Longevity Papers

Biological age is an important measure of aging that reflects an individual's physical health and is linked to various diseases. Current prediction models are still limited in precision, and the risk factors for accelerated aging remain underexplored. Therefore, we aimed to develop a precise biological age and assess the impact of socio-demographic and behavioral patterns on the aging process.We utilized Deep Neural Networks (DNN) to construct biological age from participants with physical examinations, blood samples, and questionnaires data from the China Kadoorie Biobank (CKB) between June 2004 and December 2016. △age, calculated as the residuals between biological age and chronological age, was used to investigate the associations of age acceleration with diseases. Socio-demographics (gender, education attainment, marital status, household income) and lifestyle characteristics (body mass index [BMI], smoking, drinking, physical activity, and sleep) were also assessed to explore their impact on age acceleration. 18,261 participants aged 57 ± 10 years were included in this study. The DNN-based biological age model has demonstrated accurate predictive performance, achieving a mean absolute error of 3.655 years. △age was associated with increased risks of various morbidity and mortality, with the highest associations found for circulatory and respiratory diseases, with hazard ratios of 1.033 (95% CI: 1.023, 1.042) and 1.078 (95% CI: 1.027, 1.130), respectively. Socio-demographics, including being female, lower education, widowed or divorced, and low household income, along with behavioral patterns, such as being underweight, insufficient physical activity, and poor sleep, were associated with accelerated aging. Our DNN model is capable of constructing a precise biological age using commonly collected data. Socio-demographics and lifestyle factors were associated with accelerated aging, highlighting that addressing modifiable risk factors can effectively slow age acceleration and reduce disease risk, providing valuable insights for interventions to promote healthy aging.

Cells adjust their proteome to their environment. Most prominently, ribosome expression scales near linearly with the cellular growth rate to provide sufficient translational capacity while preventing metabolically wasteful ribosomal excess. In microbes, such proteome adjustments can passively perpetuate through symmetric cell division. However, in animals, a passive propagation is hindered by the separation between soma and germline. This separation raises the crucial question whether the proteome of animals is reset at every generation or can be propagated from parent to offspring despite this barrier. We addressed this question by exploring the intergenerational effects of dietary restriction in C. elegans, combining proteomics and live imaging. While most proteins showed no intergenerational regulation, ribosomal proteins remained reduced in offspring after maternal dietary restriction. When offspring of dietarily restricted mothers were raised under improved dietary conditions, this reduced ribosome content delayed their growth until normal ribosomal protein levels were restored. Soma-specific maternal inhibition of mTORC1 signalling replicated these effects, while other growth-reducing perturbations, such as reduced insulin signalling or maternal ribosome depletion, did not impact offspring ribosomes. Thus, mTORC1 signalling bridges across the soma-germline divide to regulate ribosome levels of the next generation, likely priming the offspring for the anticipated demand in protein synthesis.

The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.

Osteoporosis, a global health concern, poses an increasing challenge due to the aging population. While dual-energy X-ray absorptiometry (DXA) scans measuring bone mineral density (BMD) remain the clinical standard for osteoporosis diagnosis, this method's inability to detect changes in bone chemical composition limits its effectiveness in early diagnosis. This study applies Raman spectroscopy on examining bone aging in Senescence Accelerated Mouse Prone 6 (SAMP6) mice compared to their senescence-resistant controls (SAMR1) over an age period from 6 to 10 months. We performed Raman spectroscopic analysis on mouse tibiae both transcutaneously and on exposed bone. Leave-one-out cross-validation combined with partial least squares regression (LOOCV-PLSR) was applied to analyze Raman spectra to predict age, BMD, and maximum torque (MT) as determined by biomechanical testing. Our results revealed significant correlations between Raman spectroscopic predictions and reference values, particularly for age determination. To our knowledge, this study represents the first demonstration of transcutaneous Raman spectroscopy for accurate bone aging prediction, showing a strong correlation with established reference measurements.

In the subterranean rodent (Nanno)spalax galili, evolutionary adaptation to hypoxia is correlated with longevity and tumor resistance. Adapted gene-regulatory networks of Spalax might pinpoint strategies to maintain health in humans. Comparing liver, kidney and spleen transcriptome data from Spalax and rat at hypoxia and normoxia, we identified differentially expressed gene pathways common to multiple organs in both species. Body-wide interspecies differences affected processes like cell death, antioxidant defense, DNA repair, energy metabolism, immune response and angiogenesis, which may play a crucial role in Spalax's adaptation to environmental hypoxia. In all organs, transcription of genes for genome stability maintenance and DNA repair was elevated in Spalax versus rat, accompanied by lower expression of aerobic energy metabolism and proinflammatory genes. These transcriptomic changes might account for the extraordinary lifespan of Spalax and its cancer resistance. The identified gene networks present candidates for further investigating the molecular basis underlying the complex Spalax phenotype.

Aging is characterized by a decline in physiological functions and an increased susceptibility to age-related diseases. This study investigates the therapeutic potential of mesenchymal stem cells (MSCs) and pyrroloquinoline quinone (PQQ), individually and in combination, to counteract aging-related physiological declines, with a specific focus on their modulation of the AMP-activated protein kinase (AMPK) pathway, a key regulator of cellular energy homeostasis and stress response. Aging was induced in thirty-seven female rats using D-galactose, simulating the metabolic imbalances and oxidative stress characteristic of aging. The experimental groups included controls, aged rats without treatment, and aged rats treated with MSCs, PQQ, or a combined MSC-PQQ regimen. MSC homing analyses and Behavioral assessments, oxidative stress assays, gene expression profiling, histopathological evaluations were conducted to provide a multidimensional view of treatment efficacy. MSC homing confirmed successful tissue localization and repair, underscoring the regenerative capacity of MSCs. Remarkably, the combined MSC-PQQ therapy (APQQST) markedly improved anxiety-related behaviors, evidenced by increased rearing and grooming activities (p < 0.01). Oxidative stress biomarkers supported these findings; treated groups exhibited significantly reduced malondialdehyde (MDA) levels and elevated antioxidant defenses, including glutathione (GSH) and glutathione peroxidase (GPX) (p < 0.01). Gene expression analysis highlighted the beneficial upregulation of key genes such as LKB1, PFKFB3, TSC2, and HMGR, crucial for cellular energy homeostasis and stress response, with the combination therapy showing the most pronounced effects. Furthermore, histopathological assessments underscored significant liver tissue recovery in treated groups, particularly with combined treatment (APQQST), with minimal vacuolar degeneration and restored hepatic architecture (p < 0.01). These findings highlight the synergistic effects of MSCs and PQQ in mitigating behavioral, molecular, and physiological aspects of aging, underscoring their potential as promising therapeutic agents for promoting healthy aging and offering a foundation for future translational research and clinical applications.

Maternal age has been reported to impair oocyte quality. However, the molecular mechanisms underlying the age-related decrease in oocyte competence remain poorly understood. Cumulus cells establish direct contact with the oocyte through gap junctions, facilitating the provision of crucial nutrients necessary for oocyte development. In this study, we obtained the proteomic and metabolomic profiles of cumulus cells from both young and old mice. We found that fatty acid beta-oxidation and nucleotide metabolism, markedly active in aged cumulus cells, may serve as a compensatory mechanism for energy provision. Tryptophan undergoes two principal metabolic pathways, including the serotonin (5-HT) synthesis and kynurenine catabolism. Notably, we discovered that kynurenine catabolism is reduced in aged cumulus cells compared to young cells, whereas 5-HT synthesis exhibited a significant decrease. Furthermore, the supplement of 5-HT during cumulus-oocyte complexes (COCs) culture significantly ameliorated the metabolic dysfunction and meiotic defects in old oocytes. In sum, our data provide a comprehensive multiple omics resource, offering potential insights for improving oocyte quality and promoting fertility in aged females.

Reproductive aging in females is characterized by a decline in oocyte quantity and quality, as well as uterine and cervical dysfunction that contributes to infertility and pregnancy complications. To investigate mechanisms underlying reproductive aging, we explored the contribution of Spag17, a cilia-related gene associated with tissue homeostasis and fibrosis. Spag17 was expressed throughout the female reproductive tract; however, its expression declined with age in ovarian tissue, while high expression levels were observed in the cervix of young females during cervical tissue remodeling in the pre- and post-parturition periods. Loss of Spag17 in mice resulted in impaired fertility, obstructed labor, and maternal death. This phenotype was associated with accelerated ovarian aging, increased fibrosis, and cervical stiffness, further complicating parturition. At the molecular level, Spag17 loss activated key aging-associated pathways, including proinflammatory, profibrotic, and senescence signaling, suggesting that SPAG17 may be a critical player in female reproductive aging.

The intricate relationship between cancer, circadian rhythms, and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis and cancer progression. Aging is a well-established primary risk factor for cancer, while disruptions in circadian rhythms are intricately associated with the tumorigenesis and progression of various tumors. Moreover, aging itself disrupts circadian rhythms, leading to physiological changes that may accelerate cancer development. Despite these connections, the specific interplay between these processes and their collective impact on cancer remains inadequately explored in the literature. In this review, we systematically explore the physiological mechanisms of circadian rhythms and their influence on cancer development. We discuss how core circadian genes impact tumor risk and prognosis, highlighting the shared hallmarks of cancer and aging such as genomic instability, cellular senescence, and chronic inflammation. Furthermore, we examine the interplay between circadian rhythms and aging, focusing on how this crosstalk contributes to tumorigenesis, tumor proliferation, and apoptosis, as well as the impact on cellular metabolism and genomic stability. By elucidating the common pathways linking aging, circadian rhythms, and cancer, this review provides new insights into the pathophysiology of cancer and identifies potential therapeutic strategies. We propose that targeting the circadian regulation of cancer hallmarks could pave the way for novel treatments, including chronotherapy and antiaging interventions, which may offer important benefits in the clinical management of cancer.

Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.

Attentional states reflect the changing behavioral relevance of stimuli in one's environment, having important consequences for learning and memory. Supporting well-established cortical contributions, attentional states are hypothesized to originate from subcortical neuromodulatory nuclei, such as the basal forebrain (BF) and locus coeruleus (LC), which are among the first to change with aging. Here, we characterized the interplay between BF and LC neuromodulatory nuclei and their relation to two common afferent cortical targets important for attention and memory, the posterior cingulate cortex and hippocampus, across the adult lifespan. Using an auditory target discrimination task during functional MRI, we examined the influence of attentional and behavioral salience on task-dependent functional connectivity in younger (19-45 years) and older adults (66-86 years). In younger adults, BF functional connectivity was largely driven by target processing, while LC connectivity was associated with distractor processing. These patterns are reversed in older adults. This age-dependent connectivity pattern generalized to the nucleus basalis of Meynert and medial septal subnuclei. Preliminary data from middle-aged adults indicates a transitional stage in BF and LC functional connectivity. Overall, these results reveal distinct roles of subcortical neuromodulatory systems in attentional salience related to behavioral relevance and their potential reversed roles with aging, consistent with managing increased salience of behaviorally irrelevant distraction in older adults. Such prominent differences in functional coupling across the lifespan from these subcortical neuromodulatory nuclei suggests they may be drivers of widespread cortical changes in neurocognitive aging, and middle age as an opportune time for intervention.

Caloric restriction (CR) is a dietary intervention that delays the onset of age-related diseases and enhances survival in diverse organisms, and although changes in adipose tissues have been implicated in the beneficial effects of CR the molecular details are unknown. Here we show shared and depot-specific adaptations to life-long CR in subcutaneous and visceral adipose depots taken from advanced age male rhesus monkeys. Differential gene expression and pathway analysis identified key differences between the depots in metabolic, immune, and inflammatory pathways. In response to CR, RNA processing and proteostasis-related pathways were enriched in both depots but changes in metabolic, growth, and inflammatory pathways were depot-specific. Commonalities and differences that distinguish adipose depots are shared among monkeys and humans and the response to CR is highly conserved. These data reveal depot-specificity in adipose tissue adaptation that likely reflects differences in function and contribution to age-related disease vulnerability.

A significant challenge in multi-omic geroscience research is the collection of high quality, fit-for-purpose biospecimens from a diverse and well-characterized study population with sufficient sample size to detect age-related changes in physiological biomarkers. The Dog Aging Project designed the precision cohort to study the mechanisms underlying age-related change in the metabolome, microbiome, and epigenome in companion dogs, an emerging model system for translational geroscience research. One thousand dog-owner pairs were recruited into cohort strata based on life stage, sex, size, and geography. We designed and built a novel implementation of the REDCap electronic data capture system to manage study participants, logistics, and biospecimen and survey data collection in a secure online platform. In collaboration with primary care veterinarians, we collected and processed blood, urine, fecal, and hair samples from 976 dogs. The resulting data include complete blood count, chemistry profile, immunophenotyping by flow cytometry, metabolite quantification, fecal microbiome characterization, epigenomic profile, urinalysis, and associated metadata characterizing sample conditions at collection and during lab processing. The project, which has already begun collecting second- and third-year samples from precision cohort dogs, demonstrates that scientifically useful biospecimens can be collected from a geographically dispersed population through collaboration with private veterinary clinics and downstream labs. The data collection infrastructure developed for the precision cohort can be leveraged for future studies. Most important, the Dog Aging Project is an open data project. We encourage researchers around the world to apply for data access and utilize this rich, constantly growing dataset in their own work.

Menopause is a major biological transition that may influence women's late-life brain health. Earlier estrogen depletion-via earlier menopause-has been associated with increased risk for Alzheimer's disease (AD). Synaptic dysfunction also incites and exacerbates AD progression. We investigated whether age at menopause and synaptic health together influence AD neuropathology and cognitive trajectories using clinical and autopsy data from 268 female decedents in the Rush Memory and Aging Project. We observed significant interactions between age at menopause and synaptic integrity on cognitive decline and tau tangles, such that earlier menopause strengthened the associations of reduced synaptic integrity with faster cognitive decline and elevated tau. Exploratory analyses showed that these relationships were attenuated in women who took menopausal hormone therapy. These findings suggest that midlife endocrine processes or their sequalae may influence synaptic vulnerability to AD. Interventions addressing both hormonal factors and synaptic health could enhance resilience to dementia in women.

The aim of this study is to investigate the association between retinal age gap and multimorbidity. Retinal age gap was calculated based on a previously developed deep learning model for 45,436 participants. The number of age-related conditions reported at baseline was summed and categorized as zero, one, or at least two conditions at baseline (multimorbidity). Incident multimorbidity was defined as having two or more age-related diseases onset during the follow-up period. Linear regressions were fit to examine the associations of disease numbers at baseline with retinal age gaps. Cox proportional hazard regression models were used to examine associations of retinal age gaps with the incidence of multimorbidity. In the fully adjusted model, those with multimorbidity and one disease both showed significant increases in retinal age gaps at baseline compared to participants with zero disease number (β = 0.254, 95% CI 0.154, 0.354; P < 0.001; β = 0.203, 95% CI 0.116, 0.291; P < 0.001; respectively). After a median follow-up period of 11.38 (IQR, 11.26-11.53; range, 0.02-11.81) years, a total of 3607 (17.29%) participants had incident multimorbidity. Each 5-year increase in retinal age gap at baseline was independently associated with an 8% increase in the risk of multimorbidity (HR = 1.08, 95% CI 1.02, 1.14, P = 0.008). Our study demonstrated that an increase of retinal age gap was independently associated with a greater risk of incident multimorbidity. By recognizing deviations from normal aging, we can identify individuals at higher risk of developing multimorbidity. This early identification facilitates patients' self-management and personalized interventions before disease onset.

Mammalian cells undergo irreversible proliferation arrest when exposed to stresses, a phenomenon termed cellular senescence. Various types of stress induce cellular senescence; nonetheless, senescent cells show similar phenotypes overall. Thus, cells undergo cellular senescence through the similar mechanisms, regardless of the type of stress encountered. Here we aimed to reveal the mechanisms underlying cellular senescence. We have previously shown that lamin b receptor (LBR), which is a protein that regulates heterochromatin organization, was downregulated in senescent cells, and downregulation of LBR induced cellular senescence. Additionally, we have shown that downregulation of protein synthesis effectively suppressed cellular senescence. Thereby, chromatin organization and protein synthesis are implicated in the regulation of cellular senescence. We examined the roles of them in cellular senescence and found that protein synthesis was upregulated during the induction of cellular senescence, and upregulated protein synthesis caused disturbed proteostasis that led to the decreased function of LBR. Furthermore, we showed that decreased LBR function induced cellular senescence through altered chromatin organization and increased genome instability. Importantly, these findings revealed a link between protein synthesis and chromatin organization and accounted for the phenotypes of senescent cells which show disturbed proteostasis, altered chromatin organization, and increased genome instability. Our findings provided the general model for the mechanisms of cellular senescence.

INTRODUCTION: Cerebral small vessel disease (CSVD) is associated with an increased risk of cognitive impairment and dementia. Understanding the brain structural changes associated with CSVD is vital to meet the related health care demands effectively. This study focuses on assessing the integrity of gray matter in relation to CSVD within the general population. METHODS & RESULTS: We examined 2,603 participants (mean age 65 years) from the Hamburg City Health Study, who underwent neuropsychological evaluations and multi-modal neuroimaging. Advanced imaging techniques were used to assess the microstructural and macrostructural integrity of cortical and subcortical gray matter, including the hippocampus. Our findings indicate that the extent of CSVD is associated with abnormalities in gray matter diffusivity, myelin content, and morphology in specific brain regions including the anterior cingulate, insular and temporal cortices, caudate, putamen, pallidum, and hippocampus. Crucially, CSVD-related gray matter abnormalities were linked to cross-domain cognitive performance, represented by the first principal component of multi-domain cognitive test scores. DISCUSSION: Complementing previous research that focuses on CSVD and white matter changes, our study highlights abnormal gray matter integrity as a possible link between small vessel pathology and cognitive disorders. The insights gained can guide diagnostic and therapeutic strategies, supporting the advancement of interventions tailored to mitigate the impact of CSVD.

The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in C. elegans. Loss of wts-1/LATS resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.

The aging process results in structural, functional, and immunological changes in the brain, which contribute to cognitive decline and increase vulnerability to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and stroke-related complications. Aging leads to cognitive changes and also affect executive functions. Additionally, it causes neurogenic and neurochemical alterations, such as a decline in dopamine and acetylcholine levels, which also impact cognitive performance. The chronic inflammation caused by aging contributes to the impairment of the blood-brain barrier (BBB), contributing to the infiltration of immune cells and exacerbating neuronal damage. Therefore, rejuvenating therapies such as heterochronic parabiosis, cerebrospinal fluid (CSF) administration, plasma, platelet-rich plasma (PRP), and stem cell therapy have shown potential to reverse these changes, offering new perspectives in the treatment of age-related neurological diseases. This review focuses on highlighting the effects of rejuvenating interventions on neuroinflammation and the BBB.

Despite the classical view of senescence as passive growth arrest, senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program. However, the mechanisms underlying this metabolic reprogramming remain poorly understood. We have identified sin-lncRNA, a previously uncharacterized lncRNA, that plays a pivotal role in this response. Sin-lncRNA is only expressed by senescent cells, induced by the senescence master regulator C/EBP{beta}. While strongly activated in senescence, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) it facilitates its localization to the mitochondria. On the other hand, sin-lncRNA depletion results in DLST nuclear translocation linked to DLST-dependent transcriptional alteration of OXPHOS genes. While in highly proliferative cancer cells, sin-lncRNA expression remains undetected, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which a lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic rewiring specific to senescent cells.

Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.

The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific Translating Ribosome Affinity Purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young (6-10 month) and old (>21 month) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity and plasticity. Genes involved in serotonergic signaling were upregulated with age only in GABA neurons and not dopamine-releasing cells. In contrast, dopaminergic neurons showed alterations in genes connected with mitochondrial function and calcium signaling, which were markedly downregulated in male mice. Sex differences were detected in both neuron types, but in general were more prominent in dopamine neurons. Multiple sex effects correlated with the differential prevalence for neurodegenerative diseases such as Parkinson's and Alzheimer's seen in humans. In summary, these results provide insight into the connection between non-pathological aging and susceptibility to neurodegenerative diseases involving the ventral midbrain, and identify molecular phenotypes that could underlie homeostatic maintenance during normal aging.

Aging-related bone loss significantly impacts the growing elderly population globally, leading to debilitating conditions such as osteoporosis. Senescent osteocytes play a crucial role in the aging process of bone. This longitudinal study examines the impact of continuous local and paracrine exposure to senescence-associated secretory phenotype (SASP) factors on biophysical and biomolecular markers in osteocytes. Significant cytoskeletal stiffening in irradiated (IR) osteocytes are found, accompanied by expansion of F-actin areas and a decline in dendritic integrity. These changes, correlating with alterations in pro-inflammatory cytokine levels and osteocyte-specific gene expression, support the reliability of biophysical markers for identifying senescent osteocytes. Notably, local accumulation of SASP factors have a more pronounced impact on osteocyte biophysical properties than paracrine effects, suggesting that the interplay between local and paracrine exposure can substantially influence cellular aging. This study underscores the importance of osteocyte mechanical and morphological properties as biophysical markers of senescence, highlighting their time dependence and differential effects of local and paracrine SASP exposure. Collectively, the investigation into biophysical senescence markers offers unique and reliable functional hallmarks for the non-invasive identification of senescent osteocytes, providing insights that can inform therapeutic strategies to mitigate aging-related bone loss.

Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.