Longevity Papers

Arsenic, a widespread environmental toxicant, is increasingly implicated in female reproductive dysfunction. Long-term exposure to low concentrations of arsenic leads to diminished ovarian reserve. However, the mechanisms by which arsenic exposure accelerates ovarian aging remain unclear. Here, we demonstrate that arsenic exposure induces widespread disruption of pre-mRNA splicing programs in granulosa cells, and these aberrantly spliced genes are predominantly responsible for maintaining genomic stability. Arsenic exposure induces proteasomal degradation of the RNA helicase DDX5 through the UBE3A-mediated ubiquitin-proteasome pathway. Loss of DDX5 impairs the alternative splicing of FANCA, a core gene in the Fanconi anemia pathway, resulting in the production of a truncated isoform. This aberration leads to the excessive accumulation of R-loops and γH2AX-marked DNA damage in ovarian granulosa cells. Consequently, arsenic-exposed mice exhibit hallmark features of premature ovarian aging. Our findings establish the DDX5-FANCA axis as a novel paradigm in which environmental toxins dysregulate RNA splicing, driving reproductive aging through R-loops-mediated genomic instability. These insights highlight splice-switching therapies as a promising strategy to counteract pollutant-induced fertility decline.

Fat accumulation with aging occurs in adults across species, yet its underlying mechanisms remain poorly understood, partly due to limited number of studiesspecifically targeting adulthood. Here, we present the first genome-wide analysis of age-associated fat accumulation during adulthood in Caenorhabditis elegans. Unprecedently, our adult-specific RNAi screen identified a limited subset of genes influencing adult fat dynamics, contrasting with the extensive gene sets uncovered in prior developmental RNAi screens. This disparity suggests a unique genetic architecture governing age-related lipid deposition. Central to this network is the evolutionarily conserved transcription factor DAF-16/FoxO, which progressively accumulates in nuclei during aging. Genetic ablation of daf-16 abolished adult fat accumulation, while its adult-specific knockdown reduced adiposity without compromising healthspan or longevity, highlighting its therapeutic potential. Critically, knockdown of the top hits, pals-17 and rege-1, markedly attenuated the nuclear localization of DAF-16 and failed to reduce the adult fat content daf-16-deficient animals, establishing DAF-16 as their essential effector. Overall, our work uncouples developmental and adult lipid regulatory mechanisms and highlights potential targets for understanding and managing adult-onset obesity.

The hippocampus (Hc), which is crucial for memory across the lifespan, is comprised of distinct subfields: dentate gyrus (DG), Cornu Ammonis (CA) sectors 1-3, and subiculum. Cross-sectional studies show that Hc subfield volumes exhibit a differential association with age across the lifespan. However, the evidence of age-related changes and individual variability in developmental trajectories is sparse. We examined changes in Hc subfield volumes in a large normative lifespan sample (N = 474 at baseline, n = 189 at follow-up; mean interval = 2.5 years) while comparing patterns of change in children (ages 5-10.9 years), adolescents (ages 11-18.9 years), young (ages 19-35.9 years), middle-aged (ages 36-55.9 years), and older adults (ages 56-73.9 years). In a pooled lifespan sample, we observed no mean change in Hc subfield volumes. Nonetheless, there were significant individual differences in change for all subfields that depended on the baseline age. A general tendency for volume gain in young individuals attenuated in adulthood and shifted toward loss in late lifespan segments. Across age groups, CA1-2 volume increased into young adulthood, whereas DG-CA3 and subiculum volumes remained stable and declined significantly after age of 55 years. Thus, our results reveal age-related differences in Hc subfield volume changes over nearly the entire human lifespan. Our findings have significant implications for models of neural development and aging and for understanding lifespan trajectories of memory.

The hippocampus plays a critical role in spatial and contextual learning, and its age-related decline significantly contributes to cognitive impairment. Adult hippocampal neurogenesis (AHN), the continuous production of new neurons in the dentate gyrus, provides a unique form of structural plasticity essential for lifelong learning and memory. AHN is notably altered in various neurodegenerative and mental health disorders characterized by cognitive deficits, suggesting its crucial involvement in maintaining neuronal populations and endogenous regenerative capacity. Given the emerging links between neurogenesis and these conditions, neurogenic therapies hold promise for improving outcomes in individuals with severe depression, cognitive impairment, and other neurodegenerative disorders. Notably, chronic stress is a significant factor influencing AHN, often serving as an independent biomarker for dementia and strongly impacting hippocampal neurogenesis. This review explores the intricate influence of stress on AHN and examines how the inhibition of neurogenesis contributes to cognitive deficits and the progression of dementia.

One of the prokaryotic partners at the origin of eukaryotes was an archaeon, but do archaea age, and if so, how? Uncovering aging in Archaea might provide more general clues about cellular senescence and rejuvenation and their origins. To fill this knowledge gap, we focused on Saccharolobus islandicus, a model archaeon for which the cell cycle can be synchronized and controlled. We generated longitudinal transcriptomes of synchronized S. islandicus populations that capture typical expression and co-expression profiles associated with chronological aging. These experiments also allowed us to infer average cellular death rates during the cell cycle. Our results are compatible with general patterns of biological aging observed in single cells. However, at the population level, we observe a peak of mortality shortly after cell division in S. islandicus, which we interpret as "negative" demographic aging or ontogenescence, i.e., pre-reproductive mortality decline. To reconcile these observations, we propose a model of S. islandicus aging and rejuvenation. Our research constitutes a first step into the study of aging in archaea on the basis of gene expression, gene co-expression patterns during the cell cycle and biodemography analyses, and proposes a hypothetical new model to explore how cellular senescence and rejuvenation in eukaryotes may have prokaryotic roots. Alternative interpretations of our transcriptomic results however are possible, encouraging future experimental validation of aging in Archaea.

Life history theory proposes a tradeoff between growth rate and lifespan, typically explained by the allocation of limited energy resources between somatic growth and maintenance. However, this explanation does not give a complete picture of the energy tradeoff. This study investigates two energy allocation mechanisms that influence growth and longevity simultaneously: the redirection of metabolic energy from growth to maintenance under energy limitation, and increased energy investment in biosynthesis, enhancing bio-tissue quality and stress resistance but also slowing growth. By analyzing empirical data from laboratory mice subjected to diet restriction (DR), dwarfism through genetic manipulations (Dwarf), rapamycin treatment (Rap), and growth hormone transgenics (Super), we quantify changes in growth rate, metabolic rate, and biosynthesis energy costs (E

Senescence of activated hepatic stellate cells (aHSCs) is thought to be a promising alternative for limiting hepatic fibrosis. However, uncontrollable accumulation and spread of senescence in neighboring hepatocytes lead to inflammation and steatosis, aggravating fibrosis and even promoting carcinogenesis. To harness senescence for fibrotic treatment, aHSCs-targeted poly (lactic-co-glycolic acid) (PLGA) nanoplatforms have been constructed to integrate senescent induction of aHSCs and senescent reprogramming. Owing to the CD44 aptamer modification, the nanoplatform specifically delivers senescent inducers and small interfering RNAs (siRNAs) that silence nuclear factor-kappa B (NF-κB) in aHSCs, thereby inducing senescence and simultaneously suppressing the production of senescence-associated secretory phenotypes (SASPs) in aHSCs. The senescence of aHSCs decreases their proliferation, and achieves permanent inactivation even upon repeated fibrotic stimulus. Meanwhile, the elimination of SASPs interrupts the vicious cycle of senescent aHSCs with surrounding hepatocytes to decrease senescent and inflammatory accumulation in liver tissues. In vitro and in vivo results confirmed the superior ability of the nanoplatform to inhibit liver fibrosis and control the spread of senescence. Our work provides a nanoplatform for specifically inducing senescence of aHSCs and reveals a promising senescence modulation strategy for the treatment of liver fibrosis.

Osteoimmunology is an interdisciplinary study of the interaction between the immune system and the skeletal system, aiming to reveal the immune regulation mechanisms that affect bone health and disease. Aging is a macro concept, which is not limited to the senescence of cells, but also includes the aging of the body as a whole. Studies have shown that aging can affect osteoimmune function through various mechanisms such as affecting the bone marrow microenvironment, causing immune cell dysfunction, triggering inflammatory responses, and destroying bone homeostasis, leading to the occurrence of bone diseases. Therefore, this review provides a comprehensive introduction to the related cells and mechanisms of osteoimmunology, elaborating in detail the characteristics of senescence of immune cells and bone cells, the mutual influences between bone cells and immune cells and the impact of aging on osteoimmune function. On this basis, we propose new insights on the mechanisms of aging and osteoimmune pathogenesis in Acute myeloid leukemia, Rheumatoid Arthritis, Osteoporosis and Periodontitis, and propose anti-aging strategies for the treatment of osteoimmune-related diseases, which provides a new idea for the treatment of osteoimmune-related diseases.

Aging-related accumulation of DNA damage adversely affects hematopoietic stem cell (HSC). However, the mechanisms underlying this accumulation and strategies for its elimination to rejuvenate aged HSC remain largely obscure. This study uncovers a notable surge in R-Loop presence within aged HSC, notably co-localized with γH2AX and replication protein A (RPA), and correlated with RNA residency in the nucleus. Targeted induction of R-Loop impairs the function of HSC. Mechanistically, RNA exportation is compromised in aged HSC due to a decline in Alyref, the primary constituent of the transcription- export complex (TREX). Specifically, Alyref dysfunction results in RNA retention within the nucleus, mimicking the functional characteristics of aged HSC. The nuclear accumulation of RNA leads to the formation of RNA:DNA hybrids, known as R-Loop structures, consequently inducing replication stress and DNA damage. Introducing a quantitative boost of Alyref in aged HSC notably reinstates RNA transportation, diminishes R-Loop formation and replication stress, and ultimately enhances the performance of aged HSC. Taken together, our research demonstrates the initial revelation that aging-triggered replication stress stems from abnormal RNA transportation-propelled R-Loop configurations, hinting at the potential of quantitatively modulating RNA transportation to mitigate the physiological drawbacks of aging on HSC.

African turquoise killifish (Nothobranchius furzeri) has emerged as a promising vertebrate model for aging research because of its unique characteristics. Its exceptionally short lifespan and rapid aging make it an ideal model for studying age-related phenomena in compressed timeframes. This species exhibits hallmarks of aging observed in longer-lived vertebrates, including motor neuron degeneration, muscle weakness, and impaired regenerative capacity. These features make it valuable for investigating molecular and cellular mechanisms of age-related diseases and tissue regeneration. However, current research has primarily focused on brain aging and neurodegeneration, while systemic age-related changes across organs remain underexplored. The impact of aging on tissue regeneration in this model needs comprehensive investigation. This review summarizes current research using African turquoise killifish on age-related diseases and tissue regeneration in multiple organs. By integrating aging and regeneration biology, this review offers a perspective that expands the utility of this species beyond neurobiology, positioning it as a promising model for gerontology and regenerative medicine. We discuss limitations and future directions to advance its use in aging studies across multiple organs. Future research on African turquoise killifish will contribute to identifying therapeutic targets and developing interventions for age-related diseases, ultimately extending healthy life expectancy in humans.

We examined the socioeconomic and health characteristics of centenarians (100 years or above) and near-centenarians (90-99 years) in India. Utilizing data from the Wave-1 of the Longitudinal Ageing Study of India (LASI), we compared the distribution of centenarians and near-centenarians with those aged 60-89 years across socioeconomic, health, and subjective well-being indicators. Our findings revealed that most of the sample centenarians and near-centenarians were female, educated, and widowed. They displayed low prevalence rates of chronic ailments (heart disease, cancer, diabetes, and hypertension). More than half of the sample centenarians were also able to perform basic activities of daily living like walking, eating, bathing, and dressing. About three-fourths of the oldest population also perceived their life to be fairly good. Our findings suggest that centenarians (near-centenarians) in India elicit a healthier profile and can be a vital source of information for advancing longevity research. The absence of reliable headcount on centenarians indicates a huge scope for building a national-level data repository for directing and navigating policy actions.

The aging-associated cardiac remodeling (AACR) is characterized by myocardial hypertrophy, fibrosis and cardiac dysfunction, which could be further aggravated by angiotensin II (Ang II) and pressure-overload in aged people. In this study, we aimed to investigate the roles and mechanisms of intermedin

Exposure to microplastics poses potential risks to human health, particularly during pregnancy and early life; however, research in this field remains scarce. Therefore, we aimed to investigate the association between prenatal microplastic exposure and telomere length (TL), a recognized marker of biological aging. Placental microplastic exposure and its potential effects on umbilical cord blood TL and placental tissues were investigated in a cohort of 1121 pregnant women from Shenyang, China. Microplastic concentrations in placental samples were quantified using LD-IR chemical imaging, while TL in umbilical cord blood and placental tissues was measured using qRT-PCR. Adjusted multivariable regression models, stratified analysis, and mixture analyses, including Bayesian Kernel Machine Regression (BKMR) and quantile g-computation, were employed to assess associations and interactions. Placental microplastics (particularly polyvinyl chloride (PVC), polypropylene (PP), and polybutylene succinate (PBS)), were prevalent, with median total concentrations of 15 n/10 g of placental tissue. In cord blood, higher PVC and PBS levels were significantly associated with reduced TL (adjusted β = -0.13 and -0.14, respectively; p ≤ 0.01). PP exposure showed no significant association with cord blood TL. For placental TL, all three microplastics demonstrated significant negative associations, with PP showing the strongest effect (β = -0.13, p < 0.001). Stratified analysis revealed no sex-based differences in associations. Quantile g-computation indicated significant cumulative effects of microplastics on TL, with PBS contributing the most to TL reduction. BKMR analysis highlighted non-linear exposure-response relationships, with lower quantiles showing positive associations and higher quantiles indicating detrimental effects on TL, potentially due to oxidative stress or inflammation. These findings underscore the pervasive presence of microplastics in placental tissues and their potential role in disrupting telomere maintenance, raising concerns about their long-term health implications for newborns.

Cellular senescence is a key driver of heart disease, yet its regulation in cardiomyocytes remains poorly understood. Selenoprotein T (SELENOT) plays a crucial role in cardiomyocyte differentiation and protection, but its role in cardiomyocyte senescence remains unknown. Here, we explore the novel role of SELENOT in preserving cardiomyocyte viability and genomic integrity during doxorubicin-induced senescence. Senescent differentiated cardiomyocytes exhibit hallmarks of cellular senescence, including increased β-galactosidase activity and elevated p53 and p21 levels, and upregulation of senescence-associated secretory phenotype (SASP) markers (i.e. MMP3, IL6, and TNFα). Additionally, senescent cells displayed disrupted cytosolic and mitochondrial redox homeostasis, which were mitigated by PSELT (a small peptide that mimics SELENOT activity). Notably, PSELT positively influenced DNA damage markers (p-γH2AX and lamin B1) and prevented ER stress regulating BIP, calnexin, IRE1α, and ERO1α expression. Intriguingly, SELENOT expression was upregulated in response to senescence, suggesting a stress-sensing redoxin function. Loss-of-function studies revealed that SELENOT deficiency led to cardiomyocyte death and DNA damage, which were only partially rescued by PSELT, supporting the existence of cross-regulatory mechanisms within the SELENOT/PSELT axis. Mechanistically, similar to SSO, an irreversible inhibitor of CD36, PSELT mitigated the senescence-induced upregulation of CD36, a key player in cardiac aging. Co-immunoprecipitation analysis demonstrated that SELENOT interacts with CD36 in both normal and senescent human cardiomyocytes. Overall, these findings underscore the essential role of SELENOT in preserving the viability and genomic integrity of senescent human cardiomyocytes and suggest that PSELT-mediated inhibition of CD36 may represent a promising therapeutic strategy for treating age-related cardiac dysfunction.

Gut health is intricately linked to energy homeostasis, stress resistance, inflammation, and longevity. Methionine (Met) intake significantly influences gut health, with both supplementation and restriction showing distinct effects. While appropriate Met supplementation offers benefits, excessive intake can be harmful, whereas Met restriction appears to improve overall health of the body, especially the gut. This review synthesizes research on Met's role in gut health, highlighting its metabolism, interactions with the intestinal microbiota, and effects on oxidative stress, inflammation, and permeability in the intestine. The possible reason for Met intake influences the risk of metabolic diseases such as obesity, diabetes, cardiovascular disease, and cognitive impairment, thus influencing lifespan was explored, which is potentially via gut health. In addition, strategies for achieving precision nutrition of Met, including dietary adjustments, production of Met-specific foods, bioengineering plant strains, and methioninase supplementation, were proposed. These insights aim to deepen the understanding of Met's effects on gut health and guide interventions for improving health outcomes.

Interpreting ambiguous environmental cues, like facial expressions, becomes increasingly challenging with age, especially as cognitive resources decline. Managing these challenges requires adaptive neural mechanisms that are essential for maintaining mental well-being. The locus ceruleus (LC), the brain's main norepinephrine source, regulates attention, arousal, and stress response. With extensive cortical connections, the LC supports adapting to cognitive demands and resolving conflicting cues from environment, particularly in later life. Previous research suggests that LC interacts with the prefrontal cortex (PFC) during high-conflict tasks. However, whether LC activity and its connectivity with the PFC support emotional ambiguity processing and contributes to emotional well-being in healthy aging remains unclear. To address this gap, we used 7T-MRI to examine LC function in 75 younger (25.8 ± 4.02 years, 35 females) and 69 older adults (71.3 ± 4.1 years, 35 females) during facial emotion recognition task morphed with varying ambiguity: unambiguous, intermediate ambiguity, and absolute ambiguity. Behaviorally, participants had longer response times and lower confidence during the absolute-ambiguity condition, while older adults perceived ambiguous faces as happy more frequently than younger adults. Neuroimaging results revealed older adults exhibited greater LC activity and enhanced connectivity with dorsolateral PFC (dlPFC) during absolute ambiguity compared with younger adults. This heightened connectivity in older adults was linked to better task-independent self-reported mental well-being questionnaires and greater emotional resilience scores derived from principal component analysis. Overall, these findings suggest that greater LC activity supports managing cognitively demanding tasks, while enhanced LC-dlPFC connectivity promotes emotional well-being, highlighting this neural pathway's role in healthy aging.

Understanding of the risk factors and underlying mechanisms of aortic dissection (AD) is critical for improved clinical management of the disease. How aging, a prominent risk factor for AD, impairs the dissection resistance capabilities of the aorta has not been elucidated. This study integrated mechanical testing, multiphoton imaging and finite element (FE) modeling to investigate the multiscale dissection behavior of human descending thoracic aortas (DTAs) from a wide range of ages. Mechanical testing demonstrated that aging diminishes bonding between the lamellar layers within the media of human DTA. Moreover, dissection propagation in aortic media is associated with dissection tension drops that follow a power-law distribution. Multiphoton imaging of dissected DTA media revealed less organized elastic lamellae and fewer visible collagen with aging. The discrete FE model of dissection propagation recapitulated the power-law behavior that originates from avalanches of interlamellar collagen fiber (ICF) failures. Simulation revealed prominent interlamellar structural rearrangement of ICFs in the aging DTA, including lower density and higher dispersion, of which the former strongly correlates with the weakened interlamellar bonding while the latter is vital in triggering the fast-propagating avalanches and power-law behavior of AD. Furthermore, small avalanches occur more often with aging, which makes dissection propagation faster and AD more dangerous for the elderly population. STATEMENT OF SIGNIFICANCE: Early diagnosis of aortic dissection (AD) is crucial for effective disease management, and it requires a comprehensive understanding of the risk factors. This study explores the microstructural mechanisms that underlie the age-augmented risk of AD through a multiscale investigation of the dissection mechanics of human descending thoracic aortas (DTAs). Our findings reveal the presence of avalanches and power-law behavior in dissection propagation, which is age-dependent and can be recapitulated using a novel computational model that accounts for the failure of discrete interlamellar fibers. Using this model, we demonstrated that aging weakens the dissection resistance of the DTA, characterized by a reduction in the number and increased dispersion of interlamellar collagen fibers. The avalanches and power-law behavior not only plays a fundamental role in the rapid progression of AD but also offers new perspectives on the interlamellar microstructure-function relationship in both aortic health and disease.

Honokiol (HKL), one of the major bioactive components of the traditional Chinese medicine Magnolia officinalis, has garnered significant attention because of its extensive pharmacological activities. Numerous studies have demonstrated that SIRT3 plays a crucial regulatory role in the disease intervention mechanisms mediated by HKL. HKL can bind to the SIRT3 protein, not only directly increasing its deacetylase activity but also forming a positive feedback loop by activating its transcription factors, thereby further promoting SIRT3 expression. This dual regulatory mechanism effectively restores the function of downstream proteins, activates intracellular protective mechanisms, and combats a variety of pathological processes, including aging, oxidative stress, inflammation, cell death, mitochondrial dysfunction, and metabolic disorders. It has shown broad prospects in the prevention and treatment of chronic diseases such as neurodegenerative diseases, cardiovascular diseases, degenerative bone and joint diseases, lung diseases, and metabolic disorders. Although HKL is a highly recognized SIRT3 activator, there is currently no comprehensive review systematically summarizing the research on HKL as a SIRT3 activator. This review comprehensively summarizes the research progress over the past decade since the discovery of HKL as a SIRT3 activator. Through in-depth analysis of the literature, we focused on elucidating the biological functions of HKL through SIRT3 activation in various disease models and the signaling pathways involved. These findings emphasize the therapeutic development value and significant application potential of HKL as a SIRT3 activator, providing a theoretical basis for the development of natural products that target SIRT3.

Aging is associated with cognitive decline, reduced hippocampal function, and decreased levels of brain-derived neurotrophic factor (BDNF) and orexin A -key regulators of neuroplasticity and energy balance. This study examined the chronic effects of intermittent fasting (IF), both alone and in combination with voluntary physical activity, on hippocampal orexin A, orexin receptor 1, and BDNF levels in middle-aged male Wistar rats. Over eight weeks, rats were divided into control (Con), IF, and IF with voluntary wheel running (IF+VA) groups. Behavioral assessments (open field, rotarod), biochemical analyses (Western blot, ELISA), and hippocampal weight measurements were conducted. IF significantly elevated hippocampal orexin A and BDNF levels compared to Con, with the IF+VA showing the most pronounced increases. Interestingly, orexin receptor 1 expression decreased in the IF+VA group, potentially indicating a negative feedback response or an alternative pathway. Moreover, a strong positive correlation between orexin A and BDNF levels suggests a possible causal relationship. The IF+VA group also showed improved motor learning and coordination as well as increased hippocampal/brain weight ratio. These findings indicate that combined fasting and voluntary physical activity may mitigate age-related cognitive and functional decline beyond IF alone by modulating orexinergic and BDNF signaling pathways, offering a potential role of the orexinergic system in the hippocampus.

Oxidative damage, primarily caused by reactive oxygen species (ROS), leads to the oxidation of cellular components, particularly in skeletal muscles. ROS accumulation in muscle fibers results in the oxidation of proteins, lipids, and nucleic acids, affecting the stability of muscle structure and function. Signaling pathways, including NF-κB, MAPK, Nrf2-ARE, PI3K-AKT, and p53 pathways, are intimately associated with oxidative stress. Understanding the impact of oxidative stress on skeletal muscles and the regulatory mechanisms of ncRNA on skeletal muscle oxidative stress is crucial for preventing muscle damage caused by oxidative stress. Oxidative stress mechanisms in skeletal muscles are intricate, and involve many regulatory factors and signaling pathways. NcRNAs play critical regulatory roles in these responses, but their specific functions and mechanisms require further research. Future research should explore in depth the interactions between ncRNAs and other molecules, providing new theoretical foundations and practical guidance for the prevention of muscle oxidative stress. This review summarizes current understanding of molecular mechanisms driving oxidative stress in skeletal muscle, with emphasis on regulatory networks mediated by ncRNAs. Future investigations should focus on multi-omics integration of ncRNA crosstalk with redox signaling pathways, potentially informing preventive strategies against muscle dysfunction in metabolic and aging-related conditions.

Living in a socioeconomically disadvantaged neighborhood is associated with worse health. However, the biological pathways underpinning this association remain unclear. Using 1388 adults from Researching Epigenetics, Weathering and Residential Disadvantage (REWARD), an ancillary study to the Survey of the Health of Wisconsin (SHOW), we examined the contribution of cumulative neighborhood disadvantage across the life course to racial and geographic disparities in epigenetic markers of biological aging. Results showed that urban Black adults experienced faster epigenetic aging than urban, suburban, and rural White adults across three epigenetic aging clocks. Approximately 37 % (GrimAge), 70 % (DunedinPACE), and 100 % (PhenoAge) of the White-urban Black disparities in epigenetic age acceleration were explained by differential exposure to cumulative neighborhood disadvantage over the life course. Interactions testing differential susceptibility to neighborhood disadvantage by race were not significant. In summary, differential exposure to cumulative neighborhood disadvantage over the life course, rather than differential biological response to these exposures, shapes racial and geographic disparities in epigenetic aging.

Cognitive decline associated with healthy ageing is multifactorial: brain-based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. In a pre-registered study (https://osf.io/6fqg7), we tested 73 healthy older adults aged 60-81 (M = 65.51, SD = 4.94) and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and cognitive data to investigate a prominent challenge for older adults: word-finding failures. fMRI signal was recorded while participants responded to a definition-based tip-of-the-tongue task, T1-weighted imaging estimated grey matter volume, and cerebral blood flow was indexed using multi-delay pseudo-continuous arterial spin labelling. Commonality analyses were used to analyse these multi-domain data (neuroimaging, cardiorespiratory fitness, language skills, demographic characteristics) and uncover associations between predictors in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness: the combination of higher cardiorespiratory fitness and functional recruitment in some older adults offsets part of the age-related variance in tip-of-the-tongues. Moreover, age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongues. Our findings can be interpreted in the context of the classic models of neurocognitive ageing, suggesting compensation. Brain health indices in concordance with cardiorespiratory fitness can provide a more holistic explanation of individual differences in age-related cognitive decline.

Histone deacetylase (HDAC) complexes regulate pathological gene programs during heart disease progression. The recently identified mitotic deacetylase complex (MiDAC), which includes DNTTIP1, ELMSAN1, and HDAC1/2, remains the least characterized among these complexes. ELMSAN1 has been implicated in left ventricular remodeling, and its global deletion in mice leads to heart malformation. To investigate its role in mouse heart, we generated cardiomyocyte-specific

Frailty and high triglyceride-glucose index (TyG) are independent risk factors for cardiovascular disease (CVD) and often coexist in middle-aged and older adults. This study aims to explore this influence in aging populations.

Resistance exercise, Taichi exercise, and the hybrid exercise program consisting of the two aforementioned methods have been demonstrated to increase the skeletal muscle mass of older individuals with sarcopenia. However, the exercise sequence has not been comprehensively investigated. Therefore, we designed a self-determined sequence exercise program, incorporating resistance exercises, Taichi, and the hybrid exercise program to overcome the decline of skeletal muscle area and reverse sarcopenia in older individuals.

Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.

Cohesin is a DNA tethering complex essential for chromosome structure and function. In fission yeast, defects in the cohesin loader Mis4 result in chromosome segregation defects and dysregulated expression of genes near chromosome ends. A genetic screen for suppressors of the thermosensitive growth defect of mis4-G1487D identified several hypomorphic mutants of the Target of Rapamycin Complex 1 (TORC1), a conserved kinase that integrates cellular signals to regulate growth and metabolism through substrate-specific phosphorylation. Here, we demonstrate that the TORC1 pathway modulates cohesin functions in chromosome segregation and gene expression. In the context of compromised cohesin loading, the incidence of chromosome segregation defects was modulated by the growth medium in a TORC1-dependent manner. Pharmacological or genetic down-regulation of TORC1 activity restored cohesin binding to its chromosomal sites and improved mitotic chromosome segregation. Notably, reduced TORC1 activity also increased cohesin binding and chromosome transmission fidelity in wild-type cells. These results suggest that environmental cues influence chromosome stability via TORC1. Biochemically, TORC1 co-purified with cohesin and reduced TORC1 activity correlated with decreased phosphorylation of specific residues on Mis4 and cohesin. Mutations in cohesin that mimic the non-phosphorylated state mirrored the effects of TORC1 downregulation, showing that TORC1 is part of the network that controls cohesin phosphorylation to modulate its functions. Finally, we show that the functional interaction between TORC1 and Mis4 extends to the regulation of stress-responsive genes. Our findings reveal a TORC1-cohesin link that may facilitate cellular adaptation to environmental changes. Given that TORC1 inhibitors and calorie restriction extend lifespan in diverse species, this connection raises the intriguing possibility that cohesin-mediated changes in chromosome structure contribute to these effects.