Aging Cell最新文献

Mitochondrial homeostasis plays a crucial role in degenerative joint diseases, including cartilaginous endplate (CEP) degeneration. To date, research into mitochondrial dynamics in IVDD is at an early stage. Since Piezo1 is a novel Ca²⁺-permeable channel, we asked whether Piezo1 could modulate mitochondrial fission through Ca²⁺ signalling during CEP degeneration. In vitro and in vivo models of inflammation-induced CEP degeneration were established with lipopolysaccharide (LPS). We found increased expression of Piezo1 in degenerated CEP tissues and LPS-treated CEP cells. The Piezo1 activator Yoda1 exacerbated CEP cell senescence and apoptosis by triggering Ca²⁺ influx. Yoda1 also induced mitochondrial fragmentation and dysfunction. In contrast, the Piezo1 inhibitor GsMTx4 exerted cytoprotective effects in LPS-treated CEP cells. Additionally, the CaMKII inhibitor KN-93 reversed Yoda1-induced mitochondrial fission and restored mitochondrial function. Mechanistically, the phosphorylation and mitochondrial translocation of Drp1 were regulated by the Ca²⁺/CaMKII signalling. The Drp1 inhibitor Mdivi-1 suppressed mitochondrial fission, then reduced mitochondrial dysfunction and CEP cell death. Moreover, knockdown of Piezo1 by siRNA hindered CaMKII and Drp1 activation, facilitating the redistribution of mitochondrial Drp1 to the cytosol in LPS-treated CEP cells. Piezo1 silencing improved mitochondrial morphology and function, thereby rescuing CEP cell senescence and apoptosis under inflammatory conditions. Finally, subendplate injection of GsMTx4 or AAV-shPiezo1 alleviated CEP degeneration in a rat model. Thus, Piezo1 may exacerbate inflammation-induced CEP degeneration by triggering mitochondrial fission and dysfunction via the Ca²⁺/CaMKII/Drp1 axis.

Epigenetic clocks provide powerful tools for estimating health and lifespan but their ability to predict brain degeneration and neuronal damage during the aging process is unknown. In this study, we use GrimAge, an epigenetic clock correlated to several blood plasma proteins, to longitudinally investigate brain cellular microstructure in axonal white matter from a cohort of healthy aging individuals. A specific focus was made on white matter hyperintensities, a visible neurological manifestation of small vessel disease, and the axonal pathways throughout each individual's brain affected by their unique white matter hyperintensity location and volume. 98 subjects over 55 years of age were scanned at baseline with 41 returning for a follow-up scan 2 years later. Using diffusion MRI lesionometry, we reconstructed subject-specific networks of affected axonal tracts and examined the diffusion cellular microstructure composition of these areas, both at baseline and longitudinally, for evidence of cellular degeneration. A chronological age-adjusted version of GrimAge was significantly correlated with baseline WMH volume and markers of neuronal decline, indicated by increased extracellular free water, increased intracellular signal, and decreased axonal signal within WMH. By isolating subject-specific axonal regions "lesioned" by crossing through a WMH, age-adjusted GrimAge was also able to predict longitudinal development of similar patterns of neuronal decline throughout the brain. This study is the first to demonstrate WMH lesionometry as a subject-specific precision imaging technique to study degeneration in aging and the first to establish a relationship between accelerated epigenetic GrimAge and brain cellular microstructure in humans.

Perioperative neurocognitive disorders (PND) is common in aged mild cognitive impairment (MCI) patients and can accelerate the progression to dementia. This process involves heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1)-mediated aggregates of stress granules (SGs), while RUVBL2 influences the dynamics of these SGs. Our research explored a new target for modulating hnRNAPA2/B1-SGs dynamics to accelerate their disassembly and potentially delay MCI progression due to PND. We assessed the effect of hippocampal RUVBL2 knockdown on hnRNPA2/B1-SGs in aged MCI rats through behavioral studies, biochemical experiments and MRI. We also examined hnRNPA2/B1-SGs dynamics using immunofluorescence staining and fluorescence recovery after photobleaching (FRAP) in rat primary hippocampal neurons. Our results revealed that hnRNPA2/B1 in the hippocampus of aged MCI rats translocates to the cytoplasm to form SGs following anesthesia. RUVBL2 knockdown promotes the disappearance of hnRNPA2/B1-SGs, allowing hnRNPA2/B1 to return to the nucleus and enhancing functional activity in the brain regions of aged MCI rats. In primary hippocampal neurons, RUVBL2 deletion facilitated hnRNPA2/B1-SGs transition from hydrogel to liquid, promoting disassembly. We compared three commonly used general anesthetics-3% sevoflurane, 40 mg·kg^-1·h^-1 propofol, and 9% desflurane. Sevoflurane upregulated RUVBL2, which decreased the intraneuronal pH and disrupted energy metabolism. These changes resulted in greater stabilization of hnRNPA2/B1- SGs. In conclusion, our findings indicated that the knockdown of RUVBL2 expression contributes to the transition of hnRNPA2/B1-SGs from the hydrogel phase to the liquid phase. Targeted interference with RUVBL2 may represent a novel approach to delay the progression to dementia due to PND in aged MCI patients.

Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1^-/Δ mice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1^-/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1^-/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1^-/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.

Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC-derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep-wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLP^Tau) for two months. Only the RBX-treated mice exhibited cognitive deficits, as evidenced by their performance in the Y-maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX-treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3β, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC-NE system could be a potential therapeutic strategy for tau-related AD.

The age-associated decline in intestinal stem cell (ISC) function is a key factor in intestinal aging in organisms, resulting in impaired intestinal function and increased susceptibility to age-related diseases. Consequently, it is imperative to develop effective therapeutic strategies to prevent ISC aging and functional decline. In this study, we utilized an aging Drosophila model screening of amino acids and found that asparagine (Asn), a nonessential amino acid in vivo, exhibits its profound anti-aging properties on ISCs. Asn inhibits the hyperproliferation of aging ISCs in Drosophila, maintains intestinal homeostasis, and extends the lifespan of aging flies. Complementarily, Asn promotes the growth and branching of elderly murine intestinal organoids, indicating its anti-aging capacity to enhance ISC function. Mechanistic analyses have revealed that Asn exerts its effects via the activation of the autophagic signaling pathway. In summary, this study has preliminarily explored the potential supportive role of Asn in ameliorating intestinal aging, providing a foundation for further research into therapeutic interventions targeting age-related intestinal dysfunction.

While moderately activated microglia in Alzheimer's disease (AD) are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition using PLX5622 in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, astrocyte hypertrophy, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.

Commensal bacteria and their derivatives hold significant promise as therapeutic interventions to delay aging. However, with the diverse nature of the soil microbiome and the long lifespan of mammalian models, the exploration of the influence of soil bacteria and bacteria-derived molecules on host aging remains limited. We conducted a lifespan screening in Caenorhabditis elegans using plant root bacterial collection. Our screening identified 8 genera of bacterial isolates capable of extending lifespan, with Mycobacterium sp. Root265 exhibits the most pronounced effect on lifespan extension. Biochemical analysis revealed two specific molecules derived from Root265, polysaccharides (PSs) and arabinogalactan peptidoglycan (AGP), responsible for lifespan extension via daf-16-dependent and -independent pathways, respectively. Notably, AGP exhibited a unique ability to enhance protein homeostasis effectively. Moreover, polar lipids originating from Root265 were found to extend lifespan while mitigating age-related BAS-1 decline in neurons. Intriguingly, even brief exposures to these bioactive compounds were sufficient to achieve the lifespan-promoting effects. We found diverse beneficial bacteria and anti-aging active compounds from soil bacteria. These findings highlight the potential of exploring bacterial derivatives as therapies targeting aging without the constraints associated with direct microbial interventions.

The risk of many human diseases including cardiovascular diseases, cancer, neurodegenerative diseases, and musculoskeletal disorders rises significantly in the elderly. With the increase in the aging population, it is becoming increasingly important to understand the biology of healthy aging and develop interventions that slow down the aging process or prevent age-related diseases. In this study, by a high-throughput screen in Caenorhabditis elegans (C. elegans), we identified 11 small molecules that promote healthy aging. Among them, Carbamazepine (a voltage-gated channels inhibitor) and Calmagite (a calcium and magnesium indicator) enhanced serotonin (5-HT) and dopamine (DA) levels, extended lifespan, and preserved several important behaviors in aging C. elegans. These behaviors include slowing responses to food, pharyngeal pumping, locomotion, and male mating. Interestingly, we further found that administration of Carbamazepine or Calmagite alleviated hyperexcitability of aging male diagonal muscles and improved behavioral performance by ameliorating Ca²⁺ homeostasis. Mechanistically, administration of Carbamazepine or Calmagite induced nuclear translocation of the transcription factor DAF-16 and thus up-regulated its downstream genes numr-1/-2, which are known to promote resistance to metal-induced stresses and longevity. Taken together, our study offers a way for the discovery of drugs that promote healthy aging, and provides potential interventions for preventing behavioral deterioration in the elderly.

Exercise preserves neuromuscular function in aging through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant in skeletal muscle and reside close to neuromuscular junctions, but their relative roles in motor neuron maintenance remain undescribed. Using direct cocultures of embryonic rat motor neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation of the motor neuron transcriptome, with FIB generally favoring neuron growth and cell migration and MuSC favoring production of ribosomes and translational machinery. Conditioned medium from FIB was superior to MuSC in preserving motor neurons and increasing their maturity. Lastly, we established the importance of donor age and exercise status and found an age-related distortion of motor neuron and muscle cell interaction that was fully mitigated by lifelong physical activity. In conclusion, we show that human muscle FIB and MuSC synergistically stimulate the growth and viability of motor neurons, which is further amplified by regular exercise.