Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan. Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. This drug was based on our laboratory's early 1990s discovery that mutating a codon for a conserved glycine-at position 119 in bovine GH or 120 in human GH-to a variety of amino acids, including lysine, ultimately converted GH from an agonist to antagonist. Since Pegvisomant has poor affinity to rodent GHR, it has not been tested for its ability to extend lifespan in rodents. To address this gap, we evaluated survival in GHA transgenic mice, a mouse line that played a crucial role in the discovery and development of Pegvisomant and has been maintained in our lab since 1991. While a prior study with several limitations failed to detect lifespan extension in GHA mice, our current study addressing these limitations shows that both median and maximal lifespan were significantly increased in male (p = 0.044; p = 0.0037) and female GHA mice (p = 2 × 10-8; p = 9 × 10-6), with maximal lifespan extended by 186 and 265 days, respectively. Analysis of an independent cohort of 2-year-old mice revealed that GHA males and females were less frail with enhanced grip strength despite increased adiposity. These findings demonstrate for the first time that GH antagonism can improve health and extend lifespan.
Cell division inevitably shortens telomeric DNA owing to the end-replication problem. Eukaryotic chromosomes possess specialized telomere structures to maintain genomic stability. In most proliferative cells, telomerase adds telomeric repeats during S-phase. In differentiated cells where telomerase is silenced, telomeres shorten progressively, thereby compromising genomic integrity. Consequently, cancer cells universally activate alternative telomere maintenance mechanisms during malignant transformation: ~80% reactivate telomerase, while a portion of the rest rely on BIR (break-induced replication)-mediated homologous recombination-based ALT (alternative lengthening of telomeres). Although these mechanisms are stable once established, the initial determinants influencing a cancer cell's choice remain poorly understood. This review discusses recent molecular insights into how telomeric chromatin properties profoundly impact this choice. After briefly introducing telomere chromatin characteristics and key players in its maintenance and dynamics, we discuss the mechanisms by which cancer cells acquire distinct telomere replication capabilities. In particular, we present an in-depth analysis linking telomere heterochromatin status to ALT. Furthermore, based on recent advances, we propose a coupled feedforward loop model explaining how the ALT state becomes "locked in" once initiated. Finally, we offer novel perspectives on rational, telomere-centric therapeutic interventions for ALT-positive cancers, focusing on strategies designed to disrupt such feedforward loops by manipulating telomeric chromatin structure.
Androgenetic alopecia (AGA) is the most common form of non-scarring hair loss, driven by genetic factors and increased sensitivity of scalp hair follicles to dihydrotestosterone (DHT), which causes progressive miniaturization of dermal papilla cells and shortens the hair growth phase. The precise molecular pathogenesis of AGA remains incompletely understood. The study aimed to elucidate the regulatory mechanism between secreted frizzled-related protein 2 (SFRP2) and follistatin-like 1 (FSTL1), explore their impact on DHT-induced mitochondrial dysfunction and senescence in dermal papilla cells (DPCs), elucidate the effect of the SFRP2-FSTL1 axis on oxidative stress-related DPCs changes, and identify new therapeutic targets for AGA treatment. In the study, SFRP2 was highly expressed in the DPCs of AGA patients. Knocking down SFRP2 improved hair regeneration and follicle morphology within AGA model mice, promoting proliferation, migration, and invasion of DPCs in vitro. SFRP2 knockdown also alleviated inflammation, senescence, mitochondrial dysfunction, and oxidative stress. SFRP2 was found to bind to FSTL1, thereby promoting FSTL1 protein stability. Knocking down FSTL1 counteracted the negative effects of SFRP2 overexpression in vitro. In conclusion, SFRP2 emerges as a critical regulator in AGA by promoting stability and activity of FSTL1, establishing a novel SFRP2-FSTL1 axis that exacerbates DHT-driven pathogenic changes in DPCs. These findings identify SFRP2 and FSTL1 as key mediators of androgen-induced cellular dysfunction and suggest that disrupting this axis could offer a promising therapeutic strategy for slowing or reversing the progression of AGA.
Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model. Midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling. Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.
Aging kidneys exhibit accumulation of senescent cells together with sterile low-grade inflammation. However, the spatial organization of senescence-associated immune cell accumulation in the aging kidney remains poorly defined. We systematically analyzed kidneys from young, middle-aged, and aged mice, focusing on the spatial relationship between senescent tubular cells and distinct immune cell populations. Senescent tubular cells showed significant local enrichment of immune cells, with macrophages representing the most prominent associated immune cell population. This spatial association was more closely linked to p16Ink4a burden as an indicator of biological aging than to chronological age alone, as kidneys with higher p16Ink4a levels displayed enhanced inflammatory and SASP-associated transcriptional signatures. Complementary spatial transcriptomic analyses identified a cortex-restricted senescence-associated neighborhood enriched for inflammatory, macrophage-related, and failed-repair tubular transcriptional programs, supporting the presence of localized senescence-associated inflammatory niches at the transcriptomic level. Both, genetic and pharmacological senolytic interventions reduced senescent-cell burden and decreased immune cell accumulation in aged kidneys. However, macrophages remained preferentially localized near residual senescent tubular structures after senolysis, consistent with persistent local immune senescent cell interactions. Our findings provide quantitative spatial evidence that senescence-associated inflammatory niches emerge in the aging kidney cortex and can be modulated by senolytic intervention. Together, these results establish a spatial framework for renal inflammaging and highlight senescence-associated inflammatory microenvironments as potential therapeutic targets in kidney aging.
The global aging trend underscores the urgent need for innovative interventions against aging-related decline. Accumulating evidence identifies Akkermansia muciniphila (A. muciniphila) as a key gut microbiota regulator of aging, with its depletion associated with age-related diseases (ARDs), whereas its abundance is enriched in healthy centenarians. This review summarized current evidence linking A. muciniphila to aging, examining their causal relationship, the roles of its bioactive derivatives, underlying mechanisms in aging and ARDs, findings from human clinical trials, and challenges in therapeutic translation. Clinically, A. muciniphila depletion correlated with aging and various ARDs, while its supplementation effectively ameliorated neurodegenerative disorders, metabolic dysfunction, musculoskeletal decline, intestinal barrier dysfunction, and atherosclerosis. Mechanistically, A. muciniphila and its derivatives (Amuc_1100, Amuc_1409, extracellular vesicles, and metabolites such as SCFAs) exerted anti-aging effects by enhancing intestinal barrier function, maintaining metabolic homeostasis, suppressing chronic inflammation, and modulating immune function, ultimately improving glucolipid metabolism, insulin sensitivity, cognitive function, musculoskeletal health, and vascular health. Emerging clinical trials further demonstrated its translational potential in ameliorating age-related sarcopenia, metabolic dysfunction, and respiratory symptoms. Despite promising preclinical and clinical results, translational applications reserve challenges related to strain heterogeneity, antimicrobial resistance gene transfer risk, biosafety, production stability, and limited clinical validation in elderly populations. Future research should prioritize large-scale clinical trials to establish optimal dosage, safety, and long-term efficacy, while exploring combined microbiota-targeted therapies. Harnessing the diverse benefits of A. muciniphila may enable novel strategies for promoting healthy aging.
The health impacts and underlying biological pathways of thigh muscle fat infiltration (TMFI) remain incompletely understood. In this study, we analyzed TMFI measured by magnetic resonance imaging in 55,120 UK Biobank participants and found that higher TMFI was significantly associated with all-cause mortality as well as with all major system-specific diseases examined (p values ranged from 2.50 × 10-88 to 9.97 × 10-04). TMFI also mediated the effects of lifestyle factors on health-related outcomes, with mediation proportions ranging from 6.7% to 71.7%. A genome-wide association study (GWAS) identified 79 lead single nucleotide polymorphisms (SNPs) linked to TMFI, and the polygenic risk score for TMFI was significantly associated with mortality and all incident diseases across examined organ systems in an independent subset of UK Biobank participants of European ancestry who were not included in the TMFI GWAS (n = 362,286, all p < 0.05). Gene-drug interactions identified multiple drugs that could potentially modulate TMFI. Analysis of single-cell transcriptomic data indicated that myogenic cells were strongly linked to TMFI (p = 7.08 × 10-08). Summary-data-based Mendelian randomization and Transcriptome-Wide Association Study analyses revealed numerous genes whose expression in specific tissues was associated with TMFI. Proteomic and metabolomic profiling uncovered a broad array of circulating biomarkers associated with TMFI, many of which mediated the effects of modifiable factors and genetic risk on TMFI. Overall, our results highlight the biological relevance of TMFI to human health and provide insights into the multi-omics mechanisms underlying TMFI, identifying potential targets for interventions.
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation. Dysregulation of the brain renin-angiotensin system, particularly hyperactivation of the angiotensin II type-1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type-2 receptor (AT2R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT2R-related Aβ reduction and the role of AT2R-interacting protein (ATIP), also known as AT2R-binding protein, remain unclear. We aimed to explore the relationship between ATIP and Aβ and tau pathologies as well as brain AT2R protein levels in older adults with AD. Using TOMAHAQ, a method that enables precise examination of numerous peptides across various samples in a single mass spectrometry analysis, we identified a specific human tryptic peptide that enables ATIP quantification. We applied this method to postmortem frontal-cortex samples to measure ATIP levels. Sixty individuals with AD were included, half of whom were users of angiotensin receptor blockers (ARBs). The ATIP peptide was quantifiable in 12 participants. Among these individuals, higher ATIP levels were associated with lower Aβ burden in the frontal-cortex and across multiple brain regions. This association remained significant after adjustment for age and ARB use. In contrast, ATIP levels were not significantly associated with AT2R, which was quantified using TOMAHAQ. This suggests that the relationship between ATIP and Aβ burden may not depend on differences in AT2R abundance. Although causality cannot be established, these findings may suggest a potential protective role for ATIP in AD that warrants further investigation.
SIRT1, a sirtuin family member, has been extensively documented to be closely linked to aging and aging-related disease. Cellular senescence is a state of irreversible cell cycle arrest that functions as a key driver of aging. During cellular senescence, LINE-1 (L1) retrotransposable elements become transcriptionally activated and stimulate a type-I interferon (IFN-I) response. L1 activity has been strongly linked to aging and a variety of age-related disorders. However, whether SIRT1 influences cellular senescence through the transposable element L1 remains unknown. In this study, we discovered that SIRT1 significantly suppresses L1 retrotransposition. Under quiescent conditions, SIRT1 exhibits increased enrichment at the L1 5'-UTR region. This recruitment enhances its interaction with the heterochromatin-regulatory factors Lamin B1 and KAP1, subsequently elevating H3K9me3 levels. This repressive chromatin mark inhibits L1 transcription, thereby maintaining genomic stability and delaying cellular senescence. Consistent with these observations, SIRT1-deficient cell lines exhibited a marked reduction of the interaction of Lamin B1 and KAP1 and a reduced presence of these factors at the L1 5'-UTR. Consequently, the elevated L1 transcription resulting from SIRT1 deficiency activated the cGAS-STING pathway and ultimately triggered cellular senescence, an effect that was rescued by treatment with 3TC (a nucleoside reverse transcriptase inhibitor). In summary, our findings demonstrate that SIRT1 suppresses L1 retrotransposition by recruiting heterochromatin factors, thereby delaying cellular senescence and providing new insights with implications for delaying aging and mitigating age-related pathologies.
Miscarriage and abnormal embryonic development in women of advanced maternal age (AMA) are often associated with impaired decidualization. mTORC2 is an evolutionarily conserved protein kinase. As a core component of mTORC2, RICTOR has been implicated in nutrient sensing and is closely linked to implantation disorders; however, its role in regulating age-related decidualization disorders remains unreported. In this study, we identified pronounced decidualization defects in AMA foster mice, accompanied by a significant reduction in RICTOR in the decidual tissues of AMA women. Uterine-specific genetic deletion of Rictor in mice resulted in pregnancy loss and impaired decidualization. Notably, Rictor knockdown led to attenuated Akt3-FoxO1 signaling and impaired nuclear export of FoxO1. Molecular and histological analyses demonstrated that the specific RICTOR activator MHY1485 effectively rescued decidualization defects in vivo and in vitro. These findings indicate that RICTOR plays an essential role in the aging decidual microenvironment and may serve as a potential biomarker for uterine stromal cell decidualization. Furthermore, therapeutic activation of RICTOR represents a promising strategy to counteract senescent decidual impairment in AMA women and improve pregnancy outcomes.
Age-related taste dysfunction impairs nutrition and quality of life, contributing to metabolic disorders and frailty in the elderly, yet its cellular and molecular basis remains poorly understood. By integrating single-cell RNA and spatial transcriptomics sequencing, we systematically mapped murine taste bud aging across five developmental stages from neonatal to aged. Our findings reveal that age-associated taste impairment is driven by the progressive depletion of stem/progenitor cell differentiation capacity, predominantly characterized in the posterior tongue, and mediated by inflamm-aging responses and micro-environmental alterations. Specifically, we identified macrophage infiltration and polarization shifts in aged circumvallate and foliate papillae, underscoring the crucial role of macrophages in age-related taste decline. A co-culture model using taste organoids with conditioned media from polarized macrophage revealed that M1-polarized cells suppress taste organoid proliferation and differentiation. Mechanistically, this inhibition may be mediated by macrophage-derived Thbs1, as recombinant Thbs1 treatment directly suppressed taste progenitor cell expansion in vitro. Together, this study provides the first comprehensive spatiotemporal atlas of taste bud aging and identifies novel therapeutic targets for the treatment of age-related taste disorders.
Ageing impairs immune function, increasing susceptibility to infection, autoimmunity and inflammation. The thymus undergoes involution during childhood, and thymocyte and thymic epithelial cell (TEC) numbers decline. Given that adaptive immunity depends on T-cells recognising diverse antigens via their unique T-cell receptor (TCR), the precise age-related changes in TCR repertoire composition are key to understand immunity. To investigate the influence of age on the thymic TCR repertoire we sequenced TCRα and TCRβ transcripts from developmentally defined thymocyte populations from 4-week, 12-month and 18-month-old mice, and from thymocytes recovering from hydrocortisone-treatment, and athymic recipients of RAG1-deficient thymus transplants. The 18-month thymus selected TCR repertoires with distinctive patterns of VxJ and CDR3 k-mer usage compared to young thymus, indicating it had a qualitatively different repertoire with different specificity. It also selected a less diverse TCRβ repertoire with more expanded clones than young thymus. On recovery from hydrocortisone-treatment, both 4-week and 12-month thymus showed bias towards foetal-like 3'TRAVx5'TRAJ rearrangements, but 12-month thymus also produced less diverse and evenly distributed TCRβ repertoires, with increased expansion of TCRβ clones at the CD4-CD8-CD25+CD44-intracellularTCRβ+ stage, increased TRBJ-1-cluster usage and distinctive patterns of combinatorial VxJ usage. Transplantation of athymic nude recipients with old RAG1-deficient thymus generated less diverse, less evenly distributed TCR repertoires with different combinatorial VxJ usage than those generated by young transplants. Taken together our experiments show that the old thymus generates qualitatively different TCR repertoires than young thymus and the non-lymphoid compartment of the thymus contributes strongly to these changes and to age-associated decline in TCR repertoire diversity.
The clinical outcomes of trabeculectomy, a standard glaucoma filtration surgery (GFS), have dramatically improved with the introduction of mitomycin C (MMC), an antimetabolite widely used to inhibit postoperative scarring. MMC exerts anti-scarring effects primarily by promoting apoptosis and suppressing fibroblast proliferation at the surgical site. However, despite these beneficial effects, MMC also induces the production of inflammatory cytokines, and its full mechanism of action remains incompletely understood. Moreover, a subset of patients continues to experience poor surgical outcomes even after MMC application, highlighting the need for complementary therapeutic strategies. Comprehensive transcriptomic analysis of postoperative GFS tissues revealed that MMC promoted the expression of genes associated with cellular senescence and inflammatory responses. Supporting this, in vitro experiments suggested that the transcriptional changes were associated with MMC-induced senescence-associated secretory phenotype (SASP)-like changes in the fibroblasts. Single-cell RNA sequencing (scRNA-Seq) analyses of postoperative GFS tissues also revealed that fibroblasts after GFS with MMC secrete SASP factors. Furthermore, Cell-Cell communication analysis identified CCL7 as one of the key molecules involved in inflammatory cell migration and the promotion of fibrosis. Importantly, we demonstrated that fibroblasts exhibiting SASP-like features can be selectively eliminated by a specific senolytic agent, suggesting a novel and promising therapeutic approach that may improve long-term surgical outcomes after GFS.
Cellular senescence is a fundamental hallmark of aging and represents a major barrier to the scalable and reproducible application of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs). Senescent human umbilical cord mesenchymal stromal cells (hUCMSCs) exhibit impaired proliferative capacity, disrupted mitochondrial homeostasis, and altered secretory phenotypes, which may compromise the biological activity and therapeutic reliability of sEVs. Here, we investigated whether overexpression of human telomerase reverse transcriptase (hTERT) attenuates senescence-associated deterioration and stabilizes sEV functional properties. Late-passage hUCMSCs displayed canonical senescence features and mitochondrial dysfunction, all of which were markedly alleviated by hTERT expression. Functionally, sEVs derived from senescent cells exhibited impaired immunomodulatory activity, whereas sEVs from hTERT-expressing cells largely restored this function. Mechanistically, senescence was associated with altered sEV cargo, including enrichment of miR-217-5p, which contributed to diminished immunomodulatory potency, at least in part through modulation of SIRT1-associated inflammatory signaling in recipient macrophages. Proteomic profiling further showed that H11-sEVs retained a young-like protein cargo profile, particularly for proteins associated with immune and inflammatory regulation. In parallel, sEVs from all three groups retained primordial follicle-activating capacity, consistent with the broad retention of PI3K-Akt pathway-related proteins in their proteomic profiles and PI3K-Akt pathway activation in ovarian tissues. In aged female mice, H11-sEVs exhibited young-like ovarian protective activity. Collectively, these findings demonstrate that hTERT uncouples cellular senescence from sEV functional decline, supporting the development of potency-stabilized sEV sources for aging-related and regenerative applications and providing insight into the biological roles of senescent cell-derived sEVs.
Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.
Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age-related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium-activated potassium (BK) channel currents (IK,f) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.
Cell therapies represent a promising frontier in modern medicine. Mesenchymal stromal cells (MSCs) constitute a valuable source due to their minimal ethical concerns, low immunogenicity, negligible tumorigenicity in vivo, and robust paracrine activity mediated by the secretion of anti-inflammatory and angiogenic factors. Despite these advantages, MSCs undergo rapid replicative senescence accompanied by a progressive loss of stemness markers and functional potency. In this context, cellular rejuvenation has been emerging as a pivotal strategy to restore their original biological features. These approaches aim to modulate the hallmarks of aging; as these processes are highly interconnected, multiple and complementary targets have been proposed. This review aims to discuss and analyze the main rejuvenation strategies reported in the literature for MSCs, with particular attention to approaches that can enhance their functionality and translational potential. In this context, the review focuses on five key categories of interventions: epigenetic modifications, metabolic reprogramming, modulation of cellular senescence, telomere biology, and extracellular vesicles. These strategies represent the fundamental axes through which cellular aging can be counteracted and the efficacy of cell-based therapies improved.
Adipose tissue senescence is increasingly recognized as a key driver of systemic aging and age-related functional decline, yet the endocrine regulators that actively promote this process remain poorly defined. Angiopoietin-like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging-related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Here, we identify ANGPTL8 as a previously unrecognized regulator of adipose tissue aging through integrative analyzes of human cohorts, animal models, transcriptomics, and cellular studies. In a large human cohort, circulating ANGPTL8 levels were strongly associated with biological aging and mortality risk and significantly improved machine learning-based models for age and survival prediction. Consistent with these findings, genetic deletion of Angptl8 in mice extended lifespan, attenuated aging-associated functional decline, and reduced senescence markers in adipose tissue. Transcriptomic analyzes revealed age-dependent upregulation of ANGPTL8 in adipocytes accompanied by activation of pro-senescent transcriptional programs. Mechanistically, ANGPTL8 directly interacted with AKT2 and activated the AKT-mTOR-S6K signaling pathway, thereby promoting cell-autonomous adipocyte senescence. Genetic or pharmacological inhibition of this pathway abolished the pro-senescent effects of ANGPTL8. Collectively, our findings identify ANGPTL8 as an endocrine regulator linking metabolic dysfunction to adipose tissue senescence and systemic aging, highlighting the ANGPTL8-AKT2-mTOR axis as a potential therapeutic target for delaying age-associated functional decline.
Ischemic postconditioning (I/Post), which is an effective intervention by activating endogenous cardioprotective pathways, recovers ischemia/reperfusion injury. However, this intervention is not as effective in older patients, and its mechanism needs to be further investigated. In this study, we found that myocardial telomeric repeat binding factor 2 (TRF2) protein expression in male aged mice (18 months of age) was lower than that in male adult mice (4 months of age). After ligation of the anterior descending branch of the heart to establish an in vivo model of ischemia/reperfusion injury, we found that TRF2 expression was further decreased after I/Post. To investigate the role of TRF2 in cardioprotection in I/Post in the senescent heart, we performed echocardiography, blood biochemical testing, and apoptosis-related detection after injecting adeno-associated virus type 9 overexpressing TRF2 into aged mice. We found that TRF2 improved myocardial I/Post protection in vivo. Knockdown of TRF2 in a cardiomyocyte cell line (HL-1) increased inflammatory factor release and aggravated mitochondrial and DNA damage in senescent myocardiocytes following hypoxic postconditioning (H/Post). TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes. Moreover, TRF2 interacted with casein kinase 2 alpha 2 polypeptide (CSNK2A2) to regulate the dephosphorylation of FUN14 domain-containing protein 1 (FUNDC1), which contributed to the protective effect of hypoxic postconditioning.
