UNASSIGNED: Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored, as is the associated impact on markers of healthy ageing. We set out to address these uncertainties.
UNASSIGNED: We compared the duration of healthy life (healthspan) in male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), versus wildtype (WT) littermates. Cognitive performance was defined using nesting studies at 3- and 24-months of age. Brain transcriptome was characterised at 3- and 18-months of age using RNA-seq.
UNASSIGNED: Healthspan was longer in DKO versus WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. Brain transcriptomics at 18 months of age revealed lower expression of canonical ageing-associated genes in DKO versus WT, although many of these findings were replicated in IRKO versus WT or IGF-1RKO vs WT.
UNASSIGNED: Reduced insulin and IGF-1 receptor expression have both common and synergistic effects upon elements of healthy mammalian ageing, suggesting future ageing studies should consider targeting both insulin and IGF-1 signalling.

A multifaceted approach in treating Alzheimer\'s disease (AD), a neurodegenerative condition that poses health risks in the aging population is explored in this investigation via encapsulating Piper betle essential oil (PBEO) in chitosan nanoparticles (ChNPs) to improve solubility and efficacy of PBEO. PBEO-ChNPs mitigated AD-like features more effectively than free PBEO by delaying paralysis progression and reducing serotonin hypersensitivity, ROS levels, Aβ deposits, and neurotoxic Aβ-oligomers in the Caenorhabditis elegans AD model. PBEO-ChNPs significantly improved lifespan, neuronal health, healthspan, cognitive function, and reversed deficits in chemotaxis and reproduction. PBEO-ChNPs also induced stress response genes daf-16, sod-3, and hsp-16.2. The participation of the DAF-16 pathway in reducing Aβ-induced toxicity was confirmed by daf-16 RNAi treatment, and upregulation of autophagy genes leg-1, unc-51, and bec-1 was noted. This study is the first to demonstrate an alternative biopolymeric nanoformulation with natural PBEO and chitosan, in mitigating AD and its associated symptoms.

BACKGROUND: Punica granatum L., commonly known as pomegranate, is renowned for its health benefits, primarily associated with the consumption of its fruit and seeds. However, its non-edible parts, including leaves, have been used in traditional medicine as a remedy with anti-inflammatory and anti-diabetic properties. Considering the abundance of bioactive compounds, predominantly flavonols, flavones, and tannins P. granatum leaf (PGL) extract holds potential as health-promoting agent. Yet, its effect on longevity and healthspan remains largely unexplored.
OBJECTIVE: Our study aims to explore the potential of PGL extract to enhance healthspan and ameliorate age-related frailty in Caenorhabditis elegans. Additionally, we seek to elucidate its effect on the molecular signaling networks associated with stress resistance and longevity.
METHODS: After characterizing the extract metabolite profile by NMR spectroscopy, phenotypic and stress analyses were performed. In order to establish the molecular mechanism of action, the involvement of signaling pathways key to longevity were investigated by means of real-time quantitative PCR (RT-qPCR) and the use of transgenic strains (MIR13, MAH240, LD1, and OH16024). In addition, the effect of PGL on metabolism and lipid accumulation, as well as mitochondrial homeostasis, was examined.
RESULTS: The PGL extract supplementation significantly enhanced stress resistance and extended the lifespan of C. elegans. Additionally, it improved locomotion, as well as metabolic and mitochondrial functions, indicating an overall improvement in health. The molecular mechanisms highlight the coordinated regulation of stress response, metabolic homeostasis, and longevity signaling pathways. Specifically, our results demonstrate the essential roles of HLH-30/TFEB, in conjunction with DAF-16/FOXO and SKN-1/NRF2, as mediators of the PGL extract effect on healthspan.
CONCLUSIONS: Our findings emphasize the potential of PGL extract to ameliorate age-related decline, induce longevity and further enhance healthspan. Given the diverse effects on the molecular network associated with stress-adaptations, longevity and metabolic control, PGL extract might become a promising natural product with a particular importance to the field of gerontology.

暂无摘要。

Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients\' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.

Axenic dietary restriction (ADR) is highly effective in extending lifespan of C. elegans but its effects on healthspan improvement is less well characterized. Using transmission electron microscopy, morphometric analyses, and functional assays, we found ADR can preserve tissue ultrastructure, including the cuticle, epidermis, and intestinal lumen, and reduce age-associated pathologies like gonad degeneration, uterine tumor clusters, pharyngeal deterioration, and intestinal atrophy. However, there was no notable improvement in behavioral and functional metrics. Our results underscore that lifespan extension through ADR does not inherently translate to broad healthspan improvements.

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.

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.

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.

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.