Association of a composite trait for anthropometrics, adiposity and energy expenditure with cardiometabolic diseases: An age-stratified cohort and genetic risk score analysis.

AIM: Various anthropometric measures capture distinct as well as overlapping characteristics of an individual's body composition. To characterize independent body composition measures, we aimed to reduce easily-obtainable individual measures reflecting adiposity, anthropometrics and energy expenditure into fewer independent constructs, and to assess their potential sex- and age-specific relation with cardiometabolic diseases. METHODS: Analyses were performed within European ancestry participants from UK Biobank (N = 418,963, mean age 58.0 years, 56% women). Principal components (PC) analyses were used for the dimension reduction of 11 measures of adiposity, anthropometrics and energy expenditure. PCs were studied in relation to incident type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). Multivariable-adjusted Cox regression analyses, adjusted for confounding factors, were performed in all and stratified by age. Genome-wide association studies were performed in half of the cohort (N = 156,295) to identify genetic variants as instrumental variables. Genetic risk score analyses were performed in the other half of the cohort stratified by age of disease onset (N = 156,295). RESULTS: We identified two PCs, of which PC1 reflected lower overall adiposity (negatively correlated with all adiposity aspects) and PC2 reflected more central adiposity (mainly correlated with higher waist-hip ratio, but with lower total body fat) and increased height, collectively capturing 87.8% of the total variance. Similar to that observed in the multivariable-adjusted regression analyses, we found associations between the PC1 genetic risk score and lower risks of CAD and T2D [CAD cases <50 years, odds ratio: 0.91 (95% confidence interval 0.87, 0.94) per SD; T2D cases <50 years, odds ratio: 0.76 (0.72, 0.81)], which attenuated with higher age (p-values 8.13E-4 and 2.41E-6, respectively). No associations were found for PC2. CONCLUSIONS: The consistently observed weaker associations of the composite traits with cardiometabolic disease suggests the need for age-specific cardiometabolic disease prevention strategies.

Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine.

Aging is a fundamental biological process characterized by a progressive decline in physiological functions and an increased susceptibility to diseases. Understanding aging at the molecular level is crucial for developing interventions that could delay or reverse its effects. This review explores the integration of machine learning (ML) with multi-omics technologies-including genomics, transcriptomics, epigenomics, proteomics, and metabolomics-in studying the molecular hallmarks of aging to develop personalized medicine interventions. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Using ML to analyze big and complex datasets helps uncover detailed molecular interactions and pathways that play a role in aging. The advances of ML can facilitate the discovery of biomarkers and therapeutic targets, offering insights into personalized anti-aging strategies. With these developments, the future points toward a better understanding of the aging process, aiming ultimately to promote healthy aging and extend life expectancy.

Contributions and future potential of animal models for geroscience research on sensory systems.

Sensory systems mediate our social interactions, food intake, livelihoods, and other essential daily functions. Age-related decline and disease in sensory systems pose a significant challenge to healthy aging. Research on sensory decline in humans is informative but can often be difficult, subject to sampling bias, and influenced by environmental variation. Study of animal models, including mice, rats, rabbits, pigs, cats, dogs, and non-human primates, plays a complementary role in biomedical research, offering advantages such as controlled conditions and shorter lifespans for longitudinal study. Various species offer different advantages and limitations but have provided key insights in geroscience research. Here we review research on age-related decline and disease in vision, hearing, olfaction, taste, and touch. For each sense, we provide an epidemiological overview of impairment in humans, describing the physiological processes and diseases for each sense. We then discuss contributions made by research on animal models and ideas for future research. We additionally highlight the need for integrative, multimodal research across the senses as well as across disciplines. Long-term studies spanning multiple generations, including on species with longer life spans, are also highly valuable. Overall, integrative studies of appropriate animal models have high translational potential for clinical applications, the development of novel diagnostics, therapies, and medical interventions and future research will continue to close gaps in these areas. Research on animal models to improve understanding of the biology of the aging senses and improve the healthspan and additional research on sensory systems hold special promise for new breakthroughs.

[Cardiovascular prevention in old age]. / Kardiovaskuläre Prävention im Alter.

The enormous potential of cardiovascular prevention in terms of expanding the life span and health span is presently nowhere near being realized. The five classical cardiovascular risk factors body mass index (BMI), systolic blood pressure, non-high-density lipoprotein (non-HDL) cholesterol, tobacco smoking, and diabetes mellitus account for more than half of the cases of incident cardiovascular diseases. Cardiovascular prevention is also effective and adequate in seemingly healthy individuals aged 70 years or above, although the association of several cardiovascular risk factors with cardiovascular diseases is less pronounced in old age. The cardiovascular risk of seemingly healthy persons aged 70 years or above can validly be determined using the Systematic COronary Risk Evaluation-Older Persons (SCORE2-OP), leading to risk-adjusted clear treatment recommendations. National and international guidelines advocate individualized cardiovascular prevention in several domains including diet, physical activity and risk factor management through to old age.

Running on empty: Exploring stem cell exhaustion in geriatric musculoskeletal disease.

Ageing populations globally are associated with increased musculoskeletal disease, including osteoporosis and sarcopenia. These conditions place a significant burden of disease on the individual, society and the economy. To address this, we need to understand the underpinning biological changes, including stem cell exhaustion, which plays a key role in the ageing of the musculoskeletal system. This review of the recent evidence provides an overview of the associated biological processes. The review utilised the PubMed/Medline, Science Direct, and Google Scholar databases. Mechanisms of ageing identified involve a reaction to the chronic inflammation and oxidative stress associated with ageing, resulting in progenitor cell senescence and adipogenic differentiation, leading to decreased mass and quality of both bone and muscle tissue. Although the mechanisms underpinning stem cell exhaustion are unclear, it remains a promising avenue through which to identify new strategies for prevention, detection and management.

The impact of carnosine on biological ageing - A geroscience approach.

Biological ageing involves a gradual decline in physiological function and resilience, marked by molecular, cellular, and systemic changes across organ systems. Geroscience, an interdisciplinary field, studies these mechanisms and their role in age-related diseases. Genomic instability, inflammation, telomere attrition, and other indicators contribute to conditions like cardiovascular disease and neurodegeneration. Geroscience identifies geroprotectors, such as resveratrol and metformin, targeting ageing pathways to extend the healthspan. Carnosine, a naturally occurring dipeptide (b-alanine and l-histidine), has emerged as a potential geroprotector with antioxidative, anti-inflammatory, and anti-glycating properties. Carnosine's benefits extend to muscle function, exercise performance, and cognitive health, making it a promising therapeutic intervention for healthy ageing and oxidative stress-related pathologies. In this review, we summarize the evidence describing carnosine's effects in promoting healthy ageing, providing new insights into improving geroscience.

The COVID-19 Pandemic, Geroscience, and Intersectional Dimensions of Health and Well-being.

The coronavirus disease 2019 (COVID-19) pandemic challenged bioethical principles of research and the ability of scientific and healthcare institutions to provide equitable care. How can geroscience adapt to build equity within research protocols to better serve minoritized and marginalized communities? What lessons can geroscience take from the COVID-19 pandemic and its response? Developing geroscience approaches that incorporate such knowledge, including vaccine distribution plans and coalition-building to improve vaccine confidence, may help to reduce health inequities.

A Pragmatic Approach to Introducing Translational Geroscience Into the Clinic: A Paradigm Based on the Incremental Progression of Aging-Related Clinical Research.

Geroscience posits that molecular drivers underlie the aging process. Gerotherapeutics entail strategies to counter molecular drivers of aging to reduce the chronic diseases and geriatric syndromes they trigger. Although the concept of gerotherapeutics for prevention has generated much excitement, the implications of prescribing potentially harmful medications to older adults who are "healthy" have been associated with many delays. Concerns regarding safety and valid endpoints have contributed to holdups. In contrast, it has been relatively easier to implement trials of medications with gerotherapeutic properties as novel approaches to remedy disease. In these applications, the risks of the medications are easier to justify when therapeutic benefits are perceived as outweighing the harms of the disease. Likewise, metrics of effective disease treatments are often seen as more reliable and quantifiable than metrics of health prolongation. Overall, clarifying geroscience mechanisms in disease therapeutic applications provides key opportunities to advance translational geroscience, especially as preventive geroscience trials are often encumbered. In this review, gerotherapeutic benefits of canakinumab, cholchicine, and zoledronic acid as parts of disease management are considered. Longevity Clinics and other opportunities to advance translational geroscience as parts of contemporary care are also discussed.

Geroscience and the Fight Against Alzheimer's Disease: Between Myth and Reality.

 Aging is associated with a gradual decline in cellular stability, leading to a decrease in overall health. In the brain, this process is closely linked with an increased risk of neurodegenerative diseases, including Alzheimer's disease. Understanding the mechanisms of brain aging is crucial for developing strategies aimed at enhancing both lifespan and health span. Recent advancements in geroscience, the study of the relationship between aging and age-related diseases, have begun to redefine our understanding of Alzheimer's disease, guiding the development of preventive medical strategies that target the aging process itself rather than merely addressing the symptomatic manifestations of the disease.

Body composition and aging: cross-sectional results from the INSPIRE study in people 20 to 93 years old.

Aging is characterized by several major changes, including altered body composition, which is associated with numerous negative clinical consequences such as sarcopenia, osteoporosis, and frailty. The study is to evaluate body composition parameters depending on age and sex in a population ranging from the young adult to the very old, and to identify break points in the association between body composition and age. In this cross-sectional study, we included the enrolment population of the French INSPIRE-T prospective cohort, accounting for 915 subjects (62% female). Age ranged from 20 to 93 years, median age (years) was 63 (IQR 27). Body composition (lean mass, fat mass, and bone mineral content) was assessed with dual-X-ray absorptiometry (DXA). Different break points in the relationship between age and body composition variables in males and females were identified using a segmented regression analysis adjusted on physical activity, nutritional status, educational level, and comorbidities. Lean mass decreased from the age of 55 years for males (CI 95% 44-66) and 31 years for females (CI 95% 23-39). For fat mass, we observed a trend towards an increase with age for males. For females, we observed an increase with age up to age 75 (CI 95% 62-86), followed by a decreasing trend. In this study, we described the relationship between body composition and age as a function of sex, establishing a foundation for further studies on predictive biomarkers of age-related body composition alteration.

The mouse Social Frailty Index (mSFI): a novel behavioral assessment for impaired social functioning in aging mice.

Various approaches exist to quantify the aging process and estimate biological age on an individual level. Frailty indices based on an age-related accumulation of physical deficits have been developed for human use and translated into mouse models. However, declines observed in aging are not limited to physical functioning but also involve social capabilities. The concept of "social frailty" has been recently introduced into human literature, but no index of social frailty exists for laboratory mice yet. To fill this gap, we developed a mouse Social Frailty Index (mSFI) consisting of seven distinct assays designed to quantify social functioning which is relatively simple to execute and is minimally invasive. Application of the mSFI in group-housed male C57BL/6 mice demonstrated a progressively elevated levels of social frailty through the lifespan. Conversely, group-housed females C57BL/6 mice manifested social frailty only at a very old age. Female mice also showed significantly lower mSFI score from 10 months of age onward when compared to males. We also applied the mSFI in male C57BL/6 mice under chronic subordination stress and in chronic isolation, both of which induced larger increases in social frailty compared to age-matched group-housed males. Lastly, we show that the mSFI is enhanced in mouse models that show accelerated biological aging such as progeroid Ercc1-/Δ and Xpg-/- mice of both sexes compared to age matched littermate wild types. In summary, the mSFI represents a novel index to quantify trajectories of biological aging in mice and may help elucidate links between impaired social behavior and the aging process.

Psychosocial and biological pathways to aging : The role(s) of the behavioral and social sciences in geroscience.

While the biological hallmarks of aging are widely recognized as fundamental mechanisms of biological aging, more recently, there have been calls within geroscience to understand the aging process more comprehensively by adding a perspective of the social hallmarks of aging. Social and behavioral factors, such as socioeconomic status, life events or behavior and beliefs can alter the aging process per se and act in complex interactions with biological pathways. In addition, underlying biological pathways have been proposed for various psychosocial concepts, such as views on age and relationship quality. The aim of the present article is to provide narrative insights into theoretical and empirical developments between social and behavioral gerontology and geroscience or biogerontology. This article focuses on the potential of an interdisciplinary aging research but it also sets out the critical perspective that social gerontology provides.

The Longevity Med Summit: insights on healthspan from cell to society.

In recent years, there has been a paradigm shift with regards to ageing, challenging its traditional perception as an inevitable and natural process. Researchers have collectively identified hallmarks of ageing, nine of which were initially proposed in 2013 and expanded in 2023 to include disabled macroautophagy, chronic inflammation, and dysbiosis, enhancing our understanding of the ageing process at microscopic, cellular, and system-wide levels. Strategies to manipulate these hallmarks present opportunities for slowing, preventing, or reversing age-related diseases, thereby promoting longevity. The interdependence of these hallmarks underscores the necessity of a comprehensive, systems-based approach to address the complex processes contributing to ageing. As a primary risk factor for various diseases, ageing diminishes healthspan, leading to extended periods of compromised health and multiple age-related conditions towards the end of life. The significant gap between healthspan and lifespan holds substantial economic and societal implications. The inaugural Longevity Med Summit (4-5 May 2023, Cascais, Portugal) provided an international forum to discuss the academic and industry landscape of healthy longevity research, preventive medicine and clinical practice to enhance healthspan.

Circulating Angiogenic and Senescent T Lymphocytes in Ageing and Frailty.

BACKGROUND: There is a need to identify vascular and geroscience-relevant markers and mediators that can physiologically link ageing to vascular disease. There is evidence of specific T cell subsets, all influenced by age, that exert positive and negative effects on vascular health. CD31+, termed angiogenic T cells, have been linked to vascular repair whereas CD28null, termed senescent T cells, display pro-inflammatory and cytotoxic effector functions. OBJECTIVE: This study sought to determine the combined influence of increasing age and frailty status on these circulating CD31+ and CD28null T cell subsets. METHODS: This cross-sectional study recruited four different cohorts of men and women; young (20-30 years, n=22), older (65-75 years, n=17), robust non-frail (76+ years, n=17), and frail (76+ years, n=15) adults. Frailty was determined using the Fried Frailty method. T cell subsets were determined by whole blood flow cytometry based on the expression of CD3, CD4, CD8, CD31 and CD28. Cognitive impairment (CI) was measured via the Montreal Cognitive Assessment test. RESULTS: Whether expressed as circulating counts or as a % of total T cells, there was a progressive decrease (p<0.05) in CD31+ T cells with increasing age but paradoxically higher values (p<0.05) in the frail compared to the robust non-frail group. These changes were similar in the CD4+ and CD8+ fractions. CD28null T cells were considerably higher (p<0.05) in the frail compared to the robust non-frail group, including in the CD8+ (47% vs 29%, p<0.05) and CD4+ (4% vs 1%, p<0.05) fractions. CD28null T cell percentage was also higher (p<0.05) in those with moderate CI compared to mild CI and normal function. CONCLUSION: CD8+CD28null T cells are considerably elevated in frailty and with cognitive impairment and may serve as a useful target for intervention. Currently, the utility of CD31+ T cells as an ageing biomarker may be confined to healthy ageing cohorts.

Prevalence and correlates of cognitive impairment among an urban geriatric population of Haryana.

Background: Severe Cognitive Impairment (CI) is a major cause of disability and dependency among the elderly worldwide, and it has a significant impact not only on individuals but also on families, communities, and societies. Early identification and management of CI are critical in geriatric medicine. Prevalence data is often scarce, and this hinders the ground-level implementation of preventive health programs. Objectives: The objective was to find the prevalence of CI and its covariates among the urban geriatric population of Haryana. Materials and Methods: This was a community-based cross-sectional study conducted among 300 geriatric participants residing in an urban area of Rohtak district, Haryana. Hindi Mental State Examination (HMSE) tool was used to assess CI. Data were analyzed using IBM Corp, released 2020, IBM SPSS statistics for windows Ver 20, Armonk, NY. Results: The prevalence of geriatric CI was found to be 27.3% and was found to be significantly associated with age, female gender, scheduled and backward caste (BC), widowhood, and low educational status and is not engaged in any occupation, low socioeconomic status, teetotalism, economic dependency, physical dependency on others, and chronic morbidity. Conclusion: Age, female gender, scheduled and backward caste, widowhood, low educational status, nil employment status, low socioeconomic status, teetotalism, economic dependency, physical dependency on others, and chronic morbidity were found to be important correlates of CI. Further analytical studies can focus on these aspects for an early targeted preventive approach.

Gut microbiota in centenarians: A potential metabolic and aging regulator in the study of extreme longevity.

Centenarians, those aged 100 years or older, are considered the most successful biological aging model in humans. This population is commonly characterized by a low prevalence of chronic diseases, with favorable maintenance of functionality and independence, thus determining a health phenotype of successful aging. There are many factors usually associated with extreme longevity: genetics, lifestyles, diet, among others. However, it is most likely a multifactorial condition where protective factors contribute individually to some extent. The gut microbiota (GM) has emerged as a potential factor associated with the establishment of a favorable health phenotype that allows for extreme longevity, as seen in centenarians. To understand the possible impact generated by the GM, its changes, and the probable causes for successful aging, the aim of this review was to synthesize evidence on the role of the GM as a potential protective factor for achieving extreme longevity, using its relationship with centenarians.

Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities.

The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand the potential context specificity of metformin treatment on skeletal muscle, we used a rat model (high-capacity runner/low-capacity runner [HCR/LCR]) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (intermyofibrillar vs. subsarcolemmal). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.

Differential Responses to Aging Among the Transcriptome and Proteome of Mesenchymal Progenitor Populations.

The biological aging of stem cells (exhaustion) is proposed to contribute to the development of a variety of age-related conditions. Despite this, little is understood about the specific mechanisms which drive this process. In this study, we assess the transcriptomic and proteomic changes in 3 different populations of mesenchymal progenitor cells from older (50-70 years) and younger (20-40 years) individuals to uncover potential mechanisms driving stem cell exhaustion in mesenchymal tissues. To do this, we harvested primary bone marrow mesenchymal stem and progenitor cells (MPCs), circulating osteoprogenitors (COP), and adipose-derived stem cells (ADSCs) from younger and older donors, with an equal number of samples from men and women. These samples underwent RNA sequencing and label-free proteomic analysis, comparing the younger samples to the older ones. There was a distinct transcriptomic phenotype in the analysis of pooled older stem cells, suggestive of suppressed proliferation and differentiation; however, these changes were not reflected in the proteome of the cells. Analyzed independently, older MPCs had a distinct phenotype in both the transcriptome and proteome consistent with altered differentiation and proliferation with a proinflammatory immune shift in older adults. COP cells showed a transcriptomic shift to proinflammatory signaling but no consistent proteomic phenotype. Similarly, ADSCs displayed transcriptomic shifts in physiologies associated with cell migration, adherence, and immune activation but no proteomic change with age. These results show that there are underlying transcriptomic changes with stem cell aging that may contribute to a decline in tissue regeneration. However, the proteome of the cells was inconsistently regulated.

Most genetic roots of fungal and animal aging are hundreds of millions of years old according to phylostratigraphy analyses of aging networks.

Few studies have systematically analyzed how old aging is. Gaining a more accurate knowledge about the natural history of aging could however have several payoffs. This knowledge could unveil lineages with dated genetic hardware, possibly maladapted to current environmental challenges, and also uncover "phylogenetic modules of aging," i.e., naturally evolved pathways associated with aging or longevity from a single ancestry, with translational interest for anti-aging therapies. Here, we approximated the natural history of the genetic hardware of aging for five model fungal and animal species. We propose a lower-bound estimate of the phylogenetic age of origination for their protein-encoding gene families and protein-protein interactions. Most aging-associated gene families are hundreds of million years old, older than the other gene families from these genomes. Moreover, we observed a form of punctuated evolution of the aging hardware in all species, as aging-associated families born at specific phylogenetic times accumulate preferentially in genomes. Most protein-protein interactions between aging genes are also old, and old aging-associated proteins showed a reduced potential to contribute to novel interactions associated with aging, suggesting that aging networks are at risk of losing in evolvability over long evolutionary periods. Finally, due to reshuffling events, aging networks presented a very limited phylogenetic structure that challenges the detection of "maladaptive" or "adaptative" phylogenetic modules of aging in present-day genomes.