Development of aging research in Caenorhabditis elegans: From molecular insights to therapeutic application for healthy aging.

Aging is a process of time-dependent degeneration of biological functions, becoming more susceptible to diseases and eventually leading to death. Along with medical advances to extend lifespan, many researchers have made efforts to understand the complexities of aging further. The nematode Caenorhabditis elegans has been a part of this journey due to its short lifespan, genetic tractability, and conservation of aging-associated genes, which significantly contribute to the progress of aging studies. Here, we summarized current knowledge on aging studies, major genes, and genetic pathways involved in the aging of C. elegans. Furthermore, the current research expands its focus from lifespan to healthspan, encompassing various nutrition and environmental factors. Despite the challenges in translating findings from C. elegans to humans, efforts continue to increase our understanding of healthy aging to improve not only lifespan but also quality of life.

Research on evaluation indicators of healthspan for veterans: A single-center exploratory study.

Objective: To explore a definition of healthspan that based on actual situation of veterans is of significance for improving their health status and life quality. Methods: This was a retrospective study. Based on the medical data of veterans from the Chinese PLA General Hospital. Total of 1,421 subjects were enrolled to this study, among which 441 deceased cases were further analyzed. The indicators of healthspan of the subjects was calculated from four dimensions (the status of chronic diseases, physical function, social function and psychological function). The risk factors for death were analyzed in a population cohort from 2008 to 2021 (including 763 subjects, among which 372 were deceased). Results: The average lifespan and adjusted healthspan of the subjects were 93.3 years and 75.1 years, respectively. The four dimensions of healthspan were: adjusted healthspan without chronic diseases was 76.3 years, social function-related healthspan was 88.8 years, physical function-related healthspan was 91.5 years, and psychological function-related healthspan was 92.7 years. By analyzing the cohort in 2008, it was inferred that the main risk factors for the death of veterans were poor nutritional status, renal function injury, high blood pressure, high blood sugar, and aging. Conclusions: This study proposed four dimensions related to "healthspan" for Chinese veterans (adjusted healthspan without chronic diseases, physical function-related healthspan, social function-related healthspan, and psychological function-related healthspan). Besides, poor nutritional status, renal function injury, and high blood pressure were the most important risk factors affecting the death of veterans.

Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations.

Studies aimed at preventing age-associated diseases are fundamental in addressing the challenges posed by an aging population. However, biomedical and technological advancements have now reached a stage where it appears increasingly possible to repair the damage caused by severe pathologies and reverse the functional decline that accompanies aging. This perspective highlights the significance of using aging models, specifically non-transgenic geriatric mice (aged over 24 months), to study interventions aimed at reversing or ameliorating age-related pathologies. While most research typically utilizes young, adult, and mid-aged mice to investigate aging mechanisms and develop preventive strategies, geriatric models provide unique insights into the efficacy and safety of treatments in conditions that mimic the complexities of multiple concurrent diseases or syndromes. This manuscript highlights the importance of considering timing responses in aging interventions, illustrated by recent findings such as those involving canagliflozin. These studies reveal that the timing of intervention can significantly influence the outcomes, highlighting aspects often overlooked. Practical challenges and resource demands associated with geriatric mouse studies including concerns related to animal husbandry and aging phenotypes are also discussed. This perspective aims to foster a deeper understanding of the potential benefits and limitations of geriatric mice models in geroscience research and emphasizes the need for continued innovation in this field to meet the critical need to develop effective treatments for age-related diseases.

Targeting multiple hallmarks of mammalian aging with combinations of interventions.

Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. This outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact. Hence solving the problem of aging may require targeting not one but many of its underlying causes at once. Here we review the challenges and successes of combination therapies aimed at increasing the lifespan of mammals and propose novel directions for their development. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.

Consolidating multiple evolutionary theories of ageing suggests a need for new approaches to study genetic contributions to ageing decline.

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy. The nematode Caenorhabditis elegans offers a strong model for post-reproductive mechanistic and therapeutic investigations, yet studies examining the mechanisms of, and countermeasures against, ageing decline largely intervene from larval stages onwards. Importantly, however, lifespan extending conditions frequently impair early-life fitness and fail to correspondingly increase healthspan. Here, we consolidate multiple evolutionary theories of ageing and discuss data supporting hyper/hypofunctional changes at a global molecular and functional level in C. elegans, and how classical lifespan-extension mutations alter these dynamics. The relevance of such mutant models for exploring mechanisms of ageing are discussed, highlighting that post-reproductive gene optimisation represents a more translatable approach for C. elegans research that is not constrained by evolutionary trade-offs. Where some genetic mutations in C. elegans that promote late-life health map accordingly with healthy ageing in humans, other widely used genetic mutations that extend worm lifespan are associated with life-limiting pathologies in people. Lifespan has also become the gold standard for quantifying 'ageing', but we argue that gerospan compression (i.e., 'healthier' ageing) is an appropriate goal for anti-ageing research, the mechanisms of which appear distinct from those regulating lifespan alone. There is, therefore, an evident need to re-evaluate experimental approaches to study the role of hyper/hypofunctional genes in ageing in C. elegans.

Multimodal Transformers and Their Applications in Drug Target Discovery for Aging and Age-Related Diseases.

Given the unprecedented rate of global aging, advancing aging research and drug discovery to support healthy and productive longevity is a pressing socioeconomic need. Holistic models of human and population aging that account for biomedical background, environmental context, and lifestyle choices are fundamental to address these needs, but integration of diverse data sources and large data sets into comprehensive models is challenging using traditional approaches. Recent advances in artificial intelligence and machine learning, and specifically multimodal transformer-based neural networks, have enabled the development of highly capable systems that can generalize across multiple data types. As such, multimodal transformers can generate systemic models of aging that can predict health status and disease risks, identify drivers, or breaks of physiological aging, and aid in target discovery against age-related disease. The unprecedented capacity of transformers to extract and integrate information from large and diverse data modalities, combined with the ever-increasing availability of biological and medical data, has the potential to revolutionize healthcare, promoting healthy longevity and mitigating the societal and economic impacts of global aging.

Phytonutrients in the promotion of healthspan: a new perspective.

Considering a growing, aging population, the need for interventions to improve the healthspan in aging are tantamount. Diet and nutrition are important determinants of the aging trajectory. Plant-based diets that provide bioactive phytonutrients may contribute to offsetting hallmarks of aging and reducing the risk of chronic disease. Researchers now advocate moving toward a positive model of aging which focuses on the preservation of functional abilities, rather than an emphasis on the absence of disease. This narrative review discusses the modulatory effect of nutrition on aging, with an emphasis on promising phytonutrients, and their potential to influence cellular, organ and functional parameters in aging. The literature is discussed against the backdrop of a recent conceptual framework which describes vitality, intrinsic capacity and expressed capacities in aging. This aims to better elucidate the role of phytonutrients on vitality and intrinsic capacity in aging adults. Such a review contributes to this new scientific perspective-namely-how nutrition might help to preserve functional abilities in aging, rather than purely offsetting the risk of chronic disease.

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.

The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan.

The drugs extending healthspan in clinic have always been searched. Nitazoxanide is an FDA-approved clinical antiprotozoal drug. Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo. Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK, oral nitazoxanide protects against experimental hyperlipidemia, hepatic steatosis, and atherosclerosis. Here, we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway. Additionally, both nitazoxanide and tizoxanide improve high glucose-induced shortening of C. elegans lifespan. Nitazoxanide has been a clinical drug with a good safety profile, we suggest that it is a novel anti-aging drug.

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.

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse.

The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression. We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6-weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.

Timut Pepper Extract Slows Age-Dependent Decline of Mobility and Collagen Loss and Promotes Longevity.

Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans' lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.

The untapped potential of cold water therapy as part of a lifestyle intervention for promoting healthy aging.

Healthy aging is a crucial goal in aging societies of the western world, with various lifestyle strategies being employed to achieve it. Among these strategies, hydrotherapy stands out for its potential to promote cardiovascular and mental health. Cold water therapy, a hydrotherapy technique, has emerged as a lifestyle strategy with the potential capacity to evoke a wide array of health benefits. This review aims to synthesize the extensive body of research surrounding cold water therapy and its beneficial effects on various health systems as well as the underlying biological mechanisms driving these benefits. We conducted a search for interventional and observational cohort studies from MEDLINE and EMBASE up to July 2024. Deliberate exposure of the body to cold water results in distinct physiological responses that may be linked to several health benefits. Evidence, primarily from small interventional studies, suggests that cold water therapy positively impacts cardiometabolic risk factors, stimulates brown adipose tissue and promotes energy expenditure-potentially reducing the risk of cardiometabolic diseases. It also triggers the release of stress hormones, catecholamines and endorphins, enhancing alertness and elevating mood, which may alleviate mental health conditions. Cold water therapy also reduces inflammation, boosts the immune system, promotes sleep and enhances recovery following exercise. The optimal duration and temperature needed to derive maximal benefits is uncertain but current evidence suggests that short-term exposure and lower temperatures may be more beneficial. Overall, cold water therapy presents a potential lifestyle strategy to enhancing physical and mental well-being, promoting healthy aging and extending the healthspan, but definitive interventional evidence is warranted.

Neuronal CBP-1 is Required for Enhanced Body Muscle Proteostasis in Response to Reduced Translation Downstream of mTOR.

BACKGROUND: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation. METHODS: This study uses genetic tools (transgenic Caenorhabditis elegans (C. elegans), RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions. RESULTS: We use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1. CONCLUSIONS: Low translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan.

In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well-being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.

Effect of Modifiable Lifestyle Factors on Biological Aging.

Biological age is a concept that uses bio-physiological parameters to account for individual heterogeneity in the biological processes driving aging and aims to enhance the prediction of age-related clinical conditions compared to chronological age. Although engaging in healthy lifestyle behaviors has been linked to a lower mortality risk and a reduced incidence of chronic diseases, it remains unclear to what extent these health benefits result from slowing the pace of the biological aging process. This short review summarized how modifiable lifestyle factors - including diet, physical activity, smoking, alcohol consumption, and the aggregate of multiple healthy behaviors - were associated with established estimates of biological age based on clinical or cellular/molecular markers, including Klemera-Doubal Method biological age, homeostatic dysregulation, phenotypic age, DNA methylation age, and telomere length. In brief, the available studies tend to show a consistent association of lifestyle factors with physiological measures of biological age, while findings regarding molecular-based metrics vary. The limited evidence highlights the need for further research in this field, particularly with a life-course approach.

Longitudinal fragility phenotyping contributes to the prediction of lifespan and age-associated morbidity in C57BL/6 and Diversity Outbred mice.

Aging studies in mammalian models often depend on natural lifespan data as a primary outcome. Tools for lifespan prediction could accelerate these studies and reduce the need for veterinary intervention. Here, we leveraged large-scale longitudinal frailty and lifespan data on two genetically distinct mouse cohorts to evaluate noninvasive strategies to predict life expectancy in mice. We applied a modified frailty assessment, the Fragility Index, derived from existing frailty indices with additional deficits selected by veterinarians. We developed an ensemble machine learning classifier to predict imminent mortality (95% proportion of life lived [95PLL]). Our algorithm represented improvement over previous predictive criteria but fell short of the level of reliability that would be needed to make advanced prediction of lifespan and thus accelerate lifespan studies. Highly sensitive and specific frailty-based predictive endpoint criteria for aged mice remain elusive. While frailty-based prediction falls short as a surrogate for lifespan, it did demonstrate significant predictive power and as such must contain information that could be used to inform the conclusion of aging experiments. We propose a frailty-based measure of healthspan as an alternative target for aging research and demonstrate that lifespan and healthspan criteria reveal distinct aspects of aging in mice.

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.