Aging Cell最新文献

Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. We investigated the efficacy of long-term oral K₃Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K₃Citrate reduced the incidence of disc calcification without affecting the vertebral bone structure, knee calcification, plasma chemistry, or locomotion in LG/J mice. Notably, a positive effect on grip strength was evident in treated mice. FTIR spectroscopy of the persisting calcified nodules indicated K₃Citrate did not alter the mineral composition. Mechanistically, activation of an endochondral differentiation in the cartilaginous endplates and nucleus pulposus (NP) compartment contributed to LG/J disc calcification. Importantly, K₃Citrate reduced calcification incidence by Ca²⁺ chelation throughout the disc while exhibiting a differential effect on NP and endplate cell differentiation. In the NP compartment, K₃Citrate reduced the NP cell acquisition of a hypertrophic chondrocytic fate, but the pathologic endochondral program was unimpacted in the endplates. Overall, this study for the first time shows the therapeutic potential of oral K₃Citrate as a systemic intervention strategy to ameliorate disc calcification.

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.

Increased life expectancy is associated with a higher risk of age-related diseases, which represent a major public health challenge. Animal models play a crucial role in aging research, enabling the study of diseases at the organism level and facilitating drug development and repurposing. Among these models, zebrafish stands out as an excellent in vivo system due to its unique characteristics. However, the longevity of zebrafish is a limitation for research, as it often takes too long to obtain results within a reasonable timeframe. To address this, we have developed a short telomere zebrafish line (ST2) with a premature aging phenotype during the larval stage. Although less extreme than the tert-deficient G2 larvae, ST2 larvae exhibit reduced telomerase expression and activity, along with shortened telomeres. they also exhibit increased cellular senescence, apoptosis, and premature death. As a proof of concept, we evaluated the antiaging effects of two compounds: resveratrol (a polyphenol) and navitoclax (a senolytic). Our results confirm the antiaging properties of resveratrol, which improves telomere maintenance. However, navitoclax does not attenuate the ST2 phenotype. Taking advantage of the zebrafish larval model, this premature aging system provides a valuable platform for in vivo testing of rejuvenating molecules through drug screening, using telomere length or survival as a readout.

The trade-off between reproduction and lifespan has been documented across a wide array of organisms, ranging from invertebrates to mammals. In malnourishing dietary conditions, inhibition of the reproductive processes generally extends the lifespan of females. However, the underlying mechanisms through which nutritional competition driven by reproduction accelerates aging remain poorly understood. Here, using female Drosophila melanogaster as a model, we show that among various dietary conditions lacking specific nutrients, only sterol deficiency significantly exacerbated both the incidence and severity of intestinal barrier deterioration during aging. Sterile mutation specifically ameliorated such damage in sterol-deprived diets, but failed to alleviate age-related intestinal barrier deterioration under other nutritional conditions. Additionally, we demonstrate that the lifespan extension and intestinal barrier amelioration, accompanied by a reproductive suppression effect, through the pharmacological inhibition of mTOR or Ras-Erk signaling using rapamycin or trametinib, were significantly modulated by cholesterol levels. Our study also identifies the morphological changes in excreta as a sensitive biomarker for early intestinal dysfunction. Collectively, these results suggest that the impairment of the intestinal barrier caused by reproductive-induced sterol competition constitutes a significant factor limiting female lifespan in nutritionally unbalanced diets. This work elucidates a salient aspect of the complex interplay between reproductive resource allocation and somatic maintenance, thereby enhancing our understanding of how diet impacts the aging process.

Aging increases the susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD). Liver sinusoidal endothelial cells (LSECs) help in maintaining hepatic homeostasis, but the contribution of age-associated LSECs dysfunction to MASLD is not clear. The aim of this study was to investigate the effect of aging-associated LSECs dysfunction on MASLD. Free fatty acid-treated AML12 cells were co-cultured with young and etoposide-induced senescent TSEC cells to evaluate the senescence-associated endothelial effects on the lipid accumulation in hepatocytes. In addition, young and aged rats were subjected to methionine-choline-deficient diet-induced metabolic dysfunction-associated steatohepatitis (MASH). Hepatic hemodynamics and endothelial dysfunction were evaluated by in situ liver perfusion. Liver tissue samples from young and aged healthy controls and MASH patients were also analyzed. Steatotic AML12 cells co-cultured with young TSEC cells showed less lipid accumulation, and such effect was abolished by eNOS inhibitor or with senescent TSEC cells. However, co-culture with resveratrol-treated senescent TSEC cells could partially resume the NO-mediated protective effects of endothelial cells. Furthermore, aged MASH rats showed more severe liver injury, steatosis, fibrosis, and endothelial and microcirculatory dysfunction. In addition, aged MASH patients showed more pronounced liver injury and fibrosis with lower hepatic eNOS, p-eNOS, and SIRT1 protein levels than in young patients. Senescence compromises the protective effects of LSECs against hepatocyte steatosis. In addition, aging aggravates not only liver steatosis and fibrosis but also intensifies LSECs dysfunction in MASH rats. Accordingly aged MASH patients also showed endothelial dysfunction with more severe liver injury and fibrosis.

Extender of chronological lifespan 1 (Ecl1) inhibits target of rapamycin complex 1 (TORC1) and is necessary for appropriate cellular responses to various stressors, such as starvation, in fission yeast. However, little is known about the effect of posttranslational modifications on Ecl1 regulation. Thus, we investigated the phosphorylation levels of Ecl1 extracted from yeast under conditions of sulfur or metal starvation. Mass spectrometry analysis revealed that Ecl1 was phosphorylated at Thr7, and the level was decreased by starvation. The phosphorylation-mimetic mutation of Thr7 significantly reduced the effects of Ecl1-induced cellular responses to starvation, suggesting that Ecl1 function was suppressed by Thr7 phosphorylation. By contrast, regardless of starvation exposure, TORC1 was significantly suppressed, even when Thr7 phosphorylation-mimetic Ecl1 was overexpressed. This indicated that Ecl1 suppressed TORC1 regardless of Thr7 phosphorylation. We newly identified that Ecl1 physically interacted with TORC1 subunit RAPTOR (Mip1). Based on these evidences, we propose that, Ecl1 has dual functional modes: quantity-dependent TORC1 inhibition and Thr7 phosphorylation-dependent control of cellular function.

Recent studies have shown that disruptions in the nicotinamide adenine dinucleotide (NAD⁺) de novo synthesis pathway accelerate ovarian aging, yet its role in spermatogenesis remains largely unknown. In this study, we investigated the impact of the NAD⁺ de novo synthesis pathway on spermatogenesis by generating Qprt-deficient mice using CRISPR-Cas9 to target quinolinate phosphoribosyl transferase (Qprt), a key enzyme predominantly expressed in spermatocytes. Our results revealed that the deletion of Qprt did not affect NAD⁺ levels or spermatogenesis in the testes of 3-month-old mice. However, from 6 months of age onward, Qprt-deficient mice exhibited significantly reduced NAD⁺ levels in the testes compared to wild-type (WT) controls, along with a notable decrease in germ cell numbers and increased apoptosis. Additionally, these mice demonstrated mitochondrial dysfunction in spermatocytes, impaired progression through prophase I of meiosis, defective double-strand break (DSB) repair, and abnormal meiotic sex chromosome inactivation. Importantly, supplementation with the NAD⁺ precursor nicotinamide riboside (NR) in Qprt-deficient mice restored NAD⁺ levels and rescued the spermatogenic defects. These findings underscore the critical role of NAD⁺ de novo synthesis in maintaining NAD⁺ homeostasis and highlight its importance in meiotic recombination and meiotic sex chromosome inactivation in spermatogenesis.

The onset of multiple sclerosis (MS) in older individuals correlates with a higher risk of developing primary progressive MS, faster progression to secondary progressive MS, and increased disability accumulation. This phenomenon can be related to age-related changes in the immune system: with age, the immune system undergoes a process called immunosenescence, characterized by a decline in the function of both the innate and adaptive immune responses. This decline can lead to a decreased ability to control inflammation and repair damaged tissue. Additionally, older individuals often experience a shift toward a more pro-inflammatory state, known as inflammaging, which can exacerbate the progression of neurodegenerative diseases like MS. Therefore, age-related alterations in the immune system could be responsible for the difference in the phenotype of MS observed in older and younger patients. In this study, we investigated the effects of age on the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). Our findings indicate that EAE is more severe in aged mice due to a more inflammatory and neurodegenerative environment in the central nervous system. Age-related changes predominantly affect adaptive immunity, characterized by altered T cell ratios, a pro-inflammatory Th1 response, increased regulatory T cells, exhaustion of T cells, altered B cell antigen presentation, and reduced NK cell maturation and cytotoxicity. Transcriptomic analysis reveals that fewer pathways and transcription factors are activated with age in EAE. These findings allow us to identify potential therapeutic targets specific to elderly MS patients and work on their development in the future.

Dietary metal ions significantly influence the lifespan and reproduction of Drosophila females. In this study, we show that not adding any of the metal ions to the diet adversely affects reproduction and lifespan. By contrast, food with no added Zn negatively impacts reproduction but does not adversely affect maternal lifespan, indicating it can dictate resource reallocation between key fitness traits. Specifically, it indicates that female flies stop producing eggs to conserve their body Zn for somatic maintenance. Although these data show that flies can sense varying dietary Zn levels to adjust their physiology, they cannot maximise egg production when faced with a choice between food with no added Zn or food with sufficient Zn to support maximum reproduction. Nonetheless, they can choose to preferentially oviposit on Zn-containing food, perhaps indicating a strategy to assure offspring survival. We also uncovered a role for the white gene in sustaining high levels of egg viability when Zn is diluted in the diet. These insights into the role of dietary metal ions, particularly Zn, point to a central role for these dietary micronutrients to indicate environmental quality and so govern trade-offs between lifespan and reproduction in flies.

Renal proximal tubular epithelial cell (PTEC) senescence and defective autophagy contribute to kidney aging, but the mechanisms remain unclear. Caveolin-1 (CAV1), a crucial component of cell membrane caveolae, regulates autophagy and is associated with cellular senescence. However, its specific role in kidney aging is poorly understood. In this study, we generated Cav1 gene knockout mice and induced kidney aging using D-galactose (D-gal). The results showed that CAV1 expression increased in the renal cortex of the aging mice, which was accompanied by exacerbated renal interstitial fibrosis, elevated levels of senescence-associated proteins γH2AX and p16^INK4a, and increased β-galactosidase activity. Moreover, autophagy and AMPK phosphorylation in PTECs were reduced. These phenotypes were partially reversed in D-gal-induced Cav1 knockout mice. Similar results were observed in D-gal-induced human proximal tubular epithelial (HK-2) cells, but these effects were blocked when AMPK activation was inhibited. Additionally, in CaMKK2 knockdown HK-2 cells, siCAV1 failed to promote AMPK phosphorylation, whereas this effect persisted when STK11 was knocked down. Besides, we examined the phosphorylation of CaMKK2 and found that siCAV1 increased its activity. Given that CaMKK2 activity is affected by intracellular Ca²⁺, we examined Ca²⁺ levels in HK-2 cells and found that D-gal treatment reduced intracellular Ca²⁺ concentration, but CAV1 knockdown did not alter these levels. Through GST pull-down assays, we demonstrated a direct interaction between CAV1 and CaMKK2. In conclusion, these findings suggest that CAV1 exacerbates renal tubular epithelial cell senescence by directly interacting with CaMKK2, suppressing its activity and AMPK-mediated autophagy via a Ca²⁺-independent pathway.