Longevity Papers

Chronological age is an imperfect estimate of molecular aging. Epigenetic age, derived from DNA methylation data, provides a more nuanced representation of aging-related biological processes. We examine the bidirectional relationship between epigenetic age and brain health events (stroke, dementia, late-life depression) using data from 4,018 participants. Participants with a prior brain health event are 4% epigenetically older (β = 0.04, SE = 0.01), indicating these conditions are associated with accelerated aging beyond that captured by chronological age. Additionally, a one standard deviation increase in epigenetic age is associated with 70% higher odds of experiencing a brain health event in the next four years (OR = 1.70, 95% CI = 1.16-2.50), suggesting epigenetic age acceleration is not just a consequence but also a predictor of poor brain health. Mendelian Randomization analyses replicate these findings, supporting their causal nature. Our results support using epigenetic age as a biomarker to evaluate interventions aimed at preventing and promoting recovery after brain health events.

Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.

Ferroptosis, a form of programmed cell death associated with lipid peroxidation and iron dependency, plays a critical role in affecting neuronal function in the aging-related neurodegenerative diseases. Macrophages, influenced by these changes, contribute significantly to the progression of aging nerve diseases. Induced neuronal reprogramming is an advanced technology, which can direct convert somatic cells, such as fibroblasts, into neurons, and offers a promising approach for drug screening aimed at correcting ferroptosis and combating aging-related nerve diseases. However, the efficiency of this reprogramming process remains a significant challenge. In this study, we aimed to manipulate macrophage phenotypes to enhance the direct conversion of fibroblasts into neurons. Specifically, we sought to correct ferroptosis through screening natural compounds using aged fibroblasts and utilizing macrophages to promote induced neuronal (iN) reprogramming. Our findings demonstrate that M2 macrophages effectively promote the direct reprogramming of fibroblasts into iNs. In a novel macrophage-fibroblast co-culture system, M2 macrophages facilitate iN reprogramming by reducing fibroblast adhesion forces and promoting asymmetric cell division. Furthermore, we discovered that manipulating matrix stiffness can induce polarization of macrophages towards the M2 phenotype, thereby enhancing fibroblast reprogramming into iNs. To facilitate these findings, we developed a mechano-cue-based drug screening chip, where soft hydrogels induced and maintained the phenotype of M2 macrophages and effectively promoted cell reprogramming. Using a combinatorial approach with 36 such chips, we screened natural compounds for their anti-aging properties, focusing on reversing fibroblast aging and inducing their conversion into neuronal cells. Notably, Vitexin, an apigenin flavone glycoside with a role as a platelet aggregation inhibitor, emerged as a promising candidate to achieve our therapeutic goals. This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases. KEY MESSAGE: This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases.

Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA sequencing on 13 tissues at six different ages in male and female African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset revealed varying strength of sex-age interactions across killifish tissues and age-altered genes and biological pathways that are evolutionarily conserved in mice and humans. We discovered a female-biased myeloid shift with age in the killifish hematopoietic organ, developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We showed the importance of sex-specific clocks for selected tissues, validated the tissue clocks with an independent transcriptomic dataset and used them to evaluate different lifespan interventions in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

Compensation has been proposed as a mechanism to explain how individuals in very old age remain able to maintain normal cognitive functioning. Previous studies have provided evidence on the role of increasing functional connectivity as a compensatory mechanism for age-related white matter damage. However, we lack direct investigation into how these mechanisms contribute to the preservation of cognition in the very old population. We examined a cohort of near-centenarians and centenarians without dementia (aged 95-103 years, n=44). We constructed a structural disconnection matrix based on the disruption of white matter pathways caused by white matter hyperintensities (WMHs), aiming to explore the relationship between functional connections, cognitive preservation and white matter damage. Our results revealed that structural damage can reliably explain the variations of functional connections or cognitive maintenance. Notably, we found significant correlations between the weights in the functional connectivity model and the weights in the cognition model. We observed positive correlations between models for brain disconnections and cognitive function in near-centenarians and centenarians. The strongest effects were found between attention and somatomotor network (SMN) (r=0.397, p<0.001), memory and SMN (r=0.333 p<0.001), fluency and visual network (VIS) - control network (CN) (r=0.406, p<0.001), language and VIS (r=0.309, p<0.001), visuospatial ability and VIS-default mode network (DMN) (r=0.464, p<0.001), as well as global cognition and VIS-DMN (r=0.335, p<0.001). These findings suggest that enhancement of functional connectivity may serve as a compensatory mechanism, such that it mitigates the effects of white matter damage and contributes to preserved cognitive performance in very old age.

Stress-induced premature senescence (SIPS) affects cellular functionality due to various stressors. In intervertebral disc degeneration (IVDD), nucleus pulposus (NP) cell dysfunction is crucial. Electroacupuncture (EA) has been used to alleviate low back pain and delay IVDD, but its potential mechanism is not yet well understood. The research was to explore EA's effect on SIPS in NP cells of degenerated intervertebral discs. Rabbits were subjected to axial compression for 28 days, and the modeling results were evaluated by Magnetic Resonance Imaging (MRI). After successful modeling, EA intervention was applied to the "Jiaji" acupoints (EX-B2) in the waist for 28 days. The comprehensive reaction scores of experimental rabbits, together with apoptosis, inflammation, and SIPS of NP cells were observed. Adeno-associated virus SIRT1-RNAi and p53 inhibitor Pifithrin-α (PFTα) were injected into degenerated intervertebral discs to reduce SIRT1 and p53 expressions, and the SIPS of NP cells was observed. The results showed that EA was effective in enhancing the comprehensive reaction ability of rabbits, improving the morphological structure of NP cells, inhibiting NP apoptosis, reducing inflammatory reactions, and delaying NP cell SIPS. Low expression of SIRT1 enhanced SIPS in NP cells, and EA inhibited the p53/p21 signaling pathway. In addition, EA could delay SIPS in NP cells by modulating the p53/p21 signaling pathway through SIRT1. This investigation provides original perspectives on the efficacy of EA as a modality for delaying IVDD. Nevertheless, additional research is warranted to firmly establish EA as a viable treatment for IVDD.

Relationships between ultraprocessed food (UPF) intakes and health have been well described in adults, but evidence of these relationships in older adults is rather limited. Demographic shifts in aging emphasize the importance of understanding the role of diet in maintaining health during later life.

Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. Here, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors, and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.

Environmental factors are linked to aging and age-related diseases. Emerging evidence suggests that enhancing body's resistance to xenobiotics might be an anti-aging strategy. The constitutive androstane receptor (CAR) regulates drug-metabolizing enzymes and transporters, coordinating metabolism and immune responses to adapt to stress triggered by exogenous exposure. However, the impact of activating CAR on aging remains unknown. In this study, Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice are used as models to explore the effects of CAR activation on lifespan and healthspan, along with the underlying mechanisms. The results showed that hCAR agonist CITCO and mCAR agonist TCPOBOP prolonged the lifespan and healthspan in model organism. The longevity effects of CITCO and TCPOBOP were attenuated in CAR homozygous nhr-8/daf-12 mutant C. elegans as well as CAR

Renal proximal tubular epithelial cell (PTEC) senescence and defective autophagy contribute to kidney aging, but the mechanisms remain unclear. Caveolin-1 (CAV1), a crucial component of cell membrane caveolae, regulates autophagy and is associated with cellular senescence. However, its specific role in kidney aging is poorly understood. In this study, we generated Cav1 gene knockout mice and induced kidney aging using D-galactose (D-gal). The results showed that CAV1 expression increased in the renal cortex of the aging mice, which was accompanied by exacerbated renal interstitial fibrosis, elevated levels of senescence-associated proteins γH2AX and p16

Sex differences in life span are widespread across animal taxa, but their causes remain unresolved. Alterations to the epigenome are hypothesized to contribute to vertebrate aging, and DNA methylation-based aging clocks allow for quantitative estimation of biological aging trajectories. Here, we investigate the influence of age, sex, and their interaction on genome-wide DNA methylation patterns in the brown anole (

Neurodegenerative diseases (NDDs) and other age-related disorders have been classically defined by a set of key pathological hallmarks. Two of these hallmarks, cell cycle dysregulation (CCD) and nucleocytoplasmic transport (NCT) defects, have long been debated as being either causal or consequential in the pathology of accelerated aging. Specifically, aberrant cell cycle activation in post-mitotic neurons has been shown to trigger neuronal cell death pathways and cellular senescence. Additionally, NCT has been observed to be progressively dysregulated during aging and in neurodegeneration, where the increased subcellular redistribution of nuclear proteins such as TAR DNA-Binding Protein-43 (TDP43) to the cytoplasm is a primary driver of many NDDs. However, the functional significance of NCT defects as either a primary driver or consequence of pathology, and how the redistribution of cell cycle machinery contributes to neurodegeneration, remains unclear. Here, we describe that pharmacological inhibition of importin-{beta} nuclear import is capable of perturbing cell cycle machinery both in mitotic neuronal cell lines and post-mitotic primary neurons in vitro. Our NemfR86S mouse model of motor neuron disease, characterized by nuclear import defects, further recapitulates the hallmarks of CCD in mitotic cell lines and in post-mitotic primary neurons in vitro, and in spinal motor neurons in vivo. The observed CCD is consistent with the transcriptional and phenotypical dysregulation observed in neuronal cell death and cellular senescence in NDDs. Together, this evidence suggests that impairment of nuclear import pathways resulting in CCD may be a common driver of pathology in neurodegeneration.

Whether adverse childhood experiences (ACEs) are associated with accelerated epigenetic aging over time among the Hispanic/Latino population remains unknown. This study examined the longitudinal association between ACEs and epigenetic age acceleration (EAA), as well as potential effect modifiers, among a sample of Hispanic/Latino adults.

Aging is associated with disrupted sleep patterns, such as fragmented sleep and reduced efficiency, leading to negative health outcomes. There is evidence of a bidirectional relationship between sleep and gut microbiota, which plays a key role in the gut-brain axis and overall health. However, studies on this relationship in older adults have limited generalizability and show conflicting results, highlighting the need for further research. This study aimed to investigate the associations between sleep quality and gut microbiota composition in healthy Chinese older adults using subjective and objective sleep measures to capture various aspects of sleep quality and explore potential impacts on emotional well-being and cognitive performance. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, while objective sleep quality was measured with actigraphy. Gut microbiota sequencing was performed on stool samples. The results show a robust positive association between gut microbiota richness and objective sleep quality in older adults, independent of subjective sleep quality and demographics, lifestyle, and health covariates. However, no significant link was found between gut microbiota richness and subjective sleep quality. Specific taxa like Bacteroidetes, Ruminococcus, Collinsella, Veillonella, and Holdemania were tentatively linked to sleep quality. These findings emphasize the connection between sleep quality and gut microbiota composition in older adults with potential research and clinical implications, improving our understanding of the mechanisms underlying the sleep-gut microbiota relationship and guiding the development of interventions for improving both sleep quality and gut health in older adults.

Regenerative capacity of skeletal muscles decreases with age. Deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) is associated with skeletal muscle weakness as well as epithelial cell senescence. However, whether and how CFTR plays a role in skeletal muscle regeneration and aging were unclear.

Age-related changes in adipose tissue impact chronic medical diseases and mobility disability but mechanism remains poorly understood. The goal of this study is to define methods for phenotyping unique characteristics of adipose tissue from older adults.

The purpose of this study was to advance our understanding of the neurobiology of healthy aging, which is crucial for improving quality of life and preventing age-related diseases. Despite its importance, a comprehensive investigation of this process has yet to be fully characterized.

This study investigated the relationship between olfactory impairment and frailty among 5,231 (mean age 75.3 (SD 5.0), 59% women, 22% Black) participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort located in the U.S.. Olfactory function, assessed from the 12-item Sniffin' Sticks Odor Identification Test at Visit 5 (2011-2013), was categorized as poor (0-8), moderate (9-10) and good (11-12). Frailty was assessed using both the Fried Frailty Phenotype and the Cumulative Frailty Index. Findings revealed that good olfaction was significantly associated with lower odds of frailty (OR=0.29, 95% CI [0.22, 0.39]) and prefrailty (OR= 0.52, 95% CI [0.45, 0.61]) in cross-sectional analyses. Results were robust to adjustment for all covariates. Longitudinal analyses, including 1,519 participants who were robust at study baseline, similarly showed a dose-response pattern, with improved olfaction associated with decreased odds of experiencing prefrailty (OR=0.63 95% CI [0.48, 0.83]) or frailty (OR=0.50, 95% CI [0.25, 1.02]). Further research is needed to elucidate the mechanisms linking olfaction and frailty and explore potential interventions.

A healthy nervous system is reliant upon an efficient transport network to deliver essential cargoes throughout the extensive and polarised architecture of neurons. The trafficking of cargoes, such as organelles and proteins, is particularly challenging within the long projections of neurons, which, in the case of axons, can be more than four orders of magnitude longer than cell bodies. It is therefore unsurprising that disruptions in axonal transport have been reported across neurological diseases. A decline in this essential process has also been identified in many aging models, perhaps compounding age-related neurodegeneration. Via intravital imaging, we recently determined that, despite a reduction in overall motility, the run speed and displacement of anterograde mitochondrial transport were unexpectedly enhanced in aged mouse peripheral nerves. Here, to determine how aging impacts a different axonal cargo, we evaluated in vivo trafficking of signalling endosomes in motor axons of mouse sciatic nerves from 3 to 22 months. Contrasting with mitochondria, we did not detect alterations in signalling endosome speed, but found a consistent rise in pausing that manifested after 18 months. We then treated muscles with brain-derived neurotrophic factor (BDNF), which regulates axonal transport of signalling endosomes in motor neurons; however, we observed no change in the processivity defect at 22 months, consistent with downregulation of the BDNF receptor TrkB at the neuromuscular junction. Together, these findings indicate that aging negatively impacts signalling endosome trafficking in motor axons likely through dampened BDNF signalling at the motor neuron-muscle interface.

Ageing is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD). Microglia, as the principal innate immune cells within the brain, exert homeostatic and active immunological defense functions throughout human lifespan. The age-related dysfunction of microglia is currently recognized as a pivotal trigger for brain diseases associated with aging. In AD, microglia exhibit alterations in gene expression, cellular morphology, and functional behavior. By focusing on the immunomodulatory functions of factors secreted by senescent microglia, such as cytokines, chemokines, complement factors, and reactive oxygen species (ROS), we explore the diverse detrimental effects of microglia in aging and AD pathogenesis, including Aβ accumulation, Tau deposition, synaptic dysfunction, and neuroinflammation. These collectively contribute to hastening the progression of. In this review, we highlight the key role of senescent microglia in the pathological processes of AD. Then we propose that targeting senescent microglia holds great promise for therapeutic interventions in neurodegenerative diseases.

Functional ability (FA), a key determinant of healthy aging, is determined by intrinsic capacity (IC), environmental factors, and their interactions. IC is a composite of physical and mental capacities that undergo constant change. Therefore, understanding the factors that influence IC requires a multi-level analysis of individuals to optimize its trajectory.

The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM

The polyamines putrescine, spermidine and spermine are ubiquitous metabolites synthesized in all cells. The intracellular levels of polyamines, especially spermidine, decrease in aging. Oral spermidine supplementation has been reported to alleviate aspects of age-related disease in animal models, including decline in learning and memory. The diverse health benefits of spermidine supplementation, often at doses that do not significantly alter spermidine levels of target organs, suggests that exogenous spermidine may have a common site of action, the gastrointestinal (GI) tract. To directly deliver spermidine to the GI tract with minimum impact on the global spermidine levels, we engineered the probiotic yeast Sacchromyces boulardii (Sb) to overproduce and secrete spermidine. We tested the effects of a spermidine-producing yeast strain (Sb576) on age-associated learning and memory decline in an olfactory classical conditioning in Drosophila melanogaster. Feeding of newly emerged adult flies [w1118(isoCJ1)] for 30 days with food supplemented with live Sb576, but not live wild-type Sb (SbWT) or free spermidine, reduced age-associated short-term memory (STM) decline. Notably, Sb576 supplementation, but not SbWT or spermidine supplementation, of either young flies or old flies for only three days also enhanced STM without affecting locomotive ability. Transcriptome analysis of the gut revealed relatively few (30) differentially overexpressed genes in the Sb576 group compared to the SbWT group including the gene coding neuropeptide Dh31, which has been implicated in memory in the flies. These results demonstrate that in situ production of spermidine by a synthetic biotic yeast in the GI tract can enhance STM, and further suggest a mechanism involving the gut-brain axis.

Lysosomes are digestive organelles that are crucial for nutrient sensing and metabolism. Lysosome impairment is linked to a broad spectrum of metabolic disorders, underscoring their importance to human health. Thus, lysosomes are an attractive target for metabolic disease therapies. In previous work, we discovered a novel class of tubular lysosomes that are morphologically and functionally distinct from traditionally described vesicular lysosomes. Tubular lysosomes are present in multiple tissues, are broadly conserved from invertebrates to mammals, are more proficient at degrading autophagic cargo than vesicular lysosomes, and delay signs of tissue aging when induced ectopically. Thus, triggering tubular lysosome formation presents one mechanism to increase lysosome activity and, notably, overproduction of the small lysosomal protein, SVIP, is a robust genetic strategy for triggering lysosomal tubulation on demand. In this study, we examine whether SVIP overexpression in the fly gut can suppress pathophysiological phenotypes associated with an obesogenic high-fat diet. Indeed, our results indicate that increasing SVIP expression in the fly gut reduces lipid accumulation, suppresses body mass increase, and improves survival in flies fed a high-fat diet. Collectively, these data hint that increasing lysosomal activity through induction of tubular lysosomal networks, could be one strategy to combat obesity-related pathologies.

The term early life stress encompasses traumatic events occurring before the age of 18 years, such as physical abuse, verbal abuse, household dysfunctions, sexual abuse, childhood neglect, child maltreatment, and adverse childhood experiences. Adverse psychological experiences in early life are linked to enduring effects on mental and physical health in adulthood. In this review, we first describe the effects and potential mechanisms of early life stress on the components of the vasculature. Next, we dive into the impact of early life stress on the vasculature across the lifespan through alterations of the epigenetic landscape. Finally, we consolidate the critical gaps in knowledge for focusing future research including the potential for resilience in combatting the impact of early life stress on vascular health.

Patched-related (Ptr) is a transmembrane protein implicated in developmental processes in Drosophila melanogaster, yet its precise role remains incompletely understood. Here, we use Ptr23c null mutants to investigate the functional significance of Ptr through the entire life cycle monitoring survival during embryonic, larval, pupal and adult development, and studying larval locomotion and muscle structure. We report that Ptr23c larvae displayed impaired hatching, indicative of defective embryonic development. Moreover, mutant larvae exhibited reduced mobility and lethargy, suggesting a potential involvement of Ptr in neuromuscular function. Morphological analysis of somatic muscles in mutant larvae revealed enlarged cell nuclei. Despite high pre-adult mortality, a subset of Ptr23c mutant adults display an unexpected extension in lifespan compared to controls, implicating Ptr in the regulation of longevity. Our findings provide critical insights into the multifaceted role of Ptr in Drosophila development, highlighting its contributions to post-embryonic survival, neuromuscular function, and lifespan regulation. This study underscores the significance of exploring broader genetic networks to unravel the complexities of developmental processes.

The DNA methylation-based epigenetic clocks are increasingly recognized for their precision in predicting aging and its health implications. Although prior research has identified connections between accelerated epigenetic aging and multiple sclerosis, the chronological and causative aspects of these relationships are yet to be elucidated. Our research seeks to clarify these potential causal links through a bidirectional Mendelian randomization study.

Research in aging often refers to animal models, particularly C57BL/6J (B6J) mice, considered gold standard. However, B6J mice are distributed by different suppliers, which results in divers substrains exhibiting notable phenotypic differences. To ensure a suitable phenotype of cardiac aging, we performed heart analyses of young (5 months) and old B6J mice (24 months) from two substrains: B6JRj (Janvier) and B6JCrl mice (Charles River). In hearts of both substrains, myocardial fibrosis increased with age; however, only in old B6JRj mice cardiac hypertrophy associated with a decreased ejection fraction was observed. Gene set enrichment analysis in heart tissue using proteomic data revealed different age-associated pathway changes between the substrains, especially in oxidative phosphorylation. Functional assessment of isolated cardiomyocytes verified cardiac impairment during aging in B6JRj mice. Overall, results demonstrate that cardiac aging manifests as a moderate systolic dysfunction in B6JRj mice, while B6JCrl mice display no functional changes with age.

Compared to our closest primate relatives, human life history involves greater longevity, which includes a distinctive postmenopausal life stage. Given mammalian reproductive physiology in which females build a finite stock of cells that can become oocytes early in life, which then continuously deplete mostly through cell death while males produce new sperm throughout adulthood, the postmenopausal stage makes the sex ratio in the fertile pool, called the adult sex ratio (ASR), male biased. Additionally, this affects a more fine-grained ratio, the operational sex ratio (OSR), defined as the ratio of males to females currently able to conceive. Here, we construct an ODE model in which males compete for paternities using either a multiple-mating or mate-guarding strategy. Our focus is on investigating the differences of strategy choice between populations with varying life histories, which include a distinct post-fertile stage for adult females. By simulating the system, we determine the dominant strategy and its dependence on various parameter combinations. Our results show that an increase in OSR and ASR correlates well with a change in the dominant strategy from multiple mating to guarding.

Age-related lung function decline is associated with small airway closure and gas trapping. The mechanisms which cause these changes are not fully understood. It has been suggested that COPD is caused by accelerated ageing. We have investigated pathological changes in the small airways during ageing, and evaluated whether the same or different processes exist in COPD. Histopathology and immunohistochemistry were used to examine small airway remodelling in healthy ageing, and then compare to age matched COPD patients. Ageing was associated with reduced alveolar attachment numbers (rho= -0.4 p = 0.049), increased epithelial area (rho = 0.5 p = 0.01), greater luminal narrowing due to epithelial expansion (rho = 0.5 p = 0.04) and increased alveolar septal neutrophils (rho = 0.6 p = 0.005). Compared to age matched controls, COPD small airways had 31% less alveolar attachments per airway (p = 0.02) and significantly more alveoalr septal neutrophils (p = 0.0007). Increased airway wall thickness was a feature of COPD but was not related to ageing in non-smokers. Alveolar attachment loss, accompanied by alveolar septum neutrophilic inflammation, and increased luminal narrowing due to epithelial expansion are major features of small airway remodelling during ageing. These features can explain the increased small airway narrowing and closure during ageing. Alveolar attachment loss is accelerated in COPD, likely due to increased neutrophilic inflammation.

The lifestyle intervention ProMuscle, which combines resistance exercise and an increased protein intake, was effective in improving muscle strength, muscle mass, and physical functioning in older adults. However, due to a growing shortage of health care professionals, the rapidly growing aging population cannot be personally guided in the future. Therefore, Uni2Move, a scalable web-based variant of ProMuscle, was designed to reach larger groups of older adults without putting additional burden on health care professionals.

Immunity declines with age. This results in a higher risk of age-related diseases, diminished ability to respond to new infections and reduced response to vaccines. The causes of this immune dysfunction are cellular senescence, which occurs in both lymphoid and non-lymphoid tissue, and chronic, low-grade inflammation known as 'inflammageing'. In this Review article, we highlight how the processes of inflammation and senescence drive each other, leading to loss of immune function. To break this cycle, therapies are needed that target the interactions between the altered tissue environment and the immune system instead of targeting each component alone. We discuss the relative merits and drawbacks of therapies that are directed at eliminating senescent cells (senolytics) and those that inhibit inflammation (senomorphics) in the context of tissue niches. Furthermore, we discuss therapeutic strategies designed to directly boost immune cell function and improve immune surveillance in tissues.

The bone marrow (BM) microenvironment plays a crucial role in regulating hematopoiesis, yet the molecular and functional changes associated with aging in humans remain poorly understood. Using single-cell RNA sequencing (scRNA-seq), we uncovered transcriptional shifts in BM endothelial cells (EC) and mesenchymal stem cells (MSC) during aging. Our analysis revealed that aged sinusoidal EC adopt a prothrombotic, exhibit mitochondrial dysfunction, and have compromised vascular function. Additionally, we identified a unique arterial EC subset, present only in aged individuals, associated with transcriptional elongation and senescence processes and characterized by RAB13 expression. MSC from aged subjects displayed an impaired matrix remodeling and epithelial-mesenchymal transition, driven partly by a subpopulation of THY1+ profibrotic stromal cells absent in young subjects. Aged MSC were also characterized by an increased ATP-oxidative metabolism and reduced protein folding capacity. Finally, using immunofluorescent imaging and spatial transcriptomics, we confirmed the presence of RAB13+ senescent EC in aged samples and revealed significant age-related changes in cell-cell communication within the BM niche. In summary, this work provides a comprehensive view of the molecular diversity, cellular interactions, and spatial organization of aged EC and MSC, offering novel insights and potential targets that could be exploited for preventing aged-associated changes in humans.

Potential pathways linking urban green spaces to improved health include relaxation, stress alleviation, and improved immune system functioning. Epigenetic age acceleration (EAA) is a composite biomarker of biological aging based on DNA methylation measurements; it is predictive of morbidity and mortality. This cross-sectional study of 116 adult residents of a metropolitan area in central North Carolina investigated associations between exposure to residential green spaces and EAA using four previously developed epigenetic age formulas. DNA methylation tests of white blood cells were conducted using Illumina MethylationEPIC v1.0 assays. EAA values were calculated as residuals from the linear regression model of epigenetic age on chronological age. Residential greenness was characterized using tree cover, total vegetated land cover, and normalized difference vegetation index (NDVI) data. An interquartile range (IQR) increase in distance-to-residence weighted average greenness within 500 m of residence was consistently associated with a reduced EAA adjusted for sociodemographic covariates, smoking status, white blood cell fractions, and the two-dimensional spline function of geographic coordinates. The reduction in the EAA estimates for the four EAA measures ranged from - 1.0 to - 1.6 years for tree cover, from - 1.2 to - 1.5 years for vegetated land cover, and from - 0.9 to - 1.3 years for the NDVI; 11 of the 12 associations were statistically significant (p < 0.05). This study produced new evidence linking reduced epigenetic aging to greater greenness near residences.

The protective effects of mangiferin (MAG) against etoposide- and high glucose (HG)-induced DNA damage and aging were investigated in human bone marrow-mesenchymal stem cells (hBM-MSCs). Etoposide, a topoisomerase II inhibitor, was used to induce double-strand breaks (DSBs) in hBM-MSCs, resulting in increased genotoxicity, elevated levels of the DNA damage sensor ATM and CDKN1A, and decreased levels of the aging markers H3 and H4. MAG activated AMPK and SIRT1, thus protecting against DSB-induced damage. Following long-term exposure to HG, MAG significantly mitigated DNA damage and delayed cellular aging, as evidenced by the preservation of H3, H4, LMNB1, and SIRT1 mRNA levels and reduction in γ-H2AX foci and DSBs. Furthermore, MAG improved genome stability, as indicated by decreased LINE1 expression and increased levels of the heterochromatin marker TRIM28, thereby maintaining H3K9me3 levels. MAG and metformin treatment enhanced cell proliferation, reduced senescence-associated β-galactosidase staining, and lowered the levels of the senescence-associated secretory phenotype factors IL-1A, IL-1B, IL-6, IL-8, CCL2, and CCL20 and senescence marker CDKN1A, CDKN2A and p53. MAG may reduce DNA damage and delay aging in hBM-MSCs under HG conditions, highlighting their potential as therapeutic agents for aging-related diseases.

Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.

The establishment of various molecular, physiological, and genetic markers for cellular senescence and aging-associated conditions has progressed the aging study. To identify such markers, a combination of optical, proteomic-, and sequencing-based tools is primarily used, often accompanying extrinsic labels. Yet, the tools for clinical detection at the molecular, cellular, and tissue levels are still lacking which profoundly hinders advancements in the specific detection and timely prevention of aging-related diseases and pathologies. Raman spectroscopy, with its capability for rapid, label-free, and non-invasive analysis of molecular compositions and alterations in aging cells and tissues, holds considerable promise for in vivo applications. In this review, we present recent advancements in the application of Raman spectroscopy to the study of aging in cells and tissues. We explore the use of Raman spectroscopy and related techniques for detecting cellular aging and senescence, focusing on the molecular alterations that accompany these processes. Subsequently, we provide a review of the application of Raman spectroscopy in identifying aging-related changes in various molecules within tissues and organs.

In the absence of telomerase, telomere shortening triggers the DNA damage checkpoint and replicative senescence, a potent tumor suppressor mechanism. Paradoxically, this same process is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics and genomic instability, we developed a system in Saccharomyces cerevisiae to generate and track the dynamics of telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as non-reciprocal translocations that result in re-elongation of the shortest telomere and likely escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival, explaining the contradictory roles of replicative senescence in oncogenesis.

Aging is a multi-organ disease, yet the traditional approach has been to study each organ in isolation. Such organ-specific studies have provided invaluable information regarding its pathomechanisms. However, an overall picture of the whole-body network (WBN) during aging is still incomplete. In this study, we analyzed the functional magnetic resonance imaging blood-oxygen level-dependent, respiratory rate and heart rate time series of a young and an elderly group during eyes-open resting-state. We constructed WBNs by exploring the time-lagged coupling between the different organs. First, we showed that our analytical pipeline could identify regional differences in the networks of both cohorts, allowing us to proceed with the remaining analyses. The comparison of the WBNs revealed a complex relationship where some connections were stronger and some weaker in the elderly. Finally, the interconnectivity and segregation of the WBNs were negatively correlated with the short-term memory and verbal learning of the young participants. This study: i) validated our methodology, ii) identified differences in the WBNs of the two groups and iii) showed correlations of WBNs with behavioral measures. In conclusion, the concept of WBN shows great potential for the understanding of aging and age-related diseases.

The aging of bone marrow mesenchymal stem cells (BMSCs) impairs bone tissue regeneration, contributing to skeletal disorders. LncRNA NEAT1 is considered as a proliferative inhibitory role during cellular senescence, but the relevant mechanisms remain insufficient. This study aims to elucidate how NEAT1 regulates mitotic proteins during BMSCs aging.

In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages. Finally, we discuss what analytic approaches are needed now that we have adequately sized case control analyses in white populations.

The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan (healthspan proteomic score (HPS)) using proteomic data from the Olink Explorer 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. The external validity was established using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explorer 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.

In the presence of stressful environments, the SKN-1 cytoprotective transcription factor is activated to induce the expression of gene targets that can restore homeostasis. However, chronic activation of SKN-1 results in diminished health and a reduction of lifespan. Here we demonstrate the necessity of modulating SKN-1 activity to maintain the longevity-promoting effects associated with genetic mutations that impair daf-2/insulin receptor signaling, the eat-2 model of dietary restriction, and glp-1-dependent loss of germ cell proliferation. A hallmark of animals with constitutive SKN-1 activation is the age-dependent loss of somatic lipids and this phenotype is linked to a general reduction in survival in animals harboring the skn-1gf allele. Surprisingly, daf-2lf; skn-1gf double mutant animals do not redistribute somatic lipids, which suggests the insulin signaling pathway functions downstream of SKN-1 in the maintenance of lipid distribution. As expected, the eat-2lf allele, which independently activates SKN-1, continues to display somatic lipid depletion in older ages with and without the skn-1gf activating mutation. In contrast, the presence of the skn-1gf allele does not lead to somatic lipid redistribution in glp-1lf animals that lack a proliferating germline. Taken together, these studies support a genetic model where SKN-1 activity is an important regulator of lipid mobilization in response to nutrient availability that fuels the developing germline by engaging the daf-2/insulin receptor pathway.

Environmental exposure such as cigarette smoke induces epigenetic changes that can induce degenerative heterogeneity and accelerate aging. In early age-related macular degeneration (AMD), the leading worldwide cause of blindness among the elderly, retinal pigment epithelial (RPE) cell heterogeneity is a key change. Since smoking is the strongest environmental risk factor for AMD, we hypothesized that cigarette smoke induces degenerative RPE heterogeneity through epigenetic changes that are distinct from aging, and that with aging, the RPE becomes vulnerable to cigarette smoke insult. We administered cigarette smoke condensate (CSC) intravitreally to young and aged mice and performed snRNA-seq and snATAC-seq on the RPE/choroid. This analysis identified separate cell clusters corresponding to healthy and abnormal, dedifferentiated RPE in both aged vehicletreated and young CSC-treated mice. The dedifferentiated RPE were characterized by a global decrease in chromatin accessibility and decreased expression of genes in functional categories that were linked to hallmarks of aging. Notably, young, dedifferentiated RPE also exhibited a compensatory upregulation of hallmarks of aging-related genes, specifically those related to mitochondrial function and proteostasis. In contrast, aged dedifferentiated RPE did not express these compensatory changes, and did not survive CSC treatment, as experimentally verified with TUNEL labeling. These changes are relevant to early AMD because we identified through scRNA-seq, similar dedifferentiated and healthy macular RPE clusters in a donor who smoked and another with early AMD, but not from a nonsmoker. Degenerative cellular heterogeneity can include an abnormal cluster that jeopardizes cell survival and may represent an additional hallmark of ocular aging.

Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. Using Mendelian Randomization (MR), we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth were also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease (LOAD), type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease (COPD). We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age 11 and childbirth before 21 significantly accelerated the risk of several diseases, and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory. We identified 126 significant single nucleotide polymorphisms (SNPs) that influenced age-related outcomes, some of which were involved in known longevity pathways, including IGF1, growth hormone, AMPK, and mTOR signaling. Our study also identified higher BMI as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy, emphasizing the importance of the thrifty gene hypothesis in explaining in part the mechanisms behind antagonistic pleiotropy. Our study highlights the complex relationship between genetic legacies and modern diseases, emphasizing the need for gender-sensitive healthcare strategies that consider the unique connections between female reproductive health and aging.

Human embryonic stem cells (hESCs) and their extracellular vesicles (EVs) hold significant potential for tissue repair and regeneration. Neural stem cells (NSCs) in the adult brain often acquire senescent phenotypes after ischemic injuries, releasing neurodegenerative senescence-associated secretory phenotype factors. In this study, we investigated the senotherapeutic effects of hESC-EVs on NSCs and confirmed their neuroprotective effects in neurons via rejuvenation of NSC secretions. Proteomic profiling of hESC-EVs identified MFGE-8 as a critical bridging molecule to NSCs. We also found that the glutathione (GSH) redox system is a key contributor to the therapeutic antioxidant activity of hESC-EVs. Additionally, EVs produced by the hypoxic preconditioning of hESCs (hESC-HypoxEVs) exhibited reinforced GSH redox capacity and further enhanced the senotherapeutic effects on NSCs compared to naïve hESC-EVs. We also demonstrated that administration of hESC-HypoxEVs, precoated with MFGE-8, significantly increased the populations of NSCs and newborn neurons in the subventricular zone of the brain and improved sensorimotor functions in a rat model of ischemic stroke. Our study suggests that combining hESC-HypoxEVs with MFGE-8 may serve as an effective therapeutic modality for reversing senescence and enhancing the neurogenic potential of NSCs to treat neurodegenerative diseases.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin, a mutant variant of lamin A. Progerin anchors aberrantly to the nuclear envelope disrupting a plethora of cellular processes, which in turn elicits senescence. We previously showed that the chromosomal region maintenance 1 (CRM1)-driven nuclear export pathway is abnormally enhanced in patient-derived fibroblasts, due to overexpression of CRM1. Interestingly, pharmacological inhibition of CRM1 using leptomycin B rescues the senescent phenotype of HGPS fibroblasts, delineating CRM1 as a potential therapeutic target against HGPS. As a proof of concept, we analyzed the beneficial effects of pharmacologically modulating CRM1 in dermal fibroblasts from HGPS patients and the LMNA

Telomere length is an important indicator of biological age and a complex multi-factor trait. To date, the telomere interactome for comprehending the high-dimensional biological aspects linked to telomere regulation during childhood remains unexplored. Here we describe the multi-omics signatures associated with childhood telomere length.

Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.

The objective of this study is to explore how adipose-derived stem cells (ASCs) regulate mitochondrial structure and function and the impact of this regulation on slowing cellular senescence. HFF-1 cells were induced by H

Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they can serve as reference genes in expression studies. Reference genes have mostly been identified and validated in young organisms, and no systematic investigation has been done across the lifespan. Here, we build upon a common pipeline for identifying reference genes in RNA-seq datasets to identify age-invariant genes across seventeen C57BL/6 mouse tissues (brain, lung, bone marrow, muscle, white blood cells, heart, small intestine, kidney, liver, pancreas, skin, brown, gonadal, marrow, and subcutaneous adipose tissue) spanning 1 to 21+ months of age. We identify 9 pan-tissue age-invariant genes, and many tissue-specific age-invariant genes. These genes are stable across the lifespan and are validated in independent bulk RNA-seq datasets and RT-qPCR. Age-invariant genes have shorter transcripts and are enriched for CpG islands. Interestingly, pathway enrichment analysis for age-invariant genes identifies an overrepresentation of molecular functions associated with some, but not all, hallmarks of aging. Thus, even though hallmarks of aging typically involve change, select genes associated with these hallmarks resist age-related change. Finally, our analysis provides a list of murine tissues where classical reference genes are appropriate for application in aging studies. However, no classical reference gene is appropriate across all aging tissues. Instead, we provide novel tissue-specific and pan-tissue reference genes for assays utilizing gene normalization (RT-qPCR) that can be applied to mice across the lifespan.

Repetitive transcranial magnetic stimulation (rTMS) is acknowledged for its critical role in modulating neuronal excitability and enhancing cognitive function. The dentate gyrus of the hippocampus is closely linked to cognitive processes; however, the precise mechanisms by which changes in its excitability influence cognition are not yet fully understood. This study aimed to elucidate the effects on granule cell excitability and the effects on cognition of high-frequency rTMS in naturally aging mice, as well as to investigate the potential interactions between these two factors. It was observed that 20 Hz high-frequency rTMS attenuated granule cell loss in aged mice, demonstrating both cumulative and real-time effects on neural excitability. Importantly, this intervention significantly ameliorated age-related cognitive decline. The findings suggest that one of the potential mechanisms underlying the amelioration of age-related cognitive decline through high-frequency rTMS may involve the attenuation of granule cell apoptosis and the enhancement of their neural excitability.

Autophagy is a housekeeping catabolic process crucial for maintaining cell, tissue and organism functions. Through the years, the study of animal models with tissue-specific inactivation of autophagy essential genes has allowed us to understand its protective roles in the context of multiple human diseases, including cancer and neurodegeneration. However, due to the essential nature of autophagy, the effects of its systemic inhibition in mammals have not been explored in detail. Here, we report the generation of ATG4A-only mice, simultaneously deficient for three of the four mammalian ATG4 proteases (ATG4B, ATG4C and ATG4D). Through extensive characterization of ATG4A-only cells, which show a severe (albeit not complete) deficiency in autophagic activity, we define the specific roles of ATG4A protease towards ATG8 proteins (its physiological substrates), shedding some light into the evolutionarily-acquired complexity of mammalian ATG4-ATG8 system. Moreover, we show that the profound whole-body autophagy deficiency of ATG4A-only mice not only impacts the function of multiple tissues, but also leads to the development of an accelerated aging phenotype, characterized by the accumulation of genetic damage, systemic senescence, and premature death. Thus, through the analysis of ATG4A-only mice and other murine models deficient for ATG4 proteases, we do not only provide new insights on how autophagy maintains cell, tissue, and organismal homeostasis, but also show for the first time that the degree of autophagic competency ultimately emerges as a critical determinant of organismal longevity.

Protein aggregates are spatially organized and regulated in cells to prevent deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) result in aggregate formation, but how the aggregates are processed especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation and ER reorganization but was independent of the anaphase-promoting complex (APC/C). Thus, dividing cells have the capacity to clear protein aggregates to maintain proteostasis in the newly divided cells, which could have implications for human disease development and aging.

Information theory has long been integrated into the study of biological aging, for example in examining the roles of genetic and epigenetic fidelity in cellular and organismal longevity. Here, we introduce a theoretical model that interprets aging in multicellular systems through the lens of Fisher information. Previous theories have suggested that the aging of multicellular organisms is an inevitable consequence of the inherent tension between individual cell reproduction and the homeostasis of the multicellular system. Utilizing concepts from information theory and statistical mechanics, we show that Fisher information parametrizes the dynamics of this tension through non-monotonic behaviour which depends on an optimal balance of competition and cooperation between cells. Moreover, Fisher information suggests that the ability to infer true biological age from a sample evolves through complex dynamics over an organisms lifespan.

LINE-1 (L1) and Alu are two families of transposable elements (TEs) occupying ~17% and ~11% of the human genome, respectively. Though only a small fraction of L1 copies is able to produce the machinery to mobilize autonomously, Alu and degenerate L1s can hijack their functional machinery and mobilize in trans. The expression and subsequent mobilization of L1 and Alu can exert pathological effects on their hosts. These features have made them promising focus subjects in studies of aging where they can become active. However, mechanisms regulating TE activity are incompletely characterized, especially in diverse human populations. To address these gaps, we leveraged genomic data from the 1000 Genomes Project to carry out a trans-ethnic GWAS of L1/Alu insertion singletons. These are rare, recently acquired insertions observed in only one person and which we used as proxies for variation in L1/Alu insertion numbers. Our approach identified SNVs in genomic regions containing genes with potential and known TE regulatory properties, and it enriched for SNVs in regions containing known regulators of L1 expression. Moreover, we identified reference TE copies and structural variants that associated with L1/Alu singletons, suggesting their potential contribution to TE insertion number variation. Finally, a transcriptional analysis of lymphoblastoid cells highlighted potential cell cycle alterations in a subset of samples harboring L1/Alu singletons. Collectively, our results suggest that known TE regulatory mechanisms may be active in diverse human populations, expand the list of loci implicated in TE insertion number variability, and reinforce links between TEs and disease.

Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.

Autophagy is the cellular processes that transport cytoplasmic components to lysosomes for degradation. It plays essential physiological roles, including in adaptation to environmental changes such as starvation and maintaining intracellular quality control. Recently, its links to aging and disease have garnered substantial attention. Although various methods to measure autophagic activity (autophagic flux) have been developed, accurate measurement remains challenging and often contentious. This review presents a discussion of techniques to measure the flux of autophagy, particularly macroautophagy, utilizing two contrasting approaches-assaying cargo degradation versus assaying the generation of degradation products-with an emphasis on the advantages of the latter.

Motor neurons (MNs) within the nucleus ambiguus innervate the skeletal muscles of the larynx, pharynx and oesophagus, which are essential for swallow. Disordered swallow (dysphagia) is a serious problem in elderly humans, increasing the risk of aspiration, a key contributor to mortality. Despite this importance, very little is known about the pathophysiology of ageing dysphagia and the relative importance of frank muscle weakness compared to timing/activation abnormalities. In elderly humans and in aged Fisher 344 (F344) rats, a variety of motor pools exhibit weakness and atrophy (sarcopenia), contemporaneous to MN death. Synchronisation of swallow is dependent on the stability of MN dendrites, which integrate neural circuits. Dendritic derangement occurs in many neuromotor degenerative conditions prior to MN death. We hypothesise behavioural weakness and death of nucleus ambiguus MNs will occur by age 24 months in F344 rats and that this will be preceded by swallow-respiration dyscoordination and dendritic arbour degenerations from 18 months compared to controls at 6 months. Using pressure catheters to estimate laryngeal and diaphragm function during naturalistic water bolus applications, we show that swallow number and post-swallow apnoeas are altered from 18 months. Swallow pressure (weakness) and nucleus ambiguus MN numbers (evaluated via stereological assessments of Nissl staining) were reduced at 24 months. Dendritic lengths, surface areas and dendritic spines were reduced in nucleus ambiguus MNs from 18 months (evaluated by confocal imaging of Golgi-Cox impregnated brainstem). These results show that synapse loss occurs prior to MN death and behavioural weakness. Strategies to preserve synapses may be of utility in ameliorating sarcopenia. KEY POINTS: Dysphagia is a major contributor to ageing morbidity and mortality, but the underling pathophysiology is unexplored. Here, in Fischer 344 rats, we use pressure and timing evaluations of swallow-respiration, showing timing impairments occur prior to frank pressure defects. In nucleus ambiguus motor neurons, dendritic defects were apparent with the onset of swallow-respiration dyscoordination, with frank motor neuron loss occurring subsequently to synapse loss. Our results show that synapse loss occurs prior to motor neuron death and behavioural impairments. Strategies to preserve synapses may be of utility in ameliorating sarcopaenia.

The space environment presents unique stressors, such as microgravity and space radiation, which can induce molecular and physiological changes in living organisms. To identify key reproducible transcriptomic features and explore potential biological roles in space-flown C. elegans, we integrated transcriptomic data from C. elegans subjected to four spaceflights aboard the International Space Station (ISS) and identified 32 reproducibly differentially expressed genes (DEGs). These DEGs were enriched in pathways related to the structural constituent of cuticle, defense response, unfolded protein response, longevity regulation, extracellular structural organization, and signal receptor regulation. Among these 32 DEGs, 13 genes were consistently downregulated across four spaceflight conditions, primarily associated with the structural constituent of the cuticle. The remaining genes, involved in defense response, unfolded protein response, and longevity regulation pathway, exhibited distinct patterns depending on spaceflight duration: they were downregulated during short-term spaceflights but upregulated during long-term spaceflights. To explore the potential space stressors responsible for these transcriptomic changes, we performed qRT-PCR experiments on C. elegans exposed to simulated microgravity and low-dose radiation. Our results demonstrated that cuticle-related gene expression was significantly downregulated under both simulated microgravity and low-dose radiation conditions. In contrast, almost all genes involved in defense response, unfolded protein response, and longevity regulation pathway were downregulated under simulated microgravity but upregulated under low-dose radiation exposure. These findings suggest that both microgravity and space radiation inhibit cuticle formation; microgravity as the primary stressor inhibit defense response, unfolded protein response, and longevity regulation pathway during short-term spaceflights, while space radiation may promote these processes during long-term spaceflights. In summary, through integrated spaceflight transcriptomic analyses and simulated space experiments, we identified key transcriptomic features and potential biological functions in space-flown C. elegans, shedding light on the space stressors responsible for these changes. This study provides new insights into the molecular and physiological adaptations of C. elegans to spaceflight, highlighting the distinct impacts of microgravity and space radiation.

INTRODUCTION: More intermuscular fat (IMF) has been associated with lower cognitive performance and faster age-associated decline in cognitive function however, the mechanisms driving this relationship have not been fully elucidated. We utilized proteomic analyses to identify the molecular mediators of the association between IMF and cognition to gain further insight into the mechanisms underlying this association. METHODS. In this cross-sectional study, the plasma proteomic profile of IMF was assessed in the Baltimore Longitudinal Study on Aging (BLSA; n=941, age=66.7+/-15.2) and validated in the Coronary Artery Risk Development in Young Adults Study (CARDIA; n=2451, age=50.2+/-3.6). The 7628 plasma proteins were assessed using an aptamer-based assay and tested for association with IMF from the thigh (BLSA) and abdomen (CARDIA). Processing speed assessed by Digit Symbol Substitution Test (DSST). Associations between the main exposures, outcome and mediators were evaluated using linear regression, and mediating effects were assessed by causal mediation analysis adjusting for age, sex, muscle area or muscle volume, self-reported race, and years of education. RESULTS. Higher IMF was associated with lower DSST performance both in the BLSA and CARDIA studies. There were 722 plasma proteins associated with IMF in both the discovery and replication cohorts (FDR-adjusted p<=0.05). Of the 722 IMF -associated proteins, 26 (24 unique proteins) mediated the relationship between IMF and processing speed with mediation effects ranging from 2.8 to 20.9% (p<=0.05). Overrepresentation analysis of the IMF-associated proteins showed enrichment of proteins in synaptic function and organization, and growth factor binding (FDR-adjusted p<=0.05). DISCUSSION. There is a robust proteomic signature explaining, at least in part, the link of IMF with DSST. This signature reflected neurological function and growth factor regulation, which are both implicated in lower processing speed. Reducing IMF through behavioral or pharmacological intervention may improve cognition through reduction in growth factor activity and improvements in synaptic activity.

Age-related cataracts (ARCs) are associated with increased oxidative stress and cellular senescence. Our objective is to investigate the function of Sirtuin 1 (SIRT1) within ARCs. In ARCs tissues and H