Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Aging research: A field grows up.

Breakthroughs in the longevity field over the past few decades have led to major shifts in how we attack the problem of aging. What have been the most important of these shifts in our perspectives, aims, and approaches that will likely guide future research?

Quantifying carboxymethyl lysine and carboxyethyl lysine in human plasma: clinical insights into aging research using liquid chromatography-tandem mass spectrometry.

OBJECTIVE: The objective of this study was to establish a methodology for determining carboxymethyl lysine (CML) and carboxyethyl lysine (CEL) concentrations in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The test results were also used for clinical aging research. METHODS: Human plasma samples were incubated with aqueous perfluorovaleric acid (NFPA), succeeded by precipitation utilizing trichloroacetic acid, hydrolysis facilitated by hydrochloric acid, nitrogen drying, and ultimate re-dissolution utilizing NFPA, followed by filtration. Cotinine-D3 was added as an internal standard. The separation was performed on an Agela Venusil ASB C18 column (50 mm × 4.6 mm, 5 µm) with a 5 mmol/L NFPA and acetonitrile/water of 60:40 (v/v) containing 0.15% formic acid. The multiple reaction monitoring mode was used for detecting CML, CEL, and cotinine-D3, with ion pairs m/z 205.2 > 84.1 (for quantitative) and m/z 205.2 > m/z 130.0 for CML, m/z 219.1 > 84.1 (for quantitative) and m/z 219.1 > m/z 130.1 for CEL, and m/z 180.1 > 80.1 for cotinine-D3, respectively. RESULTS: The separation of CML and CEL was accomplished within a total analysis time of 6 minutes. The retention times of CML, CEL, and cotinine-D3 were 3.43 minutes, 3.46 minutes, and 4.50 minutes, respectively. The assay exhibited linearity in the concentration range of 0.025-1.500 µmol/L, with a lower limit of quantification of 0.025 µmol/L for both compounds. The relative standard deviations of intra-day and inter-day were both below 9%, and the relative errors were both within the range of ±4%. The average recoveries were 94.24% for CML and 97.89% for CEL. CONCLUSION: The results indicate that the developed methodology is fast, highly sensitive, highly specific, reproducible, and suitable for the rapid detection of CML and CEL in clinical human plasma samples. The outcomes of the clinical research project on aging underscored the important indicative significance of these two indicators for research on human aging.

New Directions in Geroscience: Integrating Social and Behavioral Drivers of Biological Aging.

ABSTRACT: The "geroscience hypothesis" posits that slowing the physiological processes of aging would lead to delayed disease onset and longer healthspan and lifespan. This shift from a focus on solely treating existing disease to slowing the aging process is a shift toward prevention, including a focus on risk factors found in the social environment. Although geroscience traditionally has focused on the molecular and cellular drivers of biological aging, more fundamental causes of aging may be found in the social exposome-the complex array of human social environmental exposures that shape health and disease. The social exposome may interact with physiological processes to accelerate aging biology. In this commentary, we review the potential of these insights to shape the emerging field of translational geroscience. The articles in this special issue highlight how social stress and social determinants of health are associated with biomarkers of aging such as inflammation, epigenetic clocks, and telomeres, and spotlight promising interventions to mitigate stress-related inflammation. For geroscience to incorporate the social exposome into its translational agenda, studies are needed that elucidate and quantify the effects of social exposures on aging and that consider social exposures as intervention targets. The life course perspective allows us to measure both exposures and aging biology over time including sensitive periods of development and major social transitions. In addition, given rapid changes in the measurement of aging biology, which include machine learning techniques, multisystem phenotypes of aging are being developed to better reflect whole body aging, replacing reliance on single system biomarkers. In this expanded and more integrated field of translational geroscience, strategies targeting factors in the social exposome hold promise for achieving aging health equity and extending healthy longevity.

D3Creatine Dilution as a Direct, Non-invasive and Accurate Measurement of Muscle Mass for Aging Research.

Initial definitions of sarcopenia included the age-associated loss of skeletal muscle mass that was presumed to be associated with late-life reduced functional capacity, disability and loss of independence. Because no method for determination of muscle mass was available for large cohort studies of aging men and women, lean body mass determined by dual X-ray absorptiometry or bioelectrical impedance was used as a surrogate measure of muscle mass. The data from these studies showed either no or a poor relationship between LBM and functional capacity and health related outcomes, leading to the conclusion of many that the amount of muscle may not be associated with these age-associated outcomes. It was assumed that some undefined index of muscle quality is the critical contributor. These studies also consistently showed that muscle strength is lost more quickly than lean mass. Total body muscle mass can now be measured directly, accurately and non-invasively using the D3creatine (D3Cr) dilution method. D3Cr muscle mass, but not DXA derived LBM, is strongly associated with functional capacity, falls and insulin resistance in older men and women. In addition, D3Cr muscle mass is associated with risk of disability, hip fracture and mortality. New and emerging data demonstrate that low muscle mass may serve as a diagnostic criterion for sarcopenia.

Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research.

The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the biological aging processes is still in its infancy. In this review, we aim to provide a critical appraisal of the emerging literature focusing on how we measure biological aging systematically, and in the brain and how SMIs affect biological aging measures in older adults. We will also review recent developments in the field of cellular senescence and potential targets for interventions for SMIs in older adults, based on the geroscience hypothesis.

Cultivating Relationships as a Community-Based Recruitment Strategy in Transdisciplinary Aging Research: Lessons From an Academic-Community Partnership.

Participation of Black American older adults in community-engaged research remains challenging in health sciences. The objectives of this study were to describe the specific efforts, successes, and challenges in recruiting Black American older adults in research led by the Health and Wellness in Aging Across the Lifespan core, part of the Virginia Commonwealth University Institute for Inclusion, Inquiry, and Innovation (iCubed). We conducted a cross-case analysis of 6 community-engaged research projects using the community-engaged research continuum model. Successful recruitment strategies comprised a multifaceted approach to community-based collaboration, including a wellness program with a long standing relationship with the community, engaging key stakeholders and a community advisory board, and building a community-based coalition of stakeholders. Posting flyers and modest monetary compensation remain standard recruitment strategies. The cross-case analysis offered critical lessons on the community's nature and level of engagement in research. Relationship building based on trust and respect is essential to solving complex aging issues in the community.

Artificial Intelligence and Technology Collaboratories: Innovating aging research and Alzheimer's care.

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).

ORCA: A picture database of object-scene arrangements for cross-cultural and aging research.

In recent years, cross-cultural research on the modulation of basic cognitive processes by culture has intensified - also from an aging perspective. Despite this increased research interest, only a few cross-culturally normed non-verbal stimulus sets are available to support cross-cultural cognitive research in younger and older adults. Here we present the ORCA (Official Rating of Complex Arrangements) picture database, which includes a total of 720 object-scene compositions sorted into 180 quadruples (e.g., two different helmets placed in two different deserts). Each quadruple contains visually and semantically matched pairs of objects and pairs of scenes with varying degrees of semantic fit between objects and scenes. A total of 95 younger and older German and Chinese adults rated every object-scene pair on object familiarity and semantic fit between object and scene. While the ratings were significantly correlated between cultures and age groups, small but significant culture and age differences emerged. Object familiarity was higher for older adults than younger adults and for German participants than for Chinese participants. Semantic fit was rated lower by German older adults and Chinese younger adults as compared to German younger adults and Chinese older adults. Due to the large number of stimuli, our database is particularly well suited for cognitive and neuroscientific research on cross-cultural and age-related differences in perception, attention, and memory.

Exploring the Skin Brain Link: Biomarkers in the Skin with Implications for Aging Research and Alzheimer's Disease Diagnostics.

Neurodegenerative diseases, including Alzheimer's disease (AD), are challenging to diagnose. Currently the field must rely on imperfect diagnostic modalities. A recent study identified differences in several key bio-mechano-physiological parameters of the skin between AD patients and healthy controls. Here, we visually align these differences with the relevant histological, aging, and embryological paradigms to raise awareness for these potential biomarkers. In a study conducted by Wu et al., a series of n = 41 patients (n = 29 with AD and n = 12 healthy controls) were evaluated, demonstrating that AD patients exhibit a less acidic skin pH, increased skin hydration, and reduced skin elasticity compared to healthy controls. We constructed a visual overview and explored the relevant paradigms. We present a visual comparison of these factors, highlighting four paradigms: (1) the findings emphasize a shared ectodermal origin of the brain and the skin; (2) functional systems such as micro-vascularization, innervation, eccrine excretory functions, and the extracellular matrix undergo distinct changes in patients with AD; (3) the human skin mirrors the alterations in brain stiffness observed in aging studies; (4) assessment of physiological features of the skin is cost-effective, accessible, and easily amenable for monitoring and integration with cognitive assessment studies. Understanding the relationship between aging skin and aging brain is an exciting frontier, holding great promise for improved diagnostics. Further prospective and larger-scale investigations are needed to solidify the brain-skin link and determine the extent to which this relationship can be leveraged for diagnostic applications.

Geroscience: Aging and Oral Health Research.

Research in aging has significantly advanced; scientists are now able to identify interventions that slow the biologic aging processes (i.e., the "hallmarks of aging"), thus delaying the onset and progression of multiple diseases, including oral conditions. Presentations given during the 3-part session "Geroscience: Aging and Oral Health Research," held during the 2023 American Association for Dental, Oral, and Craniofacial Research meeting, are summarized in this publication. Speakers' topics spanned the translational research spectrum. Session 1 provided an overview of the geroscience and health span (disease-free and functional health throughout life) concepts. The common molecular mechanisms between oral cancer and aging were discussed, and research was presented that showed periodontal microflora as a potential factor in Alzheimer's disease progression. Session 2 focused on behavioral and social science aspects of aging and their oral health significance. The keynote provided evidence that loneliness and isolation can have major health effects. These social conditions, along with poor oral health, tooth loss, and cognitive decline, could potentially affect healthy eating ability and systemic health in older adults. Research could help elucidate the directions and pathways connecting these seemingly disparate conditions. Session 3 focused on the delivery of oral care in different settings and the many barriers to access care faced by older adults. Research is needed to identify and implement effective technology and strategies to improve access to dental care, including new delivery and financing mechanisms, workforce models, interprofessional provider education and practice, and use of big data from medical-dental integration of electronic health records. Research to improve the "oral health span," reduce oral health disparities, and increase health equity must be tackled at all levels from biologic pathways to social determinants of health and health policies.

[New trends in age and aging research in the post-pandemic period (research overview).]

The pandemic of coronavirus infection and the general uncertainty and variability of the post-pandemic world developing with it have called into question the already outdated concept of chronological determination of the age of the older. Within the framework of this review, analyzing the latest publications on social policy, the sociology of aging, the role of information technology in the lives of older people and their employment, using the method of thematic analysis, we consider how researchers consider the transformation of the meanings of age and the characteristics of aging in the post-pandemic period. Based on the thematic analysis of articles for the period from January 2022 to March 2023, a conclusion was made about the blurring of the previous age boundaries. This trend that developed when? has been amplified by the pandemic. This contributed to the expansion of the repertoire of aging trajectories and consideration of the inclusion and features of aging based on the various directions that the pandemic creates and strengthens. The key topics regarding the transformation of the meanings of age are related to the increasing integration of older people into the digital environment and the use of digital technologies, the development of healthcare and anti-aging services, as well as the expansion of digitalization of employment of older people and the expansion of opportunities for inclusion of the older. The analysis showed the transformation of the topic of employment of older people during the pandemic and post-pandemic, namely, the transition to the monetization of leisure, to the increasing use of employment for interaction and, consequently, social integration. The articles considered in the study are increasingly associated with the need for a multidisciplinary study of aging and the everyday life of older people, as well as the cooperation of different approaches that consider not only the medical aspects of age, but also social, environmental aspects, without which it is impossible to imagine the life of older people, it is impossible to consider the meanings of aging.

Introduction to the Special Issue on Advancing Diversity in Aging Research.

The following papers represent an early contribution of the National Institute on Aging's commitment to support high-quality research and mentor a more diverse workforce in the field of aging. The International Journal of Aging and Human Development has previously issued calls for such scholarship and has provided opportunities to share some of their teaching techniques that foster and support the next generation of gerontologists. In this issue, we feature both lessons learned from those who design and supervise National Institute of Aging-supported training programs and we highlight some of the work that these diverse scholars are contributing to the field. We hope that by disseminating "lessons learned" and specific research pieces, other labs will begin similar programs. We encourage others to develop and implement innovative training models and explore some of the funding opportunities available to support increasing diversity in aging.

Lessons Learned in Implementing an Aging Research Training Program for Underrepresented Minority Students.

This brief report provides an overview of lessons learned through evaluation of the first five years of the NIA-funded South Carolina-Advancing Diversity in Aging Research (SC-ADAR) undergraduate program, whose goal is to increase the number of qualified underrepresented minority (URM) students who pursue scientific graduate studies in programs focusing on medicine, science, technology, engineering, and mathematics and aging. Partnering with five Historically Black Colleges and Universities in South Carolina, we implemented a research training approach that included two consecutive summers of research training in a University of South Carolina faculty laboratory, as part of a comprehensive 24-month research education program. In addition to the mentored research experience in a laboratory, students had coursework in the biology of aging and social gerontology, with additional workshops tailored to emergent student needs including basic academic skills development, work-life management skills, reflective social experiences, and enhanced support in the transition from undergraduate to graduate school. We provide an overview of lessons learned throughout the early program period, and a description of the iterative changes we made in the program in response to this learning, all of which have been incorporated into the existing SC-ADAR program.

For Aging Research and Equity: Lessons Learned in Undergraduate Research Education.

Mentoring underrepresented students in aging research during the COVID-19 pandemic affords many opportunities for innovation and learning, for both students and program leaders. Here, we describe lessons learned from an Advancing Diversity in Aging Research (ADAR) program at a women-centered, minority-serving undergraduate institution. We share program elements and assessment results related to scholars' education in aging, support through community-building and mentorship, and research experiences in gerosciences. Notably, we highlight lessons learned for retaining and training undergraduate students as graduate school-ready researchers: 1) draw students into a community focused on social justice, 2) show students that geroscience is inclusive and integrative, 3) model professionalism with flexibility, 4) keep open lines of communication, and 5) build a team of mentors around each scholar. By sharing insights from our community of practice in geroscience research and education, we hope to model best practices for URM student support in aging research.

Impact of the Cancer and Aging Research Group score and treatment intensity on survival and toxicity outcomes in older adults with advanced noncolorectal gastrointestinal cancers.

BACKGROUND: Little is known regarding the predictive value of the Cancer and Aging Research Group (CARG) score, a validated chemotherapy toxicity prediction tool for older adults with cancer, for survival outcomes. METHODS: This was a prospective observational study of patients ≥65 years old receiving first-line chemotherapy for advanced noncolorectal gastrointestinal cancer for which combination chemotherapy is the standard of care. Overall survival (OS), time to treatment failure (TTF), which was defined as the time from the start of first-line chemotherapy to the discontinuation of first-line chemotherapy for any reason, and toxicity were compared in 4 groups of patients: 1) non-high-risk (nHR) CARG score (<10) and standard-intensity therapy (ST), 2) nHR score and reduced-intensity therapy (RT), 3) high-risk (HR) CARG score (≥10) and ST, and 4) HR score and RT. RESULTS: Fifty patients (median age, 71 years) were enrolled. The median OS in months was 19.7 in nHR/ST (n = 19) group, 12.7 in nHR/RT (n = 9) group, 4.5 in HR/ST (n = 12) group, and 3.9 in HR/RT (n = 10) group (log-rank test, P = .005). The median TTF in months was 9.1 in nHR/ST group, 2.5 in nHR/RT group, 2.3 in HR/ST group, and 3.0 in HR/RT group (log-rank test, P = .04). The CARG-score category was prognostic of OS (HR, 3.04; 95% confidence interval [CI], 1.59-5.83, P = .001) and TTF (HR, 2.60; 95% CI, 1.31-5.20, P = .007). The incidence of grade 3-5 toxicity was 68% in nHR/ST group, 33% in nHR/RT group, 92% in HR/ST group, and 70% in HR/RT group (Fisher exact test, P = .048). CONCLUSIONS: Risk-adapted chemotherapy based on the CARG-score may improve treatment outcomes.