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Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5'UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

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.

Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the field of geroscience, which focuses on understanding the biology of aging and developing interventions to improve health and quality of life as people age. The article highlights the goals and opportunities discussed at the Fourth Geroscience Summit, including addressing health disparities in aging, ensuring inclusion of diverse populations in research, exploring interventions for chronic disease patients and survivors, developing research models to understand multimorbidity, identifying aging-related health outcome measures, and validating predictive biomarkers of aging. The article emphasizes the need for clear communication and training in geroscience to integrate its perspectives into medical practice and improve the treatment of age-related diseases. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

This article explores the field of geroscience, which aims to target the biology of aging to prevent or treat age-related diseases. Despite its growing importance, geroscience remains unfamiliar to the general public and many healthcare providers. The article emphasizes the need for collaboration across disciplines and the training of a workforce that can shift from a disease-focused approach to one that targets aging pathways. It also highlights the importance of clear messaging and education to promote geroscience and its potential impact on human health and quality of life. The article discusses the creation of a Geroscience Education and Training Network (GET Network) to address gaps in research education and training. The GET Network aims to revolutionize the training of scientists, educators, and clinicians by providing accessible geroscience education, including shared curricula, a Certificate in Geroscience Research Program, and effective dissemination of educational materials. The network also addresses challenges such as incorporating geroscience into medical student curricula, adapting to the learning styles of millennials, promoting health equity, ensuring the sustainability of educational materials, and combating online antiaging misinformation. Overall, the network seeks to integrate geroscience into medical education and engage students and the public in discussions about geroscience. [Extracted from the article]

The proportion of older adults in the United States is growing, and the older adult population is also becoming increasingly diverse. However, there are limited data on the aging process and older adults in underserved populations. Equitable participation in research studies on aging, the research workforce, and the healthcare workforce is critical to improving health outcomes for the entire U.S. population. Health disparities frameworks offer researchers and healthcare professionals the tools to develop and evaluate aging research that addresses all levels of analysis and domains of influence. Although there have been efforts to diversify the healthcare and research workforce, significant disparities in representation remain. In this perspective, we discuss existing aging health disparities, health disparities frameworks to use as tools to better conduct aging research, methods to enhance the proportion of underrepresented populations in aging research, and the current gaps in as well as efforts to enhance the diversity of the healthcare and research workforces. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

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.

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. [ABSTRACT FROM AUTHOR]

The widespread use of the name 'geroscience' in the science of aging is sometimes met with a wary attitude by biogerontologists other than its inventors. Here, we provide an overview of its origin and evolution to assess what exactly it is and to discuss its theoretical and biological relationship to earlier movements of anti-aging medicine and biogerontology more generally. Geroscience posits that targeting aging may offer a cost-effective approach to improve late-life health in humans, and because aging is malleable in model organisms and what regulates this is sufficiently understood, the time is ripe for moving forward to translational and clinical research. The geroscience agenda has rebranded imagery of past traditions, yet the claim that therapies for human aging are ready or within the imminent future is contestable and on brand with tradition, even if biogerontology has made great progress in the past decades. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Gerontologie und Geriatrie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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 systemwide 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. [ABSTRACT FROM AUTHOR]

Background The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. Methods The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 76.4, 56.5% women, and 85.9% non-Hispanic White) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95% CI]) for the likelihood of greater multimorbidity (4 levels: 0 conditions, N  = 332; 1 condition, N  = 299; 2 conditions, N  = 98; or 3+ conditions, N  = 35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. Results Lower oxidative phosphorylation supported by fatty acids and/or complex I- and II-linked carbohydrates (eg, Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR = 1.32 [1.13, 1.54]) and separately with diabetes mellitus (OR = 1.62 [1.26, 2.09]), depressive symptoms (OR = 1.45 [1.04, 2.00]) and possibly chronic kidney disease (OR = 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease). Conclusions Lower muscle mitochondrial bioenergetic capacities were associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and are more strongly related to some conditions than others. [ABSTRACT FROM AUTHOR]

The inaugural Canadian Conferences on Translational Geroscience were held as 2 complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience, and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging, and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This article summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21–50y; BMI 22.0–27.9 kg/m2), to 25% CR or ad‐libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2‐year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12‐, and 24‐months by quantitative PCR (absolute TL; aTL) and a published DNA‐methylation algorithm (DNAmTL). Intent‐to‐treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect‐of‐Treatment‐on‐the‐Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12‐month weight‐loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24‐months, leaving it unclear whether CR‐related effects reflect long‐term detriments to telomere fidelity, a hormesis‐like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As humans, we aspire to healthy aging and ideally reaching our maximal lifespan. That, however, requires optimizing resilience to stressors and minimizing exposure to factors that accelerate aging. Understanding the complexities of aging processes involves characterizing the causal bases of physical, physiological, and cognitive deficits that accumulate over time, eventually culminating in reduced functionality and decreased resistance to disease and environmental stressors. Both the progression of age-related conditions and onset of diseases are affected by environmental stressors; however, the basis for increased susceptibility remains poorly understood. Furthermore, the actions of some environmental stressors, such as endocrine disruptors, can alter both developmental and aging processes, contributing to lifelong issues with inflammatory and neurodegenerative conditions. This manuscript focuses on the comparative biology and evolution of aging and longevity. The status of an array of animal models and potential for specific geroscience translational applications is addressed by asking these questions. What animal models are currently available for aging and translational geroscience? What are the key roadblocks and barriers for studies of healthy aging, and how might specific animal models be useful? Are research tools available? Which vertebrate animal models can specifically address targeted questions in human aging processes? Can information be synthesized for a range of vertebrate species to identify suitable animal models for addressing specific research questions in geroscience, especially relative to basic physiological function, timing and trajectory of disease progression, effects of environmental stressors, and potential for regenerative medicine? [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Emerging data support associations between the depletion of the healthy gut microbiome and aging-related physiological decline and disease. In humans, fecal microbiota transplantation (FMT) has been used successfully to restore gut microbiome structure and function and to treat C. difficile infections, but its application to healthy aging has been scarcely investigated. The marmoset is an excellent model for evaluating microbiome-mediated changes with age and interventional treatments due to their relatively shorter lifespan and many social, behavioral, and physiological functions that mimic human aging. Prior work indicates that FMT is safe in marmosets and may successfully mediate gut microbiome function and host health. This narrative review (1) provides an overview of the rationale for FMT to support healthy aging using the marmoset as a translational geroscience model, (2) summarizes the prior use of FMT in marmosets, (3) outlines a protocol synthesized from prior literature for studying FMT in aging marmosets, and (4) describes limitations, knowledge gaps, and future research needs in this field. [ABSTRACT FROM AUTHOR]

Pulsatile Myc induction, through epigenetic alterations, mediates several aspects of the exercise response and may restore muscle plasticity with age. Of the "Yamanaka factors" Oct3/4 , Sox2 , Klf4 , and c-Myc (OSKM), the transcription factor c-Myc (Myc) is the most responsive to exercise in skeletal muscle and is enriched within the muscle fiber. We hypothesize that the pulsatile induction of MYC protein after bouts of exercise can serve to epigenetically reprogram skeletal muscle toward a more resilient and functional state. [ABSTRACT FROM AUTHOR]

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-g (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors. [ABSTRACT FROM AUTHOR]

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. Treatments that remove senescent cells, senolytics, improve brain outcomes in AD mice with amyloid-β or tau deposition. 3xTgAD mice develop both AD neuropathologies; however, Ng et al. report low p16INK4a-associated senescence in the brain. Senolytic treatment by genetic removal; dasatinib with quercetin (D+Q), which enter the brain; and ABT-263 with limited brain penetrance all reduced AD neuropathology. Refined measures of senescence and brain exposure would help clarify the benefits of senolytics despite low p16INK4a-associated senescence and potential limited brain penetrance. [ABSTRACT FROM AUTHOR]

Dementia is a major cause of poor quality of life, disability, and mortality in old age. According to the geroscience paradigm, the mechanisms that drive the aging process are also involved in the pathogenesis of chronic degenerative diseases, including dementia. The dissection of such mechanisms is therefore instrumental in providing biological targets for interventions and new sources for biomarkers. Within the geroscience paradigm, several biomarkers have been discovered that can be measured in blood and that allow early identification of individuals at risk of cognitive impairment. Examples of such markers include inflammatory biomolecules, markers of neuroaxonal damage, extracellular vesicles, and DNA methylation. Furthermore, gait speed, measured at a usual and fast pace and as part of a dual task, has been shown to detect individuals at risk of future dementia. Here, we provide an overview of available biomarkers that may be used to gauge the risk of cognitive impairment in apparently healthy older adults. Further research should establish which combination of biomarkers possesses the highest predictive accuracy toward incident dementia. The implementation of currently available markers may allow the identification of a large share of at-risk individuals in whom preventive interventions should be implemented to maintain or increase cognitive reserves, thereby reducing the risk of progression to dementia. [ABSTRACT FROM AUTHOR]

The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung—particularly timely given the Corona Virus Immune Disease-2019 pandemic—along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest. [ABSTRACT FROM AUTHOR]

About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. This editorial is inspired by the wide range and variety of questions, ideas, comments and suggestions received in response to that query. The seven knowledge gaps identified in this article are arranged into three main categories: evolutionary aspects of longevity, biological survival and death aspects, and heterogeneity in the progression and phenotype of ageing. This is not an exhaustive and exclusive list, and may be modified and expanded. Implications of these knowledge gaps, especially in the context of ongoing attempts to develop effective interventions in ageing and longevity are also discussed. [ABSTRACT FROM AUTHOR]

Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888 [ABSTRACT FROM AUTHOR]

Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve lifespan and slow the progression of detrimental aging-related changes such as immune system senescence, mitochondrial dysfunction, and dysregulated nutrient sensing and metabolism. Emerging evidence suggests that gut microbiota dysbiosis is a hallmark of aging-related diseases and microbiome modulators, such as probiotics (live bacteria) or postbiotics (non-viable bacteria/bacterial byproducts) may be promising geroprotectors. However, because they are strain-specific, the geroprotective effects of probiotics and postbiotics remain poorly understood and understudied. Drosophila melanogaster, Caenorhabditis elegans, and rodents are well-validated preclinical models for studying lifespan and the role of probiotics and/or postbiotics, but each have their limitations, including cost and their translation to human aging biology. C. elegans is an excellent model for large-scale screening to determine the geroprotective potential of drugs or probiotics/postbiotics due to its short lifecycle, easy maintenance, low cost, and homology to humans. The purpose of this article is to review the geroprotective effects of microbiome modulators and their future scope, using C. elegans as a model. The proposed geroprotective mechanisms of these probiotics and postbiotics include delaying immune system senescence, preventing or reducing mitochondrial dysfunction, and regulating food intake (dietary restriction) and metabolism. More studies are warranted to understand the geroprotective potential of probiotics and postbiotics, as well as other microbiome modulators, like prebiotics and fermented foods, and use them to develop effective therapeutics to extend lifespan and reduce the risk of debilitating aging-related diseases. [ABSTRACT FROM AUTHOR]

Epidemiological studies of sugar-sweetened beverages (SSBs) and artificially sweetened beverages (ASBs) with Alzheimer's disease (AD) have provided controversial findings. Furthermore, little is known about the association between pure fruit/vegetable juices and AD. The present study aims to estimate the associations of SSBs, ASBs, and pure fruit/vegetable juices with AD, and to evaluate the theoretical effects of replacing SSBs and ASBs with the different consumption of pure fruit/vegetable juices on the risk of AD. This prospective cohort study of the UK Biobank included 206,606 participants aged 39–72 years free of dementia at baseline between 2006 and 2010. Dietary intake of SSBs, ASBs, and pure fruit/vegetable juices (naturally sweet juices) were collected using a 24-h dietary recall questionnaire completed between 2009 and 2012. Incident AD was identified by medical and mortality records. Cox proportional hazard models and substitution models were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 699 cases of AD were identified over a median follow-up of 9.5 years. The consumption of SSBs and ASBs (> 2 units/d) were associated with a higher risk of AD. However, participants who drank > 1–2 units/d of pure fruit/vegetable juices were associated with a lower risk of AD. In substitution models, replacing SSBs with an equivalent consumption of pure fruit/vegetable juices could be associated with a risk reduction of AD. [ABSTRACT FROM AUTHOR]

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day‐by‐day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity. [ABSTRACT FROM AUTHOR]

Aging is characterized by fundamental cellular and molecular hallmarks that result in physiologic decline of most body systems. This may culminate in frailty, a state of decreased reserve. Because frailty is a state of multisystem dysregulation, multimodal interventions may be necessary to mitigate and prevent progression rather than interventions targeting a single system. Movement‐based mind–body therapies, such as tai chi and yoga, are promising multimodal strategies for frailty prevention and treatment given their inherent multicomponent nature. In this review, we summarize the links between hallmarks of aging and frailty and how tai chi and yoga may impact these hallmarks. We review trial evidence for the impact of tai chi and yoga on frailty in older populations and discuss opportunities for future research. [ABSTRACT FROM AUTHOR]

• What is the primary question addressed by this study ? This aims to summarize the current literature on the emerging field of geroscience and its relation to serious mental illnesses in older adults. • What is the main finding of this study? Serious mental illnesses have been associated with abnormalities in biological aging processes and premature aging features. Such changes put these individuals at higher risk of adverse health outcomes than the general population. • What is the meaning of the finding? The geroscience hypothesis can provide novel perspectives for developing interventions to treat and prevent SMIs and their negative effects on systemic and brain health. 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. [ABSTRACT FROM AUTHOR]

Pragmatic trials aim to assess intervention efficacy in usual patient care settings, contrasting with explanatory trials conducted under controlled conditions. In aging research, pragmatic trials are important designs for obtaining real-world evidence in elderly populations, which are often underrepresented in trials. In this review, we discuss statistical considerations from a frequentist approach for the design and analysis of pragmatic trials. When choosing the dependent variable, it is essential to use an outcome that is highly relevant to usual medical care while also providing sufficient statistical power. Besides traditionally used binary outcomes, ordinal outcomes can provide pragmatic answers with gains in statistical power. Cluster randomization requires careful consideration of sample size calculation and analysis methods, especially regarding missing data and outcome variables. Mixed effects models and generalized estimating equations (GEEs) are recommended for analysis to account for center effects, with tools available for sample size estimation. Multi-arm studies pose challenges in sample size calculation, requiring adjustment for design effects and consideration of multiple comparison correction methods. Secondary analyses are common but require caution due to the risk of reduced statistical power and false-discovery rates. Safety data collection methods should balance pragmatism and data quality. Overall, understanding statistical considerations is crucial for designing rigorous pragmatic trials that evaluate interventions in elderly populations under real-world conditions. In conclusion, this review focuses on various statistical topics of interest to those designing a pragmatic clinical trial, with consideration of aspects of relevance in the aging research field.

Geroscience, a burgeoning discipline at the intersection of aging and disease, aims to unravel the intricate relationship between the aging process and pathogenesis of age-related diseases. This paper explores the pivotal role played by geroscience in reshaping our understanding of pathology, with a particular focus on age-related diseases. These diseases, spanning cardiovascular and cerebrovascular disorders, malignancies, and neurodegenerative conditions, significantly contribute to the morbidity and mortality of older individuals. We delve into the fundamental cellular and molecular mechanisms underpinning aging, including mitochondrial dysfunction and cellular senescence, and elucidate their profound implications for the pathogenesis of various age-related diseases. Emphasis is placed on the importance of assessing key biomarkers of aging and biological age within the realm of pathology. We also scrutinize the interplay between cellular senescence and cancer biology as a central area of focus, underscoring its paramount significance in contemporary pathological research. Moreover, we shed light on the integration of anti-aging interventions that target fundamental aging processes, such as senolytics, mitochondria-targeted treatments, and interventions that influence epigenetic regulation within the domain of pathology research. In conclusion, the integration of geroscience concepts into pathological research heralds a transformative paradigm shift in our understanding of disease pathogenesis and promises breakthroughs in disease prevention and treatment.

On 5 May 2023, the World Health Organization declared that COVID-19 no longer constituted a public health emergency of international concern. Medical science must now consider how it ought to recalibrate its imagination and idealism in a post-COVID-19 pandemic world. The fact that advanced age was the largest risk factor for COVID-19 mortality and serious illness, as well as for the most prevalent chronic diseases, reveals the urgency and significance of shifting the focus from mitigating each specific pathology risk, one at a time, to targeting biological ageing itself. In his 1910 JAMA Address entitled ‘Imagination and Idealism in the Medical Sciences', Christian Herter made an important distinction between two ways imagination and idealism can be invoked in the medical sciences: (i) humanitarian medicine, which emphasizes the obvious and direct paths of ameliorating human suffering; and (ii) a curiosity-oriented approach which explores pure science and the experimental laboratory. The latter examines the indirect ways of winning, in Herter's words, ‘the citadel’ of health promotion. Herter's reflections on these two contrasting approaches to medicine have significance for both the COVID-19 pandemic and the aspiration to promote the ideal of healthy ageing in the post-COVID-19 pandemic era.

Emerging data support associations between the depletion of the healthy gut microbiome and aging-related physiological decline and disease. In humans, fecal microbiota transplantation (FMT) has been used successfully to restore gut microbiome structure and function and to treat C. difficile infections, but its application to healthy aging has been scarcely investigated. The marmoset is an excellent model for evaluating microbiome-mediated changes with age and interventional treatments due to their relatively shorter lifespan and many social, behavioral, and physiological functions that mimic human aging. Prior work indicates that FMT is safe in marmosets and may successfully mediate gut microbiome function and host health. This narrative review (1) provides an overview of the rationale for FMT to support healthy aging using the marmoset as a translational geroscience model, (2) summarizes the prior use of FMT in marmosets, (3) outlines a protocol synthesized from prior literature for studying FMT in aging marmosets, and (4) describes limitations, knowledge gaps, and future research needs in this field.

• Carnosine is a geroprotective molecule, with a broad spectrum of physiological effects which are protective against age-related diseases. • Carnosine has strong direct and indirect anti-oxidant mechanisms, through direct free radical scavenging, and NRF2 pathway activation. • Carnosine also has anti-inflammatory and glucose-lowering activity, both of which are protective against an array of cardiometabolic diseases. • It is unclear whether carnosine has a direct impact on other areas of ageing physiology, such as stem cell exhaustion and proteostasis, or whether the benefits described are indirect. 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. [ABSTRACT FROM AUTHOR]

• Stem cell exhaustion is a promising avenue for regenerative therapies in musculoskeletal disease in ageing. • Mechanisms underpinning stem cell exhaustion are unclear. • Senescence of mesenchymal progenitors in bone marrow and muscle leads to decreased proliferation. • There is a shift away from myo- and osteogenesis, toward adipogenesis in both muscle and bone. • Questions remain as to whether these are a primary stem effect, or a systemic change in the niche microenvironment. 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. [ABSTRACT FROM AUTHOR]

Background: The physiopathology of sarcopenia shares common biological cascades with the aging process, as does any other age-related condition. However, our understanding of the interconnected pathways between diagnosed sarcopenia and aging remains limited, lacking sufficient scientific evidence., Methods: This narrative review aims to gather and describe the current evidence on the relationship between biological aging determinants, commonly referred to as the hallmarks of aging, and diagnosed sarcopenia in humans., Results: Among the twelve hallmarks of aging studied, there appears to be a substantial association between sarcopenia and mitochondrial dysfunction, epigenetic alterations, deregulated nutrient sensing, and altered intercellular communication. Although limited, preliminary evidence suggests a promising association between sarcopenia and genomic instability or stem cell exhaustion., Discussion: Overall, an imbalance in energy regulation, characterized by impaired mitochondrial energy production and alterations in circulatory markers, is commonly associated with sarcopenia and may reflect the interplay between aging physiology and sarcopenia biology., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function impairs intercellular interactions as well as extracellular matrix production, further hindering muscle regeneration. Other muscle-resident cells, such as fibro-adipogenic progenitors (FAPs), pericytes, and immune cells, also deteriorate with age, reducing local growth factor activities and responsiveness to stress or injury. Systemic signaling, including hormonal changes, contributes to muscle cellular catabolism and disrupts muscle homeostasis. Collectively, these cellular and environmental components interact, disrupting muscle homeostasis and regeneration in advancing age. Understanding these complex interactions offers insights into potential regenerative strategies to mitigate age-related muscle degeneration., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)