Longevity Papers

Stem cells possess an extraordinary ability for self-renewal and differentiation, making them essential for tissue repair, regeneration, and anti-aging. RNA methylation is crucial in regulating stem cell fate by modulating gene expression. This review synthesizes current research on RNA methylation modifications, such as m

Aging is a complex, universal process characterized by structural and functional decline across multiple organs. Ganoderma lucidum (G. lucidum), a renowned traditional Chinese medicinal fungus, has long been recognized for its anti-aging properties. However, the underlying mechanisms remain incompletely understood.

Advanced age increases the prevalence of rotator cuff tears and affects the success of repair surgeries. Cellular senescence is proposed as a key mechanism behind these age-related differences, likely due to contribution of the senescence-associated secretory phenotype. This state is linked to various age-related diseases, including rotator cuff injuries.

Middle-aged adults who are parents have better average cognitive performance and lower average brain age compared with middle-aged adults without children, raising the possibility that caregiving slows brain aging. Here, we investigate this hypothesis in two additional groups of caregivers: grandmothers and caregivers for people living with dementia (PLWD). Demographic, questionnaire, and structural MRI data were acquired from n=50 grandmothers, n=24 caregivers of PLWD and n=37 non-caregiver controls, and BrainAge was estimated. BrainAge estimation results suggest that after controlling for relevant covariates, grandmothers had a brain age that was 5.5 years younger than non-grandmother controls, and caregivers of PLWD had brains that were 4.7 years younger than non-caregiver controls. Women who became grandmothers at a later age had lower brain age than those who became grandmothers at an earlier age. Among caregivers of PLWD, stress and caregiving burden were associated with increased brain age, such that the beneficial effect of caregiving on brain age was reduced in caregivers reporting more burden. Our findings suggest that caring for dependents may slow brain aging.

Growth differentiation factor-15 (GDF15) is a biomarker of multiple disease states and circulating GDF15 levels are increased during aging in both pre-clinical animal models and human studies. Accordingly, multiple stressors have been identified, including mitochondrial dysfunction, that lead to induction of Gdf15 expression downstream of the integrated stress response (ISR). For some disease states, the source of increased circulating GDF15 is evident based on the specific pathology. Aging, however, presents a less tractable system for understanding the source of increased plasma GDF15 levels in that cellular dysfunction with aging can be pleiotropic and heterogeneous. To better understand which organ or organs contribute to increased circulating GDF15 levels with age, and whether changes in metabolic and mitochondrial dysfunction were associated with these potential changes, we compared young 12-week-old and middle-aged 52-week-old C57BL/6 J mice using a series of metabolic phenotyping studies and by comparing circulating levels of GDF15 and tissue-specific patterns of Gdf15 expression. Overall, we found that Gdf15 expression was increased in skeletal muscle but not liver, white or brown adipose tissue, kidney or heart of middle-aged mice, and that insulin sensitivity and mitochondrial respiratory capacity were impaired in middle-aged mice. These data suggest that early changes in skeletal muscle mitochondrial function and metabolism contribute to increased circulating GDF15 levels observed during aging.

This study aimed to explore the association between serum omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and biological aging, along with the potential mediating role of systemic immune inflammation (SII).

Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.

Osteoporosis arising from estrogen deficiency is characterized by oxidative stress and cellular senescence accompanied by calcium loss and disrupted bone metabolism. The paracrine interaction between osteoblasts and osteoclasts, along with the ratio of receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG), play a pivotal role in maintaining bone homeostasis. Eldecalcitol (ED-71), a novel active form of vitamin D, can reduce the ratio of RANKL to OPG in osteoblasts. In this study, an ovariectomized (OVX) rat model was established in vivo, and a cell model was constructed in vitro using H₂O₂ to explore the specific mechanism by which ED-71 improved the release of RANKL/OPG in senescent osteoblasts. Mitochondrial dysfunction and calcium imbalance were identified as significant factors. Under oxidative stress conditions, ED-71 alleviated endoplasmic reticulum (ER) stress by decreasing the ratio of phosphorylated protein kinase R-like ER kinase (P-PERK/PERK), and augmented the expression levels of sarcoplasmic reticulum/endoplasmic reticulum calcium ATPase 2 (SCERA2) thereby promoting calcium uptake by the ER, enhancing ER calcium influx, and effectively ameliorating calcium homeostasis between the ER and mitochondria. Consequently, it mitigates mitochondrial calcium overload and associated dysfunction. In contrast, ED-71 increased the expression of silent information regulator 1 (SIRT1) and phosphorylated AMP-activated protein kinase (P-AMPK). This alleviates mitochondrial dysfunction and promotes adenosine triphosphate (ATP). The combined effects of these two factors synergistically contribute to the improvement in osteoblast senescence.

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.

Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.

Diabetic wound healing remains a significant clinical challenge because of hyperglycaemia-induced cellular senescence, impaired angiogenesis, and chronic inflammation. To address these issues, we developed a multifunctional hydrogel (GelMA/PNS/Alg@IGF-1) that integrates gelatine methacryloyl (GelMA), Panax notoginseng saponins (PNS), and sodium alginate microspheres encapsulating insulin-like growth factor-1 (IGF-1). This hydrogel was engineered to achieve gradient and sustained release of bioactive agents to target senescence and promote vascular repair. In vitro studies demonstrated that the hydrogel significantly reduced oxidative stress, suppressed senescence markers and senescence-associated secretory phenotypes, and restored endothelial cell function under high-glucose conditions by inhibiting NF-κB pathway activation. Transcriptomic analysis revealed the modulation of pathways linked to inflammation, apoptosis, and angiogenesis. This hydrogel accelerated diabetic wound closure in a rat model in vivo and enhanced collagen deposition, granulation tissue formation, and neovascularization. Furthermore, the hydrogel mitigated oxidative stress and cellular senescence and promoted tissue remodelling. The synergistic effects of PNS and IGF-1 within the hydrogel established a pro-regenerative microenvironment to address both pathological ageing and vascular dysfunction. These findings highlight GelMA/PNS/Alg@IGF-1 as a promising therapeutic platform for diabetic wound management, as this material offers dual anti-senescence and proangiogenic efficacy to overcome the complexities of chronic wound healing.

The development of the human brain is a complex, lifelong process during which collective behaviors of neurons exhibit self-organizing dynamics. Metastable states play a crucial role in understanding the complex dynamical mechanisms of the brain, and analyzing them helps to reveal the mechanisms of functional changes in the brain throughout development and aging. Specifically, global metastable state provides a overall perspective on the flexibility of brain reorganization, while the evolution trajectories of transient functional patterns capture detailed changes in brain activity. The leading eigenvector dynamics analysis (LEiDA) method significantly reduces the dimensionality of data and is widely used to capture the temporal trajectory characteristics of transient functional patterns, i.e., metastable brain states. However, LEiDA's linear dimensionality reduction of high-dimensional raw brain data may overlook non-linear information and lose some relationships between features. We developed a framework based on Phase Coherence Graph Autoencoder (PCGAE) that employs graph autoencoders (GAE) for non-linear dimensionality reduction of phase coherence matrices. This approach clusters to identify more distinct metastable brain states and is applied to the analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data across the human lifespan. This paper investigates age-related differences and continuity changes from different perspectives: metastable state indicators and state trajectory indicators (occurrence probability, lifetime, and state transition metrics). Global metastable state shows a linear decline with age, while both linear and quadratic effects of age-related changes are observed in detailed state metastable and state trajectory indicators. Finally, the proposed feature extraction scheme demonstrates good classification performance for categorizing brain age groups. These findings can help us understand the self-organizing reorganization characteristics associated with aging and their complex dynamic changes, providing new insights into brain development throughout the entire lifespan.

Natural polysaccharides as the primary active components derived from herbal medicine often face challenges due to their large molecular weights, varying chemical structures and poor bioavailability, which significantly restrict their bioactive mechanism investigation and clinical applications. To improve the bioavailability and clarify the antiaging mechanism of polysaccharides from Polygoni Multiflori Radix Praeparata, the high-molecular-weight polysaccharides (PRP) were hydrolyzed into two low-molecular-weight fractions (PRP1 and PRP2) by hydrogen peroxide-ascorbic acid method. The results of structural characterization showed that they were glucans with the molecular weights of 13.43 kDa and 5.97 kDa, respectively. Compared with PRP and PRP1, PRP2 exhibited the most potent antiaging activity in D-galactose-treated T lymphocytes, attributed to its shorter chain length and lower molecular weight. Furthermore, oral administration with PRP2 not only decreased the levels of senescence-associated secretory phenotype (SASP)-related inflammatory cytokines, elevated the counts of T cells, NK cells, and macrophages in the blood, but also reduced the expressions of p16 and p21 proteins in spleen tissues of naturally aged C57BL/6J mice and two fast-aging (ERCC2

Aging disrupts immune regulation, affecting tissue function and increasing vulnerability to various diseases. However, the effects of aging on immune cells within human testes are not well understood. In this study, we utilized single-cell RNA sequencing to profile immune cells from 33 human testis samples from individuals aged 21 to 69. Our analysis revealed key immune cell types, including CD8

Studies have indicated that COVID-19 infection may accelerate the aging process in organisms. However, it remains unknown whether contracting COVID-19 affects life expectancy. Furthermore, the underlying biological mechanisms behind these findings are still unclear.

Skeletal muscle is essential for maintaining body shape and supporting physiological processes. Musculoskeletal function is influenced by various factors, including nutrition, infection, injury or trauma, and advanced glycation end-products (AGEs), which are known to contribute in tissue degeneration, particularly in aging and diabetic populations. This study utilized a skeletal muscle-on-a-chip system to develop three-dimensional in vitro musculoskeletal tissue, enabling a detailed investigation of the effects of AGEs on muscle function and structure. AGEs-induced alterations on muscle were verified by assessments of musculoskeletal contractility, myotube growth, and apoptosis markers. Furthermore, metabolic changes such as modifications in collagen and NADH lifetime changes were observed using fluorescence-lifetime imaging microscopy (FLIM) in the AGEs-treated group. Our result demonstrated a significant reduction in musculoskeletal contractility and structural disruptions in response to AGEs exposure. Overall, these findings provide a robust in vitro model for elucidating the mechanisms by which AGEs impair muscle functionality and integrity, with potential implications for therapeutic strategies aimed at preserving muscle health and enhancing the quality of life in affected populations.

The Shennong Bencao Jing (Shennong's Classic of Materia Medica) records that Panax ginseng C. A. Mey (ginseng) 'lightens the body and prolongs life'. Many investigations have documented that ginseng exerts neuroprotective effects by mitigating the aging of the brain. However, a comprehensive review of the impacts of ginseng on brain aging remains lacking.

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and heme oxygenase 1 (HO‑1) attenuate intervertebral disc degeneration (IVDD). However, whether BMSC‑derived exosomes attenuate IVDD by delivering HO‑1 to nucleus pulposus (NP) cells remains to be elucidated. Mouse BMSCs were characterized by multilineage differentiation and surface marker molecule detection. Exosomes Exo and Exo‑HO‑1 were isolated from BMSCs and HO‑1‑overexpressing BMSCs by ultracentrifugation and characterized by observing their morphology, detecting the exosome marker proteins, tumor susceptibility gene 101 (TSG101) and CD63 and analyzing their particle size. Interleukin‑1 β (IL‑1β)‑stimulated NP cells were used as the IVDD cell model. The influence of Exo or Exo‑HO‑1 on IL‑1β‑urged apoptosis and senescence in NP cells was determined by flow cytometry, western blotting and senescence‑associated β‑galactosidase (SA‑β‑gal) staining. Exo and Exo‑HO‑1 did not vary in size or morphology. Exo‑HO‑1 markedly repressed IL‑1β‑prompted apoptosis in NP cells, accompanied with a prominent increase in Cleaved caspase 3 and Bax protein levels and a marked decrease in Bcl‑2 protein levels. Exo and Exo‑HO‑1 both decreased the number of SA‑β‑gal‑positive NP cells and arrested NP cells in the G

Cognition and its underlying neurobiology change throughout the trajectory of aging, with prominent sex differences and influences of sex-specific factors. Research has shown that parity (pregnancy and parenthood) uniquely altered various biomarkers of brain health in middle age depending on presence of Alzheimers disease (AD) risk. The present study builds on prior work by providing a comprehensive view of functional connectivity changes and elucidating how network-level dynamics contribute to cognitive outcomes depending on primiparity and APOEe4 genotype, the top genetic risk factor for late-onset sporadic AD risk. We assessed neural activation in middle-aged wildtype and hAPOEe4 rats that were either nulliparous (0 litters) or primiparous (1 litter). Activation of the immediate early gene zif268 was quantified across 19 brain regions implicated in memory and AD. Primiparous hAPOEe4 rats exhibited widespread reductions in neural activation, particularly in the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex. Network analyses further revealed that primiparous wildtype rats had the most cohesive and efficient functional connectivity networks. Notably, the hierarchy of influence of brain regions within the neural network shifted based on parity and hAPOEe4 genotype. Activation of hippocampal new-born neurons in conjunction with subregions of the dorsal striatum, frontal cortex, and retrosplenial cortex dynamically predicted cognitive performance in a parity- and genotype-dependent manner. These findings underscore the lasting impact of reproductive history on brain health and cognitive aging, highlighting the need to consider sex-specific experiences in aging and AD research.

The protein Klotho, known for its connection to longevity, has attracted growing interest among researchers for its positive effects on the cognitive function and dementia during aging. Nevertheless, the precise correlation between levels of Klotho and cognitive function and dementia remains inadequately elucidated, with conflicting conclusions arising from different studies.

Increased accumulation of senescent cells with aging is associated with reduced ability of insulin-target tissues to utilize glucose, resulting in increased insulin resistance and glucotoxicity. We investigated the role of the senescent-associated secretory phenotype (SASP) within C2C12, skeletal muscle cells on glucose homeostasis and if such effects could be reduced by blocking pro-inflammatory pathways. C2C12 myotubes were treated with 40% conditioned media from senescent fibroblasts. Indirect glucose uptake and glycogen content were measured. The effect of SASP on the generation of reactive oxygen species [1] and mitochondrial function was also measured. The experiments above were repeated with a p38 inhibitor. 40% SASP treatment significantly decreased glucose utilization and glycogen storage within myotubes (

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

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.

Astrocytes are neuromodulator cells. Their complex and dynamic morphology regulates neuronal signaling, synaptic plasticity, and neurogenesis. The impact of aging on astrocyte morphology is still under ongoing debate. Therefore, this study aimed to characterize astrocyte morphology in the hippocampus of older rats. 2-, 18-, and 20-month-old male Wistar rats were submitted to the object recognition test to assess their short- and long-term memories. CA1, CA2, CA3, and the dentate gyrus were collected for immunohistochemistry analysis and glial fibrillary acid protein (GFAP) immunostaining. Our results indicate that 20-month-old rats did not recognize or discriminate the novel object in the long-term memory test. Also, GFAP staining was greater in the oldest group for all analyzed areas. Morphometric and fractal analysis indicated shorter branch lengths and smaller sizes for astrocytes of 20-month-old rats. Overall, our results suggest that 20-month-old rats have long-term memory impairment, increased GFAP staining, and astrocyte dystrophy. These age-related alterations in astrocyte morphology are a resource for future studies exploring the role of astrocytes in age-related cognitive decline and age-related diseases.

Sarcopenia presents a pressing public health concern due to its association with age-related muscle mass decline, strength loss and reduced physical performance, particularly in the growing older population. Given the absence of approved pharmacological therapies for sarcopenia, the need to discover effective pharmacological interventions has become critical.

Nicotinamide adenine dinucleotide kinase (NADK) is essential to the generation of nicotinamide adenine dinucleotide phosphate (NADP(H)), an important metabolic coupling factor involved in glucose-stimulated insulin secretion. In the present study, we showed that the expression of Nadk and Nadk2 transcripts and NADP(H) content were lower in islets of 80-week-old (aged) mice than those of 8-week-old (young) mice. This was associated with diminished oral glucose tolerance of old mice and the glucose-stimulated insulin secretion (GSIS) response of islets. Knockdown (KD) of Nadk or Nadk2 gene expression in NIT-1 cells impaired glucose-stimulated insulin secretion. Metabolomic analysis revealed that Nadk KD specifically affected purine metabolism in glucose-stimulated cells. The levels of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were higher in KD cells than in the non-targeting control (NTC) cells. Phosphorylation of AMP-activated protein kinase (AMPK) was elevated in glucose-treated KD cells compared to that of NTC cells. Increased AICAR level and AMPKα phosphorylation were observed in the glucose-stimulated islets of the aged mice. Genetic and pharmacological inhibition of AMPK promoted glucose-stimulated insulin release by KD cells and the aged mouse islets. It is likely that NADK is modulatory to AMPK activation in pancreatic β-cells and to their GSIS response. Enhanced AICAR formation in KD cells was accompanied by significantly increased conversion from inosine monophosphate (IMP) in a tetrahydrofolate (THF)-dependent manner. Folate supplementation augmented the GSIS response of KD cells and aged mouse islets. Taken together, these findings suggest that the aging-associated decline in NADK expression may underlie the reduced insulin secretory capacity of pancreatic β-cells.

Characterizing age-related alterations in brain networks is crucial for understanding aging trajectories and identifying deviations indicative of neurodegenerative disorders, such as Alzheimer's disease. In this study, we developed a Fully Hyperbolic Neural Network (FHNN) to embed functional brain connectivity graphs derived from magnetoencephalography (MEG) data into low dimensions on a Lorentz model of hyperbolic space. Using this model, we computed hyperbolic embeddings of the MEG brain networks of 587 individuals from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Notably, we leveraged a unique metric-the radius of the node embeddings-which effectively captures the hierarchical organization of the brain, to characterize subtle hierarchical organizational changes in various brain subnetworks attributed to the aging process. Our findings revealed that a considerable number of subnetworks exhibited a reduction in hierarchy during aging, with some showing gradual changes and others undergoing rapid transformations in the elderly. Moreover, we demonstrated that hyperbolic features outperform traditional graph-theoretic measures in capturing age-related information in brain networks. Overall, our study represents the first evaluation of hyperbolic embeddings in MEG brain networks for studying aging trajectories, shedding light on critical regions undergoing significant age-related alterations in the large cohort of the Cam-CAN dataset.

This study proposes using accumulated neurotoxicity, defined as the time integral of A{beta} oligomer concentration, as a biomarker for neuronal aging. A relationship between biological age and accumulated neurotoxicity is proposed. Numerical analysis guided the development of a new analytical solution linking the biological and calendar ages of neurons. The effects of A{beta} monomer and oligomer half-lives - key indicators of proteolytic efficiency - on biological age are examined. Both constant and age-dependent (exponentially increasing) half-life scenarios are considered. The findings indicate that increasing the half-life of A{beta} monomers and oligomers with age accelerates biological aging. Reducing A{beta} monomer production is shown to slow biological aging, with a linear relationship established between these two quantities. Additionally, biological age is found to depend linearly on the half-deposition time of A{beta} oligomers into senile plaques.

SPP1+ macrophages, characterized by elevated expression of the osteopontin gene (secreted phosphoprotein 1, SPP1), have emerged as key players in various pathological contexts, including aging, chronic inflammatory diseases, and cancer. While frequently classified as a subclass of tumor-associated macrophages in oncological settings, their presence in noncancer conditions, such as aging-related disorders and muscular diseases, suggests a broader role beyond tumors. These macrophages share conserved traits, including fibrosis promotion, extracellular matrix remodeling, and immune modulation, often linked to poor clinical outcomes. This perspective explores the multifaceted roles of SPP1+ macrophages across diseases and advocates for their reclassification as a distinct macrophage subtype associated with chronic or prolonged inflammation. Recognizing their cross-disease relevance could reshape macrophage biology and inform targeted therapeutic strategies.

The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus.

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive X (Xi) and active X (Xa), in contrast to males with only an Xa. Thus, reactivation of silent Xi genes may contribute to sex differences. We use allele-specific, single-nucleus RNA sequencing to show that aging remodels transcription of the Xi and Xa across hippocampal cell types. Aging preferentially changed gene expression on the X's relative to autosomes. Select genes on the Xi underwent activation, with new escape across cells including in the dentate gyrus, critical to learning and memory. Expression of the Xi escapee

Susceptibility to cartilage degeneration increases in an age-dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age-related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K-7174 interferes with the ZMIZ1-GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1-GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K-7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age-related degeneration.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease linked to aging. Mitochondrial dysfunction in circulating T cells, often caused by disruption of mitochondrial DNA (mtDNA), may play a role in age-related conditions like IPF. In our previous study, we found high mtDNA mutational loads in blood lymphocytes from IPF patients, especially in regions critical for mtDNA expression. Since Complex I of the electron transport chain, partly encoded by mtDNA, is essential for energy production, we conducted a preliminary study on its activity. We found significantly reduced Complex I activity (p < 0.001) in lymphocytes from 40 IPF patients compared to 40 controls, which was positively correlated with lung function decline, specifically in functional vital capacity and diffusing capacity for carbon monoxide. These findings indicate that T cell mitochondrial dysfunction is associated with disease progression in IPF. Future work will explore the mechanisms linking T cell mitochondrial disruption with fibrosis, potentially uncovering new therapeutic targets.

It is now understood that iron crosses the blood-brain barrier

Aging is a major risk factor for cardiovascular disease, with hypertension being the most common outcome. Hypertension often stems from resistance arteries endothelial dysfunction. Recent research highlights the pivotal role of perivascular adipose tissue (PVAT) in regulating endothelial function. We hypothesized that PVAT senescence contributes to vascular dysfunction and hypertension during aging. We showed that naturally aged mice developed hypertension and elevated pro-inflammatory cytokines levels. Moreover, resistance mesenteric arteries showed impaired vascular relaxation that was normalized by apocynin, an antioxidant. The vascular dysfunction was endothelium- and PVAT-dependent, and marked by: decreased NO- and COX-dependent vascular relaxation, decreased expression of endothelial nitric oxide synthase (eNOS), and increased cyclooxygenase 2 (COX-2) and NADPH oxidase subunits p22phox and gp91phox expressions in the endothelium and PVAT. Additionally, we observed that PVAT shows greater signs of senescence, particularly with higher p16 expression, indicating that PVAT is more prone to age-related cellular aging. Our findings suggest that in resistance mesenteric arteries PVAT-derived factors are crucial for triggering and amplifying vascular dysfunction in aging, leading to hypertension. The underlying mechanisms involve downregulation of eNOS-derived NO, NADPH-oxidase-dependent oxidative stress, and COX-2-derived vascular contractile factors. This research improves our understanding of the mechanisms behind age-related vascular dysfunction and associated hypertension and opens perspectives for targeted therapeutic strategies.

Moment-to-moment neural variability plays a crucial role in learning and behavioral flexibility. Changes in this variability have been linked to age-associated differences in both task performances and resting-state activity. However, the effect of neural variability on specific computations and subjective experience remain unclear. Here, we demonstrate that changes to cortical neural variability during naturalistic experience serves as a readout of changes to region-specific computations, distinct from resting-state variability and mean neural activity. During affective experience, older adults exhibited an increase in neural variability within the orbitofrontal cortex (OFC). By employing a Bayesian learning model, we revealed that this corresponded to heightened uncertainty in the computational estimates of evolving valence in older adults. This model prediction was observed neurally with frequent state switching and temporally distorted representations within the OFC in older adults, compared to stable representations in the young. Crucially, these representational changes mirrored the arousal responses of the two groups. These results advance our understanding of how neural variability might carry unique information in aging, particularly to their changing and possibly idiosyncratic affective experiences.

Evidence on the association of clinical biomarker-based biological age (BA) with cardiovascular disease (CVD) and mortality remains insufficient, particularly concerning aging trajectories' relationship with these two outcomes.

Aging of the retinal pigment epithelium (RPE) leads to a gradual decline in RPE homeostasis over time, significantly impacting retinal health. Understanding the mechanisms underlying RPE aging is crucial for elucidating the background in which many age-related retinal pathologies develop. In this study, we compared the transcriptomes of young and aged mouse RPE and observed a marked upregulation of immunogenic, proinflammatory, and oxidative stress genes in aging RPE. Additionally, aging RPE exhibited dysregulation of pathways associated with visual perception and extracellular matrix production. Research on aging in post-natal quiescent RPE is hindered by the absence of relevant

Maimendong decoction (MMDD) originates from the ancient Chinese medical text Synopsis of the Golden Chamber and is a well-established remedy for treating lung diseases. It has demonstrated efficacy in the long-term clinical management of idiopathic pulmonary fibrosis (IPF); however, its underlying mechanisms remain unclear.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

Cardiac endogenous senescence will gradually change and aggravate with age. Recent research showed that 17β-estradiol (17β-E2), an estrogen with numerous biological activities including the prevention of vascular senescence. However, how 17β-E2 against cardiac aging is still unknown. This work addressed the underlying mechanism with regard to Beclin1 and autophagy activity to better understand the anti-senescent effect of 17β-E2 on a well-established animal model of cardiac aging.

Imbalanced mitochondrial quality control is strongly linked to the onset and development of osteoarthritis (OA). However, current research primarily focuses on local cartilage repair and phenotype maintenance, lacking a systematic approach to subcellular mitochondrial quality control. To address this, the present study proposes a mitochondrial quality control strategy based on nanozyme hydrogel microspheres ("mitochondrial inspector"), constructed through electrostatic self-assembly, incorporation of dynamic diselenide bonds, and microfluidic technology. The mitochondrial oxidative stress microenvironment is improved by cerium dioxide nanoparticles and combined with metformin to activate autophagy to clear persistently dysfunctional mitochondria, thereby inhibiting OA progression. In vitro results showed that "mitochondrial inspector" not only significantly improved the oxidative stress microenvironment of chondrocytes, but also efficiently scavenged the damaged mitochondria, increased the mitochondrial membrane potential by over 20-fold, and notably improved the mitochondrial function and chondrocyte homeostasis. In a rat OA model, minimally invasive intra-articular injection of the "mitochondrial inspector" effectively regulated mitochondrial quality, alleviated cartilage matrix degradation, reduced osteophyte formation by ≈80%, and reduced the Mankin score for cartilage damage by over 70%. In summary, this study presents a novel nanozyme microsphere-based mitochondrial quality control strategy for the treatment of OA, providing new insights for subcellular therapies for other aging-related diseases.

Physical exercise has been associated with healthier aging trajectories, potentially preventing or mitigating age-related declines. This occurs through a complex, yet poorly characterized network of multi-organ interactions involving mitochondrial, inflammatory, and cell death/survival pathways. Here, we comprehensively evaluated the 12-week VIVIFRAIL multicomponent exercise protocol in physically frail (n = 16, mean age 81.4 ± 5.6) and robust (n = 50, mean-age 73.6 ± 4.7) old individuals. Before (T0) and after (T1) the protocol, functional outcomes were assessed alongside a detailed exploratory analysis of mitochondrial, inflammatory, apoptotic, and neuro-muscular mediators concerning their plasmatic/serum concentrations, and/or mRNA expression from peripheral blood mononuclear cells (PBMCs). Besides significant functional improvements across both groups, our findings highlighted unique and overlapping modulations of key biological pathways. Both groups showed refined mitochondrial integrity/turnover (upregulated mt-ND1, downregulated TFAM, and ULK1), anti-inflammatory responses (upregulated IL10, and TGF-B, and downregulated IL6/IL10 mRNA ratio), as well as reduced cellular damage/apoptosis (reduced plasmatic ccf-nDNA, downregulated BAX, and upregulated BCL-2/BAX ratio). Plasmatic ccf-mtDNA was significantly reduced in robust subjects, while plasmatic IL6 and IL6/IL10 ratio were reduced in frail subjects uniquely. Spearman correlations between physical improvements and biological pathway variations also suggested different adaptation mechanisms influenced not only by chronological age but also by frailty status. In conclusion, this study confirms the benefits of physical activity in the older population and provides novel insights into specific biological mediators of the mitochondria-inflammation axis as key players in such effects. Moreover, our findings establish PBMCs as a valuable tool for monitoring the biological trajectories of aging and health-promoting lifestyle interventions.

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.

Skeletal muscle is the most abundant tissue in the human body and is responsible for movement, metabolism, energy production and longevity. Muscle atrophy is a frequent complication of several diseases and occurs when protein degradation exceeds protein synthesis. Genetics, ageing, nerve injury, weightlessness, cancer, chronic diseases, the accumulation of metabolic byproducts and other stimuli can lead to muscle atrophy. Muscular dystrophy is a neuromuscular disorder, part of which is caused by the deficiency of dystrophin protein and is mostly related to genetics. Muscle atrophy and muscular dystrophy are accompanied by dynamic changes in transcriptomic, translational and epigenetic regulation. Multiple signalling pathways, such as the transforming growth factor-β (TGF-β) signalling pathway, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, inflammatory signalling pathways, neuromechanical signalling pathways, endoplasmic reticulum stress and glucocorticoids signalling pathways, regulate muscle atrophy. A large number of long noncoding RNAs (lncRNAs) have been found to be abnormally expressed in atrophic muscles and dystrophic muscles and regulate the balance of muscle protein synthesis and degradation or dystrophin protein expression. These lncRNAs may serve as potential targets for treating muscle atrophy and muscular dystrophy. In this review, we summarized the known lncRNAs related to muscular dystrophy and muscle atrophy induced by denervation, ageing, weightlessness, cachexia and abnormal myogenesis, along with their molecular mechanisms. Finally, we explored the potential of using these lncRNAs as therapeutic targets for muscle atrophy and muscular dystrophy, including the methods of discovery and clinical application prospects for functional lncRNAs.

Adult neurogenesis in the hippocampus, involving the generation and integration of new neurons, is essential for behavioral pattern separation, which supports accurate memory recall and cognitive plasticity. Here, we explore the role of the DNA repair protein NEIL3 in adult hippocampal neurogenesis and behavioral pattern separation. NEIL3 is required for efficient proliferation and neuronal differentiation of neonatal NSPCs and adult-born NPCs in the hippocampus following a behavioral pattern separation task. NEIL3-depleted mice exhibited a reduced preference for the novel object location, indicating a deficit in pattern separation. NEIL3-deficient adult-born neurons exhibited a significant reduction in mature-like membrane properties, indicating impaired functional maturation. Interestingly, these impairments were not associated with the decreased genomic integrity but with the altered transcriptional regulation of the Wnt signaling pathway. Given the importance of adult neurogenesis in cognitive function, targeting NEIL3 could offer therapeutic potential for addressing age-related hippocampal dysfunction and cognitive decline.

Gender-affirming hormone therapy (GAHT) is a necessary treatment for many transgender people, and there is a critical need to further improve treatment experience and mitigate possible risks. Here we investigated whether DNA methylation (DNAm) biomarkers of health and aging are modified during the first year of GAHT and whether these vary by treatment type. Cohort consisted of 13 trans women and 13 trans men. Sampling occurred at baseline (pre-GAHT), and at 6- and 12-month follow-up. We tracked the longitudinal dynamics of three epigenetic clocks (Horvath, Hannum, PhenoAge), DNA methylation-based telomere length (DNAmTL), and DunedinPACE. At baseline, the Horvath and Hannum showed accelerated epigenetic aging, particularly pronounced among trans men, while the PhenoAge and DunedinPACE showed lower pace of aging in both groups. This discrepancy may reflect possible effects of minority stress in an otherwise healthy cohort. While GAHT did not affect the three clocks, DNAmTL and DunedinPACE showed treatment-specific patterns but with notable inter-individual variability in trajectories. Trans women had increased DunedinPACE (estimate = 0.057, p=0.002) and slight DNAmTL gains (estimate = 0.024, ns); trans men exhibited stable to slight decline in DunedinPACE (estimate = -0.013, ns), and reduction in DNAmTL (estimate = -0.057, p=0.037). The marked heterogeneity is indicative of an individualized response to treatment and highlights the potential value of incorporating such biomarkers in comprehensive health monitoring. Our findings emphasize the need for larger, long-term studies to optimize personalized strategies for gender-affirming healthcare.

Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.

Cytomegalovirus (CMV) infection has been linked to accelerated biological aging, potentially increasing the risk of cardiovascular disease. DNA methylation of the gene Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) is a molecular biomarker for aging, and its gene product is involved in polyunsaturated fatty acid synthesis, which impacts immune and inflammatory responses. This study, conducted in the MARK-AGE population, aimed to investigate the relationship between CMV infection and ELOVL2 methylation in adults aged 35-75, as well as the influence of CMV IgG levels on lipid metabolism, inflammation, DNA damage, and DNA repair. Our data revealed a higher prevalence of ischemic heart disease, atrial fibrillation, hypertension, and diabetes in CMV-positive individuals. CMV IgG levels were positively associated with ELOVL2 methylation at specific CpG sites and with increased expression of DNA methyltransferase-1 (DNMT1). CMV IgG was linked to lipid imbalances, such as increased BMI, VLDL-cholesterol, triglycerides, and HDL1-cholesterol. Additionally, ELOVL2 methylation was associated with systemic inflammation markers, lipid parameters and altered T-cell subsets. A negative correlation was observed between CMV IgG levels and both baseline DNA integrity and repair capacity. These results suggest that CMV infection might promote cardiovascular disease through ELOVL2 hypermethylation, lipid dysregulation, inflammation, and DNA damage.

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.

Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.

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.

Depletion of TRF2 from chromosome ends results in telomeric fusions and genome instability in mammals. Here we show that although TRF2 is indispensable for the proliferation and survival of mouse neural stem cells (mNSCs), surprisingly, this is due to non telomeric transcriptional function of TRF2, and not telomere protection. Complementing recent work showing TRF2 is dispensable for telomere protection in pluripotent stem cells. Deletion of TRF2 in adult mNSCs (TRF2fl/fl, Nestin Cre) resulted in markedly reduced proliferation and impaired differentiation into neurons. However, telomere dysregulation induced DNA damage was not observed, as indicated by the unaltered DNA damage response. Similarly, in SHSY5Y cells, TRF2 depletion induced differentiation without causing telomere dysfunction. Mechanistically, nontelomeric TRF2 directly binds to the promoters of key genes that regulate differentiation. TRF2 dependent recruitment of the polycomb repressor complex (PRC2) and subsequent H3K27 trimethylation repress differentiation associated genes, thereby maintaining NSC identity. Interestingly, G quadruplex (G4) motifs are necessary for TRF2 binding. Disrupting the TRF2 G4 interaction, either through G4 binding ligands or the G4 specific helicase DHX36 induces differentiation genes, thereby promoting neurogenesis. These findings reveal a pivotal non-telomeric role of TRF2 in NSC survival, providing key mechanistic insights into neurogenesis with implications for aging related neurodegeneration.

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.

Rnd3 is a small Rho-GTPase that has been implicated in various cardiovascular diseases. Yet, its role in diabetes-induced cardiomyocyte senescence remains unknown. Here we tested the role of Rnd3 in cardiomyocyte senescence and diabetic cardiomyopathy (DCM). The expression of Rnd3 was found to be reduced in peripheral blood mononuclear cells from diabetic patients and correlated negatively with age but positively with cardiac function. In 96-week-old Sprague Dawley (SD) rats, cardiac function was impaired, accompanied by an increased number of SA-β-gal-positive cells and elevated levels of the senescence-associated secretory phenotype (SASP) related factors, compared to those of 12-week-old rats. Diabetes and high glucose (HG, 35 mmol/L D-glucose) suppressed Rnd3 expression in cardiomyocytes and induced cardiomyocyte senescence. The deficiency of Rnd3 exacerbated cardiomyocyte senescence in vitro and in vivo. MicroRNA sequencing in AC16 cells identified a conserved miR-103a-3p (present in humans and rats) as a key HG-upregulated microRNA that bound to the Rnd3 3'-UTR. In cultured cardiomyocytes, miR-103a-3p inhibitors antagonized HG-induced cardiomyocyte senescence dependent on Rnd3 expression. Treatment with AAV9 vectors carrying miR-103a-3p sponges and Rnd3-overexpressing plasmids alleviated cardiomyocyte senescence and restored cardiac function in diabetic SD rats. HG stimulation increased STAT3 (Tyr705) phosphorylation and promoted its nuclear translocation in H9C2 cells, an effect exacerbated by Rnd3 knockout. Mechanistically, Rnd3 interacted with p-STAT3 in the cytoplasm, facilitating proteasome-mediated ubiquitination and p-STAT3 degradation. The STAT3 inhibitor S3I-201 blocked HG-induced STAT3 activation and mitigated cardiomyocyte senescence. These findings suggest that diabetes induces cardiomyocyte senescence via the miR-103a-3p/Rnd3/STAT3 signaling pathway, highlighting a potential therapeutic target for DCM.

Greater walking automaticity facilitates maintenance of gait speed without prefrontal cortex (PFC) resources. Brain aging may cause shifts to more attentional gait with greater engagement of the PFC. Nigrostriatal dopaminergic integrity likely facilitates walking automaticity and maintenance of gait speed during attentional dual-tasks. Older adults (n=201; age=74.9; 63.2% women, gait speed=1.10 m/s) completed a dual-task protocol of saying every other letter of the alphabet while walking. PFC activation was measured by functional near-infrared spectroscopy. Four groups were defined based on PFC activation (increased during dual-task, PFC+, or not, PFC-) and gait speed performance (maintained during dual-task, gait+, or slowed, gait-). To compare nigrostriatal dopaminergic integrity across groups, we assessed binding of the type-2 vesicular monoamine transporter (VMAT2) density in the sensorimotor and associative striatum using [11C]-(+)-alpha-dihydrotetrabenazine (DTBZ) positron emission tomography. Multinomial regression estimated adjusted associations of DTBZ binding with group membership. We hypothesized that DTBZ binding was highest for those who maintained gait speed without additional PFC activation when switching from single- to dual-task (PFC-/gait+; i.e., highest gait automaticity). In bivariate analyses, the PFC-/gait+ group had the highest DTBZ binding in the sensorimotor striatum (p=0.05); binding in the associative striatum was similar across groups (p=0.1). Results were similar in adjusted regression analyses; DTBZ binding in sensorimotor striatum was associated with lower likelihood to be in the PFC-/gait- (OR=0.28; 95% CI: 0.08, 0.94) or the PFC+/gait+ (OR=0.29; 95% CI: 0.10, 0.84) groups compared to PFC-/gait+ reference group. These results provide support for dopaminergic involvement in sustaining gait automaticity at older ages.