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Physical inactivity among older adults remains a global burden, leading to a variety of health challenges and even mortality. This study evaluated the impact of a novel virtual humanoid coach-driven physical exercise program among older adults. A non-randomized (quasi) experimental research was conducted in two community senior centers. The recruited participants (n = 130) were primarily female older adults with a mean age of 66.40 and agreed to be purposively assigned either experimental or control groups. Trained healthcare providers performed health assessments in three time points using valid and reliable tools. Descriptive statistics, t-tests, and RM-ANOVA were used to quantitatively analyze the data using SPSS version 22. There are significant mean differences between the groups across all functional capacity assessments and Time 2-3 assessment of sleep quality. RM-ANOVA revealed significant differences in physical assessment over time between the two groups. The analyses of time and group interaction revealed significant improvement in health assessments among the members of the mixed reality group compared to the traditional groups. The impact of virtual coaches in community-based enhancing physical activity programs is comparable to the traditional mode and introduces a novel approach to promoting physical activity among older adults.
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Ejercicio Físico , Humanos , Femenino , Anciano , Masculino , Filipinas , Persona de Mediana Edad , Realidad Virtual , Promoción de la Salud/métodosRESUMEN
Large Language Models (LLMs) stand on the brink of reshaping the field of aging and dementia care, challenging the one-size-fits-all paradigm with their capacity for precision medicine and individualized treatment strategies. The "Large Pre-Trained Models with a Focus on AD/ADRD and Healthy Aging" symposium, organized by the National Institute on Aging and the Johns Hopkins AI & Technology Collaboratory for Aging Research, served as a platform for exploring this potential. The symposium brought together diverse experts to discuss the integration of LLMs in aging and dementia care. They highlighted the roles LLMs can play in clinical decision support and predictive analytics, while also addressing critical ethical concerns including bias, privacy, and the responsible use of AI. The discussions focused on the need to balance technological advancement with ethical considerations in AI deployment. In conclusion, the symposium projected a future where LLMs not only revolutionize healthcare practices but also pose significant challenges that require careful navigation.
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Background: Physical inactivity and a sedentary lifestyle among community-dwelling older adults poses a greater risk for progressive physical and cognitive decline. Mixed reality technology-driven health enhancing physical activities such as the use of virtual coaches provide an emerging and promising solution to support healthy lifestyle, but the impact has not been clearly understood. Methods and analysis: An observational explanatory sequential mixed-method research design was conceptualized to examine the potential impact of a user-preferred mixed reality technology-driven health enhancing physical activity program directed toward purposively selected community-dwelling older adults in two senior centers in the Philippines. Quantitative components of the study will be done through a discreet choice experiment and a quasi-experimental study. A total of 128, or 64 older adults in each center, will be recruited via posters at community senior centers who will undergo additional screening or health records review by a certified gerontologist to ensure safety and proper fit. Treatments (live coaching with video-based exercise and mixed reality technology-driven exercise) will be assigned to each of the two senior center sites for the quasi-experiment. The participants from the experimental group shall be involved in the discreet choice experiment, modeling, and usability evaluations. Finally, a qualitative sample of participants (n = 6) as key informants shall be obtained from the experimental group using purposive selection. Discussion: This study protocol will examine the health impact of a promising mixed reality program in health promotion among older adults. The study utilizes a human-centered mixed method research design in technology development and evaluation in the context of developing nations.Clinical trial registration: ClinicalTrials.gov, identifier NCT06136468.
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Ejercicio Físico , Promoción de la Salud , Vida Independiente , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Promoción de la Salud/métodos , Filipinas , Proyectos de InvestigaciónRESUMEN
Tryptophan catabolism is highly conserved and generates important bioactive metabolites, including kynurenines, and in some animals, NAD+. Aging and inflammation are associated with increased levels of kynurenine pathway (KP) metabolites and depleted NAD+, factors which are implicated as contributors to frailty and morbidity. Contrastingly, KP suppression and NAD+ supplementation are associated with increased life span in some animals. Here, we used DGRP_229 Drosophila to elucidate the effects of KP elevation, KP suppression, and NAD+ supplementation on physical performance and survivorship. Flies were chronically fed kynurenines, KP inhibitors, NAD+ precursors, or a combination of KP inhibitors with NAD+ precursors. Flies with elevated kynurenines had reduced climbing speed, endurance, and life span. Treatment with a combination of KP inhibitors and NAD+ precursors preserved physical function and synergistically increased maximum life span. We conclude that KP flux can regulate health span and life span in Drosophila and that targeting KP and NAD+ metabolism can synergistically increase life span.
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Quinurenina , Triptófano , Animales , Quinurenina/metabolismo , Triptófano/metabolismo , Longevidad , NAD/metabolismo , Drosophila/metabolismoRESUMEN
This perspective outlines the Artificial Intelligence and Technology Collaboratories (AITC) at Johns Hopkins University, University of Pennsylvania, and University of Massachusetts, highlighting their roles in developing AI-based technologies for older adult care, particularly targeting Alzheimer's disease (AD). These National Institute on Aging (NIA) centers foster collaboration among clinicians, gerontologists, ethicists, business professionals, and engineers to create AI solutions. Key activities include identifying technology needs, stakeholder engagement, training, mentoring, data integration, and navigating ethical challenges. The objective is to apply these innovations effectively in real-world scenarios, including in rural settings. In addition, the AITC focuses on developing best practices for AI application in the care of older adults, facilitating pilot studies, and addressing ethical concerns related to technology development for older adults with cognitive impairment, with the ultimate aim of improving the lives of older adults and their caregivers. HIGHLIGHTS: Addressing the complex needs of older adults with Alzheimer's disease (AD) requires a comprehensive approach, integrating medical and social support. Current gaps in training, techniques, tools, and expertise hinder uniform access across communities and health care settings. Artificial intelligence (AI) and digital technologies hold promise in transforming care for this demographic. Yet, transitioning these innovations from concept to marketable products presents significant challenges, often stalling promising advancements in the developmental phase. The Artificial Intelligence and Technology Collaboratories (AITC) program, funded by the National Institute on Aging (NIA), presents a viable model. These Collaboratories foster the development and implementation of AI methods and technologies through projects aimed at improving care for older Americans, particularly those with AD, and promote the sharing of best practices in AI and technology integration. Why Does This Matter? The National Institute on Aging (NIA) Artificial Intelligence and Technology Collaboratories (AITC) program's mission is to accelerate the adoption of artificial intelligence (AI) and new technologies for the betterment of older adults, especially those with dementia. By bridging scientific and technological expertise, fostering clinical and industry partnerships, and enhancing the sharing of best practices, this program can significantly improve the health and quality of life for older adults with Alzheimer's disease (AD).
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Enfermedad de Alzheimer , Isotiocianatos , Estados Unidos , Humanos , Anciano , Enfermedad de Alzheimer/terapia , Inteligencia Artificial , Gerociencia , Calidad de Vida , TecnologíaRESUMEN
Despite its known importance in the cardiovascular system, the specific role and impact of the angiotensin type 2 receptor (AT2R) in lung physiology and pathophysiology remain largely elusive. In this study, we highlight the distinct and specialized lung-specific roles of AT2R, primarily localized to an alveolar fibroblast subpopulation, in contrast to the angiotensin type 1 receptor (AT1R), which is almost exclusively expressed in lung pericytes. Evidence from our research demonstrates that the disruption of AT2R (AT2R-/y), is associated with a surge in oxidative stress and impaired lung permeability, which were further intensified by Hyperoxic Acute Lung Injury (HALI). With aging, AT2R-/y mice show an increase in oxidative stress, premature enlargement of airspaces, as well as increased mortality when exposed to hyperoxia as compared to age-matched WT mice. Our investigation into Losartan, an AT1R blocker, suggests that its primary HALI lung-protective effects are channeled through AT2R, as its protective benefits are absent in AT2R-/y mice. Importantly, a non-peptide AT2R agonist, Compound 21 (C21), successfully reverses lung oxidative stress and TGFß activation in wild-type (WT) mice exposed to HALI. These findings suggest a possible paradigm shift in the therapeutic approach for lung injury and age-associated pulmonary dysfunction, from targeting AT1R with angiotensin receptor blockers (ARBs) towards boosting the protective function of AT2R.
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Lesión Pulmonar Aguda , Receptor de Angiotensina Tipo 2 , Ratones , Animales , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/agonistas , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Receptor de Angiotensina Tipo 1/genética , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/prevención & controlRESUMEN
While physical frailty has been recognized as a clinical entity for some time, the concept of cognitive frailty (CF) is now gaining increasing attention in the geriatrics research community. CF refers to the co-occurrence of physical frailty and cognitive impairment in older adults, which has been suggested as a potential precursor to both dementia and adverse physical outcomes. However, this condition represents a challenge for researchers and clinicians, as there remains a lack of consensus regarding the definition and diagnostic criteria for CF, which has limited its utility. Here, using insights from both the physical frailty literature and cognitive science research, we describe emerging research on CF. We highlight areas of agreement as well as areas of confusion and remaining knowledge gaps, and provide our perspective on fine-tuning the current construct, aiming to stimulate further discussion in this developing field.
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Disfunción Cognitiva , Fragilidad , Geriatría , Humanos , Anciano , Fragilidad/diagnóstico , Anciano Frágil/psicología , Disfunción Cognitiva/diagnóstico , CogniciónRESUMEN
Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer's dementia, cognitive function, and pathologic Alzheimer's disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with ß-amyloid levels (beta = - 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.
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Enfermedad de Alzheimer , Esclerosis del Hipocampo , Humanos , Enfermedad de Alzheimer/genética , Genómica , Encéfalo , ADN Mitocondrial , Envejecimiento/genéticaRESUMEN
Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-ß load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.
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Angiotensinas , Receptores de Angiotensina , Humanos , Anciano , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina , AnticuerposRESUMEN
Understanding the physiological basis of physical resilience to clinical stressors is crucial for the well-being of older adults. This article presents a novel framework to discover the biological underpinnings of physical resilience in older adults as part of the "Characterizing Resiliencies to Physical Stressors in Older Adults: A Dynamical Physiological Systems Approach" study, also known as The Study of Physical Resilience and Aging (SPRING). Physical resilience, defined as the capacity of a person to withstand clinical stressors and quickly recover or improve upon a baseline functional level, is examined in adults aged 55 years and older by studying the dynamics of stress response systems. The hypothesis is that well-regulated stress response systems promote physical resilience. The study employs dynamic stimulation tests to assess energy metabolism, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the innate immune system. Baseline characteristics influencing resilience outcomes are identified through deep phenotyping of physical and cognitive function, as well as of biological, environmental, and psychosocial characteristics. SPRING aims to study participants undergoing knee replacement surgery (n = 100), bone and marrow transplantation (n = 100), or anticipating dialysis initiation (n = 60). Phenotypic and functional measures are collected pre-stressor and at multiple times after stressor for up to 12 months to examine resilience trajectories. By improving our understanding of physical resilience in older adults, SPRING has the potential to enhance resilient outcomes to major clinical stressors. The article provides an overview of the study's background, rationale, design, pilot phase, implementation, and implications for improving the health and well-being of older adults.
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Resiliencia Psicológica , Humanos , Anciano , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Envejecimiento/fisiología , EmpleoRESUMEN
Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty.
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Fragilidad , Interleucina-6 , Ratones , Humanos , Animales , Interleucina-6/genética , Interleucina-6/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Músculo Esquelético/metabolismoRESUMEN
BACKGROUND: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. RESULTS: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. CONCLUSION: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.
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Resilience, which relates to one's ability to respond to stressors, typically declines with age and the development of comorbid conditions in older organisms. Although progress has been made to improve our understanding of resilience in older adults, disciplines have employed different frameworks and definitions to study various aspects of older adults' response to acute or chronic stressors. "Overview of the Resilience World: State of the Science," a bench-to-bedside conference on October 12-13, 2022, was sponsored by the American Geriatrics Society and National Institute on Aging. This conference, summarized in this report, explored commonalities and differences among the frameworks of resilience most commonly used in aging research in the three domains of resilience: physical, cognitive, and psychosocial. These three main domains are intertwined, and stressors in one domain can lead to effects in other domains. The themes of the conference sessions included underlying contributors to resilience, the dynamic nature of resilience throughout the life span, and the role of resilience in health equity. Although participants did not agree on a single definition of "resilience(s)," they identified common core elements of a definition that can be applied to all domains and noted unique features that are domain specific. The presentations and discussions led to recommendations for new longitudinal studies of the impact of exposures to stressors on resilience in older adults, the use of new and existing cohort study data, natural experiments (including the COVID-19 pandemic), and preclinical models for resilience research, as well as translational research to bring findings on resilience to patient care.
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COVID-19 , Geriatría , Humanos , Estados Unidos , Anciano , Envejecimiento/fisiología , National Institute on Aging (U.S.) , Estudios de Cohortes , PandemiasRESUMEN
The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT1R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT1R, AT2R, and AT4R. The AT1R promotes inflammation and mitochondrial reactive oxygen species generation. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer's dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70-90 years old, n = 30 in each group). We show that ARB use is associated with higher brain AT4R, lower oxidative stress, and amyloid-ß burden in NCI participants. In AD, ARB use was associated with lower brain AT1R but had no impact on inflammation, oxidative stress, or amyloid-ß burden. Our results may suggest a potential role for AT4R in the salutary effects for ARB on the brains of not cognitively impaired older adults.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Regulación hacia Arriba , Inhibidores de la Enzima Convertidora de Angiotensina , Encéfalo/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Angiotensinas , Inflamación/complicacionesRESUMEN
Dysregulation of energy producing metabolic pathways has been observed in older adults with frailty. In this study, we used liquid chromatography-mass spectrometry technology to identify aging- and frailty-related differences in metabolites involved in glycolysis, the tricarboxylic (TCA) cycle, and other energy metabolism-related pathways in the serum of a cohort of community-dwelling adults aged 20-97 (n = 146). We also examined the relationship between serum levels of metabolites and functional measures, physical frailty, and risk status for adverse health outcomes. We observed elevated levels of TCA cycle and glycolytic intermediates in frail subjects; however, the differences in the levels of ATP and other energy metabolites between young, nonfrail, and frail adults were not significant. Instead, we found that serum levels of neurotransmitters N-acetyl-aspartyl-glutamate, glutamate, and γ-aminobutyric acid were significantly elevated in older adults with frailty. These elevations of glycolytic and TCA cycle intermediates, and neurotransmitters may be part of the biological signature of frailty.
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Fragilidad , Humanos , Anciano , Metabolómica , Envejecimiento , Glucólisis , Espectrometría de Masas , Anciano FrágilRESUMEN
Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker-Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.