Aging Cell最新文献

Aging is accompanied by a progressive decline in tissue regenerative capacity, driven by intrinsic stem cell dysfunction and age-associated deterioration of the surrounding stem cell niche. Mesenchymal stromal cells (MSCs) are ubiquitous components of stem cell niches, where they integrate structural, metabolic, inflammatory, and paracrine cues to regulate stem cell quiescence, activation, and differentiation. With age, MSCs undergo functional decline and senescence, altering their secretory and signaling profiles. Across tissues, MSC senescence emerges as an intermediate amplifier of aging: molecular, metabolic, epigenetic, and inflammatory stressors promote the senescent state, which converts these upstream insults into chemokine imbalance, chronic inflammation, and progressive loss of stem cell support. Here, we synthesize classical and emerging literature to examine how age-associated changes in MSC chemokine synthesis contribute to stem cell aging, and we propose a synthesis-based model in which MSCs translate age-associated stressors into altered chemokine repertoires that disrupt stem cell-supportive signaling. We also discuss therapeutic strategies, including chemokine-directed therapies, senolytics, and MSC rejuvenation, that may restore regenerative capacity by normalizing MSC-derived signals. Together, the evidence identifies dysregulated chemokine synthesis as a conserved mechanism linking tissue-resident MSC aging to declining regenerative capacity.

The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function. Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence. Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.

Ageing profoundly impairs vaccine efficacy, leaving older individuals highly susceptible to infectious diseases despite vaccination. Although B cells retain the intrinsic capacity to generate germinal centre (GC) responses in older people, age-associated defects in T cells, dendritic cells and follicular dendritic cells (FDCs) limit the development of high-affinity, class-switched antibody responses. Here, we hypothesised that senescent fibroblasts disrupt B cell activation and expansion, thus contributing to the diminution of the humoral response in ageing. To test this hypothesis, we established an in vitro system in which human tonsil-derived YK6 fibroblasts expressing CD40L are co-cultured with PBMC-derived B cells. B cell activation, proliferation, and phenotype in response to low- and high-stimulation conditions was determined in co-culture with control or bleomycin-treated YK6 fibroblasts. Control YK6 fibroblasts promoted B-cell activation and proliferation in both 2D and 3D cultures, whereas bleomycin-treated fibroblasts robustly inhibited B-cell proliferation without impairing early activation. Conditioned media from bleomycin-treated fibroblasts partially reduced B cell proliferation, although to a lesser extent than direct co-culture, suggesting cell-cell contact was key to inhibiting B cell proliferation. Bleomycin-treated YK6 fibroblasts upregulated genes associated with impaired lymphocyte responses, such as PDCD1LG2, which may impact B cell activation. Indeed, B cells co-cultured with bleomycin-treated fibroblasts failed to fully initiate glycolysis and were essentially unable to synthesise new protein. Together, these findings suggest that senescence-like changes in fibroblasts could restrict B-cell proliferative capacity, which may contribute to impaired B cell responses in ageing.

Aging represents a major contributor to the deterioration of female fertility, with oocyte quality being the central determinant of ovarian aging, a key factor underlying infertility. Although several natural compounds with anti-aging activity have been documented, highly effective strategies to reverse ovarian aging remain elusive. Here, we report that the peptide elamipretide preserves ovarian function and sustains female fertility during maternal aging. We found that elamipretide administration increases litter size in aged mice and ameliorates oocyte quality decline. Metabolomic and transcriptomic profiling revealed substantial restoration of multiple biological processes in aged oocytes after elamipretide injection. Elamipretide improved both nuclear and cytoplasmic maturation of aged oocytes, accompanied by enhanced cytoskeletal dynamics, mitochondrial metabolism, and organelle reorganization. Mechanistically, elamipretide alleviated age-associated oocyte maturation defects through synergistic activation of the vitamin B6-VEGF axis. Furthermore, elamipretide significantly promoted maturation, fertilization, and cleavage of aged human oocytes. Elamipretide treatment also rescued the developmental competence of porcine oocytes under oxidative damage. Collectively, this study identifies a novel peptide therapeutic candidate for aging-related infertility, showing that elamipretide restores the quality of aged oocytes for fertility by coordinately boosting nuclear and cytoplasmic maturation via activation of the VEGF signaling pathway.

Testosterone levels decline progressively with age from the third decade of life, impairing spermatogenesis and contributing to age-related disorders, underscoring the importance of enhancing endogenous testosterone production. DNA methyltransferase 1 (DNMT1) promotes testosterone synthesis in Leydig cells (LCs), yet the underlying mechanism remains unclear. Here, we found that DNMT1 expression is downregulated in aging rat testes and senescent LCs in vitro, correlating with reduced testosterone levels. Gain- and loss-of-function experiments confirmed that DNMT1 positively regulates testosterone synthesis and alleviates LC senescence, and that DNMT1 overexpression reverses the senescent phenotype and restores testosterone production. Mechanistically, RNA-seq of DNMT1-knockdown LCs identified FTO as a downstream target; DNMT1 suppresses FTO expression by promoting Fto promoter methylation. catRAPID prediction and RIP-qPCR validated Hsp90aa1 mRNA as a direct FTO substrate; FTO regulates HSP90AA1 expression through m⁶A modification, with DNMT1 indirectly modulating HSP90AA1 via FTO. Using HSP90AA1 overexpression, pharmacological inhibition, and rescue experiments, we confirmed that the DNMT1-FTO axis inhibits LC apoptosis through HSP90AA1-mediated AKT activation, thereby promoting testosterone synthesis. Expression patterns of this axis in aging rat testes and senescent LCs further corroborated its involvement in age-related testosterone dysregulation. In vivo AAV-mediated testicular DNMT1 knockdown recapitulated these findings. Collectively, our study elucidates the physiological role of DNMT1 in age-related testosterone decline and delineates the mechanism by which DNMT1 governs LC senescence and steroidogenic function, providing a potential therapeutic target for reproductive system aging.

Age-related hearing loss (ARHL) is a prevalent sensory disorder in the elderly, yet the molecular mechanisms underlying cochlear aging remain incompletely understood. While insulin-like growth factor 1 (IGF-1) has been implicated in ARHL, its role in the stria vascularis, particularly in pericyte-mediated blood-labyrinth barrier (BLB) regulation, is poorly defined. We performed transcriptomic analysis of FACS-purified pericytes from young and aged mouse stria vascularis. Functional studies were conducted using primary pericyte cultures, lentiviral gene modulation, and AAV-mediated in vivo delivery. Auditory function was assessed by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). Molecular changes were evaluated via qPCR, western blot, immunofluorescence, flow cytometry, and transmission electron microscopy (TEM). Transcriptomics revealed significant downregulation of Igf1 and Slc25a33 in aged pericytes, with enrichment of the TGF-β signaling pathway. IGF-1 deficiency suppressed SLC25A33 expression in vitro, leading to mitochondrial ROS (mtROS) accumulation, activation of TGF-β/Smad2 signaling, and pericyte phenotypic switching, characterized by increased α-SMA and decreased E-cadherin. In vivo, suppression of IGF-1 or SLC25A33 activated TGF-β/Smad2 signaling in the stria vascularis, disrupted BLB ultrastructure, and exacerbated hearing loss. Conversely, exogenous IGF-1 or SLC25A33 overexpression attenuated these effects and partially restored auditory function. Our findings identify a novel IGF-1/SLC25A33-TGF-β/Smad2 axis that regulates pericyte activation and BLB integrity in the aging cochlea. This pathway provides mechanistic insight into ARHL pathogenesis and highlights a potential therapeutic target for preserving hearing in older adults.

Aging exacerbates the incidence of discogenic chronic low back pain by excessive inflammation and immune cell presence. Aging reduces intervertebral disc (IVD) Wnt signaling, which is associated with IVD cell differentiation, IVD cell proliferation and anti-inflammatory signaling. However, it is unclear how in vivo Wnt signaling-absent IVD cells, which model aged IVD cells, regulate chemotactic signaling and immune cell recruitment. We hypothesized that Wnt signaling-absent IVD cells attenuate chemotactic transcription and immune cell recruitment to naive IVD and in response to IVD injury. First, because aging reduces Wnt signaling in all IVD cells, we deleted β-catenin using the AcanCreERT2. β-catenin deletion reduced monocyte chemoattractant protein-1 (MCP1/CCL2) Ccl2 in male and female IVDs by 58% and 79%, respectively (n = 5-6/sex). Using positron emission tomography/computed tomography (PET/CT) imaging of myeloid cells in 5-month-old mice (n = 4 IVD/sex/grp), deletion of β-catenin reduced myeloid-derived cell burden in naive IVD by 79% and attenuated IVD injury-induced recruitment by 48%. Next, because nucleus pulposus (NP) cells begin losing Wnt signaling early in life, we deleted β-catenin using the ShhCreERT2. Compared to RNA-sequencing of WT IVD post injury (n = 3/grp), deletion of β-catenin in NP cells impaired the activation of immune cell pathways, such as MCP1/CCL2. Together, the chemotactic transcriptomic response and myeloid cell accumulation due to IVD injury were impaired by the absence of IVD Wnt signaling transcription cofactor β-catenin. These data suggest that low-grade IVD inflammation and chronic IVD immune cell accumulation in aged IVD cells are regulated by IVD Wnt signaling.

Transcription factor-based direct conversion of somatic cells represents an interesting avenue for generating induced neural stem cells (iNSCs) from peripheral blood without transit through a pluripotent stage. While this paradigm has been shown to be associated with epigenetic de-aging, the dynamics of this process have remained unclear. Here, we used overexpression of the two reprogramming factors SOX2 and cMYC to generate iNSCs from erythroid progenitors of donors ranging from neonatal to 101 years of age. Using an epigenetic aging clock algorithm, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging, preserving around 13% and 5% of the original donor age at low and high passages, respectively. Studying the dynamics of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted, continuing for several weeks and even under proliferation-inhibiting conditions. Transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too. Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Interestingly, time course analysis of DNA methylation and RNA sequencing data revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge. The unexpected slow dynamics of these processes make iNSC conversion an attractive model for dissecting the mechanisms underlying somatic transdifferentiation and epigenetic de-aging.

Skeletal muscle is increasingly recognized as a secretory organ that communicates with distant tissues through the release of bioactive factors, including extracellular vesicles (EVs). During aging, muscle-derived EVs have emerged as important mediators of interorgan communication, influencing tissue homeostasis, regeneration, metabolism, and disease progression. Recent studies demonstrate that skeletal muscle EVs carry diverse cargos such as proteins, lipids, metabolites, and regulatory RNAs that can modulate the function of recipient cells in multiple organs. In particular, aging-associated alterations in EV biogenesis, cargo composition, and secretion may contribute to chronic inflammation, stem cell dysfunction, metabolic decline, and age-related pathologies. In this review, we summarize current advances in skeletal muscle-derived EV biology and their roles in interorgan communication during aging. We discuss mechanisms regulating EV formation and cargo loading, their impact on stem cell function and tissue regeneration, and their involvement in aging-related diseases. We also highlight the translational potential of muscle EVs as biomarkers and therapeutic targets. Together, these findings identify muscle-derived EVs as key regulators of systemic aging and interorgan signaling.