Aging Cell最新文献

Early-life nutrition can exert long-lasting effects on later-life health. Given that lactose is extensively consumed during early mammalian development, this raises the intriguing possibility that lactose or its constituent galactose may exert beneficial nutritional programming effects. We tested here whether early-life (larval period) co-consumption of galactose and glucose (GALGLU; as in hydrolysed lactose) shapes later-life (adult) lifespan in Drosophila melanogaster. Larval GALGLU versus isocaloric glucose consumption (GLU) significantly extended the developmental time of larvae, increased the pupal volume, decreased pupal oxygen consumption, and reduced the pupal mitochondrial mass. These early-life effects were translated into sexually dimorphic effects on adult lifespan. Specifically, larval GALGLU consumption extended the lifespan of females when challenged with an obesogenic adult diet, whereas it reduced lifespan in males. To identify molecular correlates of the female-specific benefit, we profiled transcriptomes and lipidomes. Notably, larval GALGLU induced later-life transcriptional activation of cuticular hydrocarbon (CHC)-synthesizing enzymes, including the diene-producing desaturase Fad2, without changes in the monounsaturated fatty acid (MUFA)-producing desaturase Desat1, indicating increased MUFA demand without increased supply. Lipidomic analysis revealed decreased MUFA-containing and increased polyunsaturated fatty acid (PUFA)-containing glycerophospholipids. These data suggest that enhanced CHC biosynthesis depletes cellular MUFAs, driving compensatory incorporation of PUFAs into glycerophospholipids. Concluding, early-life galactose and glucose co-consumption programs sexually dimorphic lifespan, specifically by counteracting the lifespan-shortening effects of obesogenic diets in adult females, and redirects adult female lipid metabolism toward a PUFA-enriched glycerophospholipid profile.

Immunosenescence represents a critical aspect of the aging process. Centenarians, serving as a nature model of "healthy aging," demonstrate a distinctive immune "compensatory adaptation" mechanism that contributes to the maintenance of immune homeostasis. However, the specific immune cell subsets involved and the molecular mechanisms underlying these phenotypic traits remain incompletely understood. In this study, we integrated single-cell RNA sequencing data spanning the entire lifespan of East Asian populations with bulk transcriptomic data from a centenarian cohort in Guangxi. Utilizing the Scissor algorithm, we identified immune cell subpopulations positively (Scissor⁺) and negatively (Scissor^-) associated with longevity phenotypes, thereby constructing an immune cell atlas of "Longevity Molecular Tag." Our findings indicate that Scissor⁺ cells predominantly comprise natural killer (NK) cells, CD8⁺ T cells, and γδ T cells, characterized by enhanced cytotoxic and immunomodulatory functions. Conversely, Scissor^- cells mainly include CD4⁺ T cells, B cells, and dendritic cells (DCs), which are linked to inflammatory signaling pathways and Th17/Th1 differentiation. Trajectory analysis elucidated the differentiation pathways of NK, CD8⁺ T cells, CD4⁺ T cells, and B cells. Differentially expressed genes were enriched in pathways such as NF-κB signaling, T cell receptor signaling, and NK cell cytotoxicity. Furthermore, co-localization analysis revealed five eQTL-colocalized events (rs3793537-GLIPR2/CD72/TLN1 and rs8019902-TRDV2/TRDC) associated with longevity. Collectively, these results suggest that centenarians achieve immune equilibrium by remodeling cytotoxic immune lineages and finely tuning inflammatory responses, thereby promoting health span and longevity. This study offers novel insights into potential strategies for modulating immunosenescence.

Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation (including soluble oligomers and deposited aggregates), lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of Aβ42 are established drivers of pathology, the mechanisms connecting oligomeric amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood. Here, we employed complementary Drosophila and mouse models to dissect these relationships. Panneuronal, glial or mushroom body specific expression of humanized App^NLG and Aβ42 in Drosophila resulted in locomotor deficits, disrupted sleep-circadian rhythms, memory impairments, lipid accumulation, synaptic loss, and neuroinflammatory signatures. Comparable lipid accumulation, metabolic dysregulation and neuroinflammation were detected in the App^NLG-F knock-in mouse model, underscoring their conserved relevance to AD pathogenesis. We further identified diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme catalyzing the final step of triglyceride synthesis, as a critical modulator of AD-related phenotypes. Dgat2 expression was altered in both animal models and human AD tissues. Notably, panneuronal knockdown of Dgat2 in Drosophila attenuated lipid accumulation, restored synaptic integrity, and ameliorated locomotor and cognitive deficits, while also reducing neuroinflammation. Additionally Dgat2 suppression improved sleep and circadian behavior, highlighting its pleiotropic protective effects. Together, these findings support a mechanistic link between amyloid pathology, lipid dysregulation, and neuroinflammatory processes. The conservation of lipid homeostasis mechanisms across species underscores the translational potential of this approach for delaying or mitigating AD progression. Moreover, targeting Dgat2 may therefore represent a novel therapeutic strategy to counteract AD-associated metabolic and neuronal dysfunction.

Cellular senescence contributes to aging and age-related diseases. Deep identifications of the senescence-specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4-fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha-KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT-PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl-CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha-KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co-inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy-induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.

Increased life expectancy brought about by improved healthcare and lifestyle has heightened the challenge of neurodegenerative disorders like Alzheimer's disease (AD) and other age-related disorders. Neurodegeneration is known to be accompanied by loss of memory, changes in brain morphology, and neuroinflammation, and multiple factors contribute to the progression and pathogenesis of the condition. Of these factors, metabolic dysregulation is known to influence the process, but the precise mechanisms remain unexplored. In this study, we investigated the brain-specific role of the metabolic enzyme hexokinase domain-containing 1 (HKDC1) in neurodegeneration and observed that HKDC1 expression declines in humans with cognitive decline, which matches similar findings in mouse models of AD and aging. We observed age-dependent anxiety, compromised memory and learning, senescence, neuroinflammation, and mitochondrial function deficit in HKDC1-brain knockout mouse models. Furthermore, Chromatin immunoprecipitation (ChIP), RT-PCR, and Western blotting assays reveal that an age-related decline in HKDC1 expression stems from changes in chromatin conformation, which decrease the ability of transcription factor EB to regulate its transcription. These findings suggest an important role for the metabolic gene HKDC1 in the brain in relation to cognitive decline and the progression of neurodegeneration in mice and humans.

Intervertebral disc degeneration (IVDD) is an age-related degenerative spinal disorder, with age as the primary independent risk factor. To investigate the key pathogenic mechanisms of IVDD, we conducted biochemical analyses on IVD specimens from elderly and young groups. In this study, we found that methylmalonic acid (MMA) levels are significantly elevated within the discs of the elderly group, suggesting that MMA may be a critical metabolite involved in aging-induced IVDD. In in vitro experiments, we observed that MMA treatment of nucleus pulposus cells (NPCs) upregulated the expression of extracellular matrix catabolic markers and downregulated the expression of anabolic markers. Further validation in an in vivo mouse model of needle puncture-induced IVDD confirmed that MMA accelerates IVDD progression. Mechanistically, we demonstrated that MMA upregulates the expression of C-C motif chemokine ligand 7 (CCL7) in NPCs. CCL7 acts as a chemoattractant, further enhancing Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling transduction, ultimately leading to upregulated vascular endothelial growth factor (VEGF) expression. This promotes abnormal growth of vascular endothelial cells, resulting in disc vascularization. Additional in vivo and in vitro experiments confirmed that disc vascularization is a key progression factor in IVDD. As a rescue strategy, we administered lenvatinib, a VEGF receptor inhibitor, which delayed IVDD progression. Therefore, VEGF and disc vascularization represent a promising therapeutic target for IVDD, offering an innovative approach to addressing IVDD treatment in clinical practice.

Aging is characterized by reduced physiological resilience, linked to declines in both cardiac autonomic control (assessed via Heart Rate Variability, HRV) and immune function (immunosenescence, inflammaging). While static immune-autonomic links are known, how baseline immune status dynamically influences autonomic responses to acute stress in aging remains unclear. This study investigated the association between baseline immune cell profiles and dynamic HRV changes during rest, acute exercise, and recovery in older adults. We quantified baseline lymphocyte subsets and assessed HRV during an exercise test. Using Bayesian mixed-effects models, we found that while exercise significantly altered HRV as expected, baseline levels of specific immune cell subsets (e.g., B-cells, T-cells, CD4+/CD8+ ratio, and NK cells) were significantly associated with the pattern and magnitude of exercise-induced HRV changes. This indicates that the pre-existing immune state modulates the dynamic cardiac autonomic response to stress. Our findings highlight the critical role of immune-autonomic crosstalk in shaping physiological resilience in aging, offering insights into heterogeneity in exercise responses and suggesting potential avenues for personalized health strategies.

Entropy may play an underappreciated role in human aging, such as in skeletal muscle functional declines. Histologically, muscle appears increasingly disorganized with aging, with greater fiber size variability and fiber-type grouping. We tested the hypothesis that entropy is associated with reduced physical performance and muscle function, independent of muscle mass. We quantified a homeostatic dysregulation index of muscle (HDI_M) as a proxy for entropy of muscle fiber disorganization based on cross-sectional images of vastus lateralis biopsies from 299 adults age 70 or older. HDI_M was derived from three traits: fiber area diversity, fiber-type heterogeneity, and the mean of the shortest path lengths through adjacent fiber networks. HDI_M derived from muscle fibers was highly correlated with Shannon entropy, a different measure of entropy of muscle fiber traits. Higher HDI_M derived from participants was associated with slower 400-m walk speed, lower peak VO₂, muscle power, and decreased maximum rate of oxidative phosphorylation by mitochondria in muscle. These findings suggest that muscle fibers accumulate entropy with aging which contributes to decline in physical performance, muscle power, and mitochondrial energetics, advancing the entropy framework in aging research.

Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with S. pneumoniae. We observed significant transcriptomic differences across host age. Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Conversely, PMNs in aged mice displayed a higher senescence-associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow-up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL-10, TNFα, and ROS, had a lower incidence of apoptosis, and had a higher proportion of cells positive for senescence-associated β-galactosidase, features of a senescent-like phenotype. Importantly, blocking TNFα, one of the SASP factors, altered the senescent-like phenotype and boosted the antibacterial activity of PMNs from aged hosts and increased host resistance to S. pneumoniae pulmonary infection. In conclusion, host aging is associated with altered PMN phenotype, including a shift toward senescent-like energy-deficient cells, which contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.

Epigenetic clocks are commonly used aging biomarkers based on DNA methylation that predict long-term morbidity and mortality risk. Increased cellular senescence with age is also posited to contribute to age-related disease and mortality. However, prior studies have found that existing epigenetic clocks show inconsistent associations with cellular senescence and no reductions after senolytic treatment. We hypothesize this reflects that senescence-related CpGs are a small proportion of age-related CpGs, and that an epigenetic clock focused on a core senescence signal conserved across different cell types and different senescence inducers would be a better tool for monitoring senescence and senolytic treatment compared to traditional epigenetic clocks. In our study, we find that senescence, age and mortality risk intersect at a small subset of the DNA methylome (9363 CpGs out of 396,333 analyzed; 2.4%). Utilizing these CpGs, we generated three different epigenetic clocks trained to predict in vitro senescence, age, and mortality, respectively. Surprisingly, all three of these predictors stayed the same or even accelerated after senolytic treatment in both in vivo and in vitro data. Our findings not only call into question whether cellular senescence can be captured by DNA methylation but also challenge the assumption that aging biomarkers decrease after geroscience interventions.