG-1alpha and PCG-1beta, which are the upstream regulators of mitochondrial structure and function. SIRT1v1 upregulated mitofusin-1 (MFN1), the mitochondrial dynamin-like GTPase (OPA1) gene, and the transcription factor A mitochondrial (TFAM) gene. In contrast, the SIRT1-v2 isoform repressed the MFN1, MFN2, and TFAM genes, while the SIRT1-v3 isoform repressed the MFN1 gene. In addition, the three SIRT1 isoforms differentially affected the mitochondrial respiratory complex I genes, including NDUFAB1, NDUFS1, NDUFV1, NDUFV2. The data indicates that SIRT1 regulates mitochondrial biogenesis and function through a signaling pathway involving PGC-1alpha, PCG-1beta, mitofusin 1 and 2, OPA1, and TFAM genes. Taken together, alternative splicing generated three SIRT1 isoform proteins with diverse functions. Age-related changes in the alternative splicing events are likely to impact sirtuin-regulated cellular functions and signaling pathways in aging and senescence.
Caregiver Support for Asian American Alzheimer’s Disease and Related Dementias Caregivers: A Conceptual Synthesis
Authors: Hu Mengyao , Squires Allison , Wu Bei
Published: December 2021

Informal caregiver support has been defined as different types of interventions. However, it has not been well explained in the social context and not well discussed as an integrative concept for dementia caregivers who are Asian Americans. Therefore, the aim of this study was to conduct a dimensional analysis--a type of evidence synthesis--to explore caregiver support in the context of Asian American dementia caregivers. A synthesis of 40 articles produced four interrelated dimensions of caregiver support: Individual (language, information, psychological issue, and culture); Family (family member support, availability of extended family, and decision making); Community (bilingual and bicultural help, and religion and spiritual source); and Professional healthcare system (expectations from healthcare professionals and caregivers for caregiver interventions, communication concordance, initiative in seeking help, and trust). The findings provide guidance for future studies on this population in promoting caregiver’s health and developing caregiver interventions.
Association of GrimAge DNA methylation components and 2-year mortality in the Health and Retirement Study
Authors: Meier Helen , Mitchell Colter , Crimmins Eileen , Thyagarajan Bharat , Faul Jessica
Published: December 2021

DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes. We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and Retirement Study (HRS) to determine if any of the DNAm subcomponents were driving observed associations. A representative subsample of individuals who participated in the HRS 2016 Venus Blood Study were included in this analysis (N=3430). DNAm was measured with the Infinium Methylation EPIC BeadChip. Deaths that occurred between 2016 and 2018 contributed to 2-year mortality estimates (N=159, 4.5% of the sample). Weighted logistic regression estimated the association first between GrimAge and 2-year mortality and second between the DNAm subcomponents and 2-year mortality. All models were adjusted for age, sex, race/ethnicity, education, current smoking status, smoking pack years and cell composition of the biological sample. The average GrimAge for participants with and without 2-year mortality was 77 years 68 years respectively. A one-year increase in GrimAge was associated with 17% higher odds of 2-year mortality (95% CI: 1.16, 1.17). Two of the seven DNAm blood protein subcomponents of GrimAge (TIMP metallopeptidase inhibitor 1, adrenomedullin) and DNAm smoking pack years were associated with 2-year mortality and DNAm smoking pack years appeared to drive the overall GrimAge association with 2-year mortality. GrimAge was a better predictor of 2-year mortality than the DNAm subcomponents individually.
Global phosphoproteomic profiling of skeletal muscle in ovarian hormone-deficient female mice
Authors: Peyton Mina , Yang Tzu-Yi , Higgins LeeAnn , Markowski Todd , Parker Laurie , Lowe Dawn
Published: December 2021

Dynapenia, the age-related loss of skeletal muscle strength without the loss of muscle mass, significantly impacts the activities and quality of life of the aging population. Studies have shown that dynapenia occurs earlier in females than males in both human and rodent studies. Moreover, in females, estrogen deficiency has been shown to contribute to the loss of skeletal muscle strength as well as blunted recovery of strength after injury. The maintenance of skeletal muscle contractile function is vital to the overall health of women, especially as women live 1/3 of their life in an estrogen deficient state. Reversible protein phosphorylation is an indispensable post-translational modification, playing a key role in signal transduction pathways. Phosphorylation of skeletal muscle proteins have been shown to regulate sarcomeric function, excitation-contraction coupling, energy metabolism, and fiber-type composition. To define the physiological changes in the skeletal muscle phosphoproteome associated with estrogen deficiency, we used an ovariectomy model coupled with mass spectrometry. We identified, in total, 5,424 unique phosphorylation sites and 1,177 phosphoproteins in the tibialis anterior muscle. Ingenuity Pathway Analysis show decreased phosphorylation of contractile proteins and significant predicted inhibition of the upstream kinase, CDK6 (z-score -2.0) in ovariectomized compared to control muscles. Our results suggest that estrogen deficiency remodels the skeletal muscle phosphoproteome which may alter phosphorylation signaling that might contribute to the loss of strength in females.
Nuclear Architecture Disruption During Aging Causes Misexpression of Genes Lacking CpG Islands
Authors: Lee Jun-Yeong , Davis Ian , Beck Samuel
Published: December 2021

Global disorganization of chromatin architecture, characterized by disrupted nuclear lamina and associated heterochromatin, is commonly observed in various aging contexts, including premature aging diseases, cellular senescence, and normative aging. Although these conserved structural changes have been reported for over two decades, their impact on transcription and contribution to age-related degenerative changes remain unclear. Here we show that genes not associated with CpG islands (CGI- genes), which form heterochromatin when transcriptionally silent, are globally misexpressed in aged nuclei with disrupted chromatin architectures. Our data also show that CGI- gene misexpression is a direct outcome of nuclear architecture disruption. Notably, CGI- gene misexpression explains the molecular basis of various defects observed during aging, including loss of cellular identity and increased noises in transcription. We also show that uncontrolled secretory phenotypes commonly observed during aging are largely attributable to CGI- gene misexpression, which drives disruption of intercellular communication and fuel chronic inflammation in aged tissues. Our large-scale meta-analysis further demonstrates that CGI- gene misexpression is a common feature of mammalian aging and age-associated diseases. Interestingly, CGI- gene misexpression can be suppressed by anti-aging interventions. Our study suggests that age-associated CGI- gene misexpression is a novel biomarker of physiological aging which offers an effective therapeutic target for delaying or ameliorating degenerative changes associated with aging.
Perceived Control and Cognitive Function Among Acute Ischemic Stroke Patients in China
Authors: Liu Zhijian , Kong Xiangjing , Wang Jing , Wang Qin , Wu Bei , Li Juan
Published: December 2021

This study explored an association between perceived control and cognitive function among 437 acute ischemic stroke (AIS) patients in China. We collected data from one stroke center in each of the three cities (Shanghai, Nanjing, and Linyi) from June to December, 2020. Cognitive function was assessed by the Montreal Cognitive Assessment (MoCA), and perceived control was assessed by Perceived Control in Health Care Questionnaire at acute stage. Hierarchical linear regression was used. The average of perceived control and MoCA were 81.36±0.877 and 19.66±0.304, respectively. A number of 374 (85.6%) patients were in cognitive impairment and 63(14.4%) were cognitively normal. Perceived control was positively associated with cognitive function (β=0.103, p＜0.001). After controlling for stroke severity, age, gender and education, the association was still significant (β=0.041, p=0.014). These findings suggest that perceived control may be a potential target in cognitive interventions for AIS patients.
Early Life Thymectomy Induces Glucose Intolerance in Middle-Aged Mice
Authors: Buckley David , Sharma Sunita , Trott Daniel
Published: December 2021

Previously we have found that T cells contribute to age-related glucose intolerance. The purpose of this study was to test the hypothesis that early life thymectomy at 3wks of age induces T cell aging and subsequent impairments in glucose homeostasis in otherwise young animals. Male C57BL6 mice underwent thymectomy (thymex; n=7) or sham surgery (control; n=7) at 3wks of age. A glucose (2g/kg) tolerance test (GTT) was performed at 6 and 9mo via intraperitoneal injection. Following euthanasia at 9mo of age, splenic T cell phenotype was assessed by flow cytometry. Group differences were assessed by independent samples t-test or repeated measures ANOVA and Bonferroni post-hoc test. Data are presented as mean±SEM. At 6mo, the thymex animals had a significantly lower fasting glucose compared to controls (156.8±7.9mg/dl,174.1±5.8mg/dl, p=0.06). During the GTT, 6mo old thymex mice had a greater area under the curve (AUC) compared to controls (31893.8±612.3mg/dl, 28020.9±1112.9mg/dl, p=0.03). At 9mo, the thymex mice had greater fasting glucose compared to controls (215.6±11.6mg/dl, 176.3±7.9mg/dl, p=0.016), as well as a greater GTT AUC (61445.4±1949.2mg/dl, 41527.5±2530.3mg/dl, p=0.0001). The thymex group also had increased fasting and glucose stimulated insulin levels compared to controls (0=1.3±0.2ng/ml 0.3±0.1ng/ml, p=0.01; 15=1.7±0.2ng/ml,0.44±0.1ng/ml, p=0.0014). Thymex mice exhibited a blunted splenic CD4:CD8 ratio (0.5±0.2, 1.1±0.2, p=0.04) compared to controls and a trend toward a memory CD8+ T cell phenotype (23.1±11.6%, 7.1±2.6, p=0.08), both consistent with aging. This data indicates that early life thymectomy may accelerate T cell aging, resulting in impairments in glucose tolerance in otherwise young and middle aged mice.
The Role of the Human Immune System in the Aging Process: a Mathematical Model of Cell and Cytokine Activation
Authors: Talaei Kian , Garan Steven , Martins Nuno , Cho Joshua , Jahansooz Julia , Bhullar Puneet , Suen Elliott , Piszker Walter
Published: December 2021

The role of the human immune system as a factor in the aging process has led to extensive research in the field of infection biology and bioinformatics. Cell-based mathematical models have previously been used to simulate the immune system in response to pathogens. A variety of cells, such as activated and resting macrophages, plasma cells, antibodies, helper T cells, T-lymphocytes, and B-lymphocytes, have already been simulated by mathematical models. This work aims to incorporate cytokines in these mathematical models to create a more comprehensive simulation that can predict cytokine levels in response to a Gram-positive bacterium, S. aureus. To accomplish this, the cytokines Tumor Necrosis Factor Alpha (TNF-α), Interleukin 6 (IL-6), Interleukin 8 (IL-8), and Interleukin 10 (IL-10) were studied to quantify the relationship between cytokine release from macrophages and the concentration of the pathogen, S. aureus ex vivo. The results of the simulation were compared to ex vivo human whole blood data to test its accuracy. The future expansion of this model may provide a clearer image of the various interactions within the immune system and this improved model of the immune system may also facilitate a better understanding of the mechanisms that lead to the degradation of the immune system during the aging process.
The Impact of Social Isolation on Cognition and Quality of Life Among Stroke Patients in China
Authors: Kong Xiangjing , Li Juan , Liu Zhijian , Wang Jing , Wu Bei
Published: December 2021

This study examined the impactof social isolation on cognitive function and Quality of Life (QoL) among acute ischemic stroke (AIS) patients in China. We conducted in-person interviews among 206 AIS patients during the acute stage and at 3-month after onset in three cities between May 2020 and February 2021. The data was collected during and post-COVID-19 period in China. We conducted bivariate and multipleregression analyses.Results show that over time, average level of social isolation decreased, and cognitive function and QoL increased.After controllingfor covariates, social isolation was negatively associated with cognitive function (β=-0.438, p<0.01) and QoL (β=-2.521, p<0.01). These findings suggest that addressing the issue of social isolation could potentially impact patients’ cognitive function and QoL.Future studies are needed to further examine the linkages between long-term social isolation and changes in cognitive function and QoL among AIS patients.
Mechanisms of Cell Non-Autonomous Longevity Regulation
Authors: Leiser Scott , Choi Hyo , Miller Hillary , Bhat Ajay , Howington Marshall , Dean Elizabeth , Huang Shijiao
Published: December 2021

An organism’s ability to respond to stress is crucial for long-term survival. These stress responses are coordinated by distinct but overlapping pathways, many of which also regulate longevity across taxa. Our previous work identified a cell non-autonomous signaling pathway led by the hypoxia-inducible factor and resulting in induction of flavin-containing monooxygenase-2 (fmo-2) to promote health and longevity. Our current work identifies a distinct cell non-autonomous pathway downstream of dietary restriction (DR) that also relies on fmo-2 induction to promote health and longevity. We now find that these cell non-autonomous pathways can be mimicked by small molecule interventions that increase longevity by inducing fmo-2. Based on the commonalities of these pathways, we hypothesized that fmo-2, a classically annotated xenobiotic enzyme, might play a key endogenous role in responding to metabolic stress. Our resulting data, using metabolic profiling and further epistatic analysis, both support this hypothesis and link fmo-2’s mechanism to modifications in one-carbon metabolism (OCM), a key intermediate pathway consisting of the folate and methionine cycles. Using mathematical modeling and a labeled metabolomics approach, we were able to further identify the likely mechanism of fmo-2-mediated metabolic effects and connect them to both OCM and downstream components. We propose that fmo-2 is induced cell non-autonomously to modify systemic metabolism and longevity, and that fmo-2 is a key member of a conserved metabolic stress response.
Total Transcriptome Responses to Low and Higher Intensity Aerobic Exercise Interventions in Older Adults
Authors: Smith Meghan , McWilliams Gabriella , Bryan Angela , Seals Douglas , LaRocca Thomas
Published: December 2021

Aerobic exercise is a universally recommended strategy for increasing healthspan, and recent advances in next-generation sequencing and bioinformatics (e.g., RNA-seq/transcriptomics) have made it possible to broadly profile the molecular transducers of exercise. However, most transcriptome studies of exercise have focused on coding genes only, and the transcriptomic response to different exercise interventions has not been characterized by RNA-seq in older adults. Therefore, we performed total RNA-seq (to capture both coding and non-coding gene expression) on peripheral blood mononuclear cells collected from healthy, previously sedentary older adults (males and females, aged 70 ± 1 years). Samples were collected before and after 16 weeks of either low-intensity continuous training (LICT, 50% maximum heart rate, 3 x 30 min/week) or moderate-intensity continuous training plus interval training (MICT+IT, 60-80% maximum heart rate, progressively increased to include IT, 3 x 30 min/week). We found that both interventions modified biological processes (transcriptome modules) related to oxygen transport and reduced inflammatory signaling/immune activation processes (more pronounced with LICT). Interestingly, transcriptome changes unique to LICT subjects included increased expression of genes linked with vascularization and endothelial cell migration, whereas MICT+IT was uniquely associated with a robust increase in antioxidant response gene expression. We also observed numerous changes in long non-coding RNAs and microRNAs that could be linked with these exercise-associated gene expression changes with both interventions. These data provide a first comprehensive look into transcriptomic changes associated with moderate vs. low intensity aerobic exercise in older adults, and they suggest distinct benefits of each exercise strategy.