National Institute on Aging's 50th anniversary: Advancing aging research and the health and well-being of older adults.

The National Institute on Aging (NIA), part of the National Institutes of Health (NIH), was founded in 1974 to support and conduct research on aging and the health and well-being of older adults. Fifty years ago, the concept of studying aging generated much skepticism. Early NIA-funded research findings helped establish the great value of aging research and provided the foundation for significant science advances that have improved our understanding of the aging process, diseases and conditions associated with aging, and the effects of health inequities, as well as the need to promote healthy aging lifestyles. Today, we celebrate the many important contributions to aging research made possible by NIA, as well as opportunities to continue to make meaningful progress. NIA emphasizes that the broad aging research community must continue to increase and expand our collective efforts to recruit and train a diverse next generation of aging researchers.

INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC): An NIA and VA-sponsored initiative to increase veteran participation in aging and dementia research.

INTRODUCTION: Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers one avenue to advance the field and improve health outcomes. METHODS: To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC), provided funding for five sites and cross-site organizing structure. Diverse and innovative recruitment strategies were used. RESULTS: Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups. CONCLUSIONS: This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans.

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD. It was the unanimous consensus that cumulative data from multiple studies in humans and animal models support that lowering APOE4 should be a target for therapeutic approaches for APOE4 carriers. ANN NEUROL 2024;95:625-634.

NIAGADS Alzheimer's GenomicsDB: A resource for exploring Alzheimer's disease genetic and genomic knowledge.

INTRODUCTION: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site Alzheimer's Genomics Database (GenomicsDB) is a public knowledge base of Alzheimer's disease (AD) genetic datasets and genomic annotations. METHODS: GenomicsDB uses a custom systems architecture to adopt and enforce rigorous standards that facilitate harmonization of AD-relevant genome-wide association study summary statistics datasets with functional annotations, including over 230 million annotated variants from the AD Sequencing Project. RESULTS: GenomicsDB generates interactive reports compiled from the harmonized datasets and annotations. These reports contextualize AD-risk associations in a broader functional genomic setting and summarize them in the context of functionally annotated genes and variants. DISCUSSION: Created to make AD-genetics knowledge more accessible to AD researchers, the GenomicsDB is designed to guide users unfamiliar with genetic data in not only exploring but also interpreting this ever-growing volume of data. Scalable and interoperable with other genomics resources using data technology standards, the GenomicsDB can serve as a central hub for research and data analysis on AD and related dementias. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) offers to the public a unique, disease-centric collection of AD-relevant GWAS summary statistics datasets. Interpreting these data is challenging and requires significant bioinformatics expertise to standardize datasets and harmonize them with functional annotations on genome-wide scales. The NIAGADS Alzheimer's GenomicsDB helps overcome these challenges by providing a user-friendly public knowledge base for AD-relevant genetics that shares harmonized, annotated summary statistics datasets from the NIAGADS repository in an interpretable, easily searchable format.

Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop.

The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, or life span spent free of significant disease and disability. Studies are underway to examine several possible pharmacological interventions for this purpose. As part of a National Institute on Aging workshop on the development of function-promoting therapies, scientific content experts provided literature reviews and state-of-the-field assessments for the studies of senolytics, nicotinamide adenine dinucleotide (NAD+) boosters, and metformin. Cellular senescence increases with age, and preclinical studies demonstrate that the use of senolytic drugs improves healthspan in rodents. Human studies using senolytics are in progress. NAD+ and its phosphorylated form, NADP+, play vital roles in metabolism and cellular signaling. Increasing NAD+ by supplementation with precursors including nicotinamide riboside and nicotinamide mononucleotide appears to extend healthspan in model organisms, but human studies are limited and results are mixed. Metformin is a biguanide widely used for glucose lowering, which is believed to have pleiotropic effects targeting several hallmarks of aging. Preclinical studies suggest it improves life span and healthspan, and observational studies suggest benefits for the prevention of several age-related diseases. Clinical trials are underway to examine metformin for healthspan and frailty prevention. Preclinical and emerging clinical studies suggest there is potential to improve healthspan through the use of pharmacologic agents reviewed. However, much further research is needed to demonstrate benefits and general safety for wider use, the appropriate target populations, and longer-term outcomes.

Senescence and Inflammation: Summary of a Gerontological Society of America and National Institute on Aging-Sponsored Symposium.

The National Institute on Aging sponsored a symposium at the Gerontological Society of America (GSA) annual meeting in Indianapolis, Indiana, to discuss recent discoveries related to senescent and inflammatory mechanisms in aging and disease. Consistent with the 2022 Biological Sciences GSA program led by Dr. Rozalyn Anderson, the symposium featured early-stage investigators and a leader in the field of geroscience research. Cell senescence and immune interactions coordinate homeostatic and protective programming throughout the life span. Dysfunctional communication in this exchange eventuates in inflammation-related compositional changes in aged tissues, including propagation of the senescence-associated secretory phenotype and accumulation of senescent and exhausted immune cells. Presentations in this symposium explored senescent and immune-related dysfunction in aging from diverse viewpoints and featured emerging cellular and molecular methods. A central takeaway from the event was that the use of new models and approaches, including single-cell -omics, novel mouse models, and 3D culture systems, is revealing dynamic properties and interactions of senescent and immune cell fates. This knowledge is critical for devising new therapeutic approaches with important translational relevance.

An overview of the resilience world: Proceedings of the American Geriatrics Society and National Institute on Aging State of Resilience Science Conference.

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.

The Role of the National Institute on Aging in the Development of the Field of Geroscience.

The conceptualization of the field of geroscience, which began about 10 years ago, marks, together with the publication of "The hallmarks of aging" (see López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Cell 153: 1194-1217, 2013), a significant watershed in the development of aging research. Based on a very simple and commonly accepted premise, namely, that aging biology is at the core the most significant risk factor for all chronic diseases affecting the elderly, geroscience became possible because of earlier significant developments in the field of aging biology. Here we describe the origins of the concept, as well as its current status in the field. The principles of geroscience provide an important new biomedical perspective and have spawned a significantly increased interest in aging biology within the larger biomedical scientific community.

Let's Not Repeat History's Mistakes: Two Cautions to Scientists on the Use of Race in Alzheimer's Disease and Alzheimer's Disease Related Dementias Research.

Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) research has advanced gene and biomarker technologies to aid identification of individuals at risk for dementia. This innovation is a lynchpin in development of disease-modifying therapies. The emerging science could transform outcomes for patients and families. However, current limitations in the racial representation and inclusion of racial diversity in research limits the relevance of these technologies: AD/ADRD research cohorts used to define biomarker cutoffs are mostly White, despite clinical and epidemiologic research that shows Black populations are among those experiencing the greatest burdens of AD/ADRD. White cohorts alone are insufficient to characterize heterogeneity in disease and in life experiences that can alter AD/ADRD's courses. The National Institute on Aging (NIA) has called for increased racial diversity in AD/ADRD research. While scientists are working to implement NIA's plan to build more diverse research cohorts, they are also seeking out opportunities to consider race in AD/ADRD research. Recently, scientists have posed two ways of including race in AD/ADRD research: ancestry-based verification of race and race-based adjustment of biomarker test results. Both warrant careful examination for how they are impacting AD/ADRD science with respect to specific study objectives and the broader mission of the field. If these research methods are not grounded in pursuit of equity and justice, biases they introduce into AD/ADRD science could perpetuate, or even worsen, disparities in AD/ADRD research and care.

Age-related changes in gait biomechanics and their impact on the metabolic cost of walking: Report from a National Institute on Aging workshop.

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed.

National Institute on Aging Butler-Williams Scholars Program: The first 30 years.

The development of a skilled research workforce in aging is fundamental to understanding conditions associated with growing older and extending healthy, active years of life. The National Institutes of Health (NIH) supports the training of health scientists, and its National Institute on Aging (NIA) prioritizes the professional development of investigators with an interest in aging. Since 1987, NIA's Summer Institute on Aging Research, renamed the Butler-Williams (B-W) Scholars Program in 2013, has offered an intensive one-week experience on issues, opportunities, and challenges of research on aging, with emphasis on disparities and health equity. The first 30 years of the Program are described in this report, including its history, selected curriculum highlights, Scholar outcomes, and qualitative data from faculty, and the program's impact on the training, growth, and development of scientists in aging research. Questions raised over a decade ago by the Committee on the Future Health Care Workforce for Older Americans Board on Health Care Services are revisited, and recommendations for the future are provided. This important Program remains an exemplar for the training and development of health scientists for careers that advance biomedical research and emphasize an equitable understanding of factors related to extending healthy years of life.

Association between hearing loss and development of dementia using formal behavioural audiometric testing within the Mayo Clinic Study of Aging (MCSA): a prospective population-based study.

BACKGROUND: Hearing loss has been identified as a potential major modifiable risk factor for developing dementia. This study examined associations between formal behavioural pure-tone and speech audiometry assessed by an audiologist with development of dementia in the Mayo Clinic Study of Aging (MCSA). METHODS: The MCSA is a prospective population-based study examining the incidence, prevalence, and risk factors of mild cognitive impairment and dementia in Olmsted County, Minnesota, USA. Participants undergo clinical examinations with neuropsychological testing at enrolment and every 15 months. Participants were 50 years or older at enrolment between Nov 29, 2004, and Dec 23, 2019, who underwent formal behavioural audiometric evaluation by an audiologist due to concerns about hearing loss or as a part of annual comprehensive health assessments. Associations of pure-tone average (PTA) and word recognition scores (WRS) with the development of dementia were evaluated using Cox proportional hazards regression with age as the timescale, and associations with changes in cognitive testing scores over time were evaluated using linear mixed-effects models. FINDINGS: Among 1200 eligible participants, the mean age at enrolment was 79 years (SD 9), 593 (49%) were men, and 207 developed dementia during a mean of 7·0 years (SD 3·7) of follow-up. After adjusting for sex, years of education, smoking status, diabetes, hypertension, apolipoprotein E ε4 carriership, and hearing rehabilitation (defined as hearing aid or cochlear implant use), neither PTA (hazard ratio [HR] per 10-decibels hearing level increase of 0·99 (95% CI 0·89-1·12; p=0·91) nor WRS (HR per 10% decrease of 0·98, 95% CI 0·89-1 ·07; p=0·65) was significantly associated with the development of dementia. However, both PTA and WRS were significantly associated with poorer performance in cognitive testing over time: participants with a PTA higher than 25 decibels hearing level or a WRS lower than 100% had significantly worse declines in cognitive testing scores. Informant-based hearing difficulties assessed by the participant's study partner were significantly associated with the development of dementia (HR 1·95, 95% CI 1·45-2·62; p<0·0001). INTERPRETATION: In this prospective population-based study, subjective informant-based hearing difficulties were associated with development of dementia, whereas objective measures on formal behavioural audiometry were predictive of poorer performance on cognitive testing over time but not the development of dementia. Other factors related to central processing might potentiate the effects of peripheral hearing loss detected on behavioural audiometric testing. FUNDING: National Institute of Health, the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic, the GHR Foundation, the Mayo Foundation for Medical Education and Research, the Liston Award, the Schuler Foundation, the Rochester Epidemiology Project medical records linkage system, and the National Institute on Aging.

Public Health Need, Molecular Targets, and Opportunities for the Accelerated Development of Function-Promoting Therapies: Proceedings of a National Institute on Aging Workshop.

BACKGROUND: People ≥ 65 years are expected to live a substantial portion of their remaining lives with a limiting physical condition and the numbers of affected individuals will increase substantially due to the growth of the population of older adults worldwide. The age-related loss of muscle mass, strength, and function is associated with an increased risk of physical disabilities, falls, loss of independence, metabolic disorders, and mortality. The development of function-promoting therapies to prevent and treat age-related skeletal muscle functional limitations is a pressing public health problem. METHODS: On March 20-22, 2022, the National Institute on Aging (NIA) held a workshop entitled "Development of Function-Promoting Therapies: Public Health Need, Molecular Targets, and Drug Development." RESULTS: The workshop covered a variety of topics including advances in muscle biology, novel candidate molecules, findings from randomized trials, and challenges in the design of clinical trials and regulatory approval of function-promoting therapies. Leading academic investigators, representatives from the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA), professional societies, pharmaceutical industry, and patient advocacy organizations shared research findings and identified research gaps and strategies to advance the development of function-promoting therapies. A diverse audience of 397 national and international professionals attended the conference. CONCLUSIONS: Function-promoting therapies to prevent and treat physical disabilities associated with aging and chronic diseases are a public health imperative. Appropriately powered, well-designed clinical trials and synergistic collaboration among academic experts, patients and stakeholders, the NIH and the FDA, and the pharmaceutical industry are needed to accelerate the development of function-promoting therapies.