Enhancing Cellular Homeostasis: Targeted Botanical Compounds Boost Cellular Health Functions in Normal and Premature Aging Fibroblasts.

The human skin, the body's largest organ, undergoes continuous renewal but is significantly impacted by aging, which impairs its function and leads to visible changes. This study aimed to identify botanical compounds that mimic the anti-aging effects of baricitinib, a known JAK1/2 inhibitor. Through in silico screening of a botanical compound library, 14 potential candidates were identified, and 7 were further analyzed for their effects on cellular aging. The compounds were tested on both normal aged fibroblasts and premature aging fibroblasts derived from patients with Hutchinson-Gilford Progeria Syndrome (HGPS). Results showed that these botanical compounds effectively inhibited the JAK/STAT pathway, reduced the levels of phosphorylated STAT1 and STAT3, and ameliorated phenotypic changes associated with cellular aging. Treatments improved cell proliferation, reduced senescence markers, and enhanced autophagy without inducing cytotoxicity. Compounds, such as Resveratrol, Bisdemethoxycurcumin, Pinosylvin, Methyl P-Hydroxycinnamate, cis-Pterostilbene, and (+)-Gallocatechin, demonstrated significant improvements in both control and HGPS fibroblasts. These findings suggest that these botanical compounds have the potential to mitigate age-related cellular alterations, offering promising strategies for anti-aging therapies, particularly for skin health. Further in vivo studies are warranted to validate these results and explore their therapeutic applications.

Inhibition of poly(ADP-Ribosyl)ation reduced vascular smooth muscle cells loss and improves aortic disease in a mouse model of human accelerated aging syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder associated with features of accelerated aging. HGPS is an autosomal dominant disease caused by a de novo mutation of LMNA gene, encoding A-type lamins, resulting in the truncated form of pre-lamin A called progerin. While asymptomatic at birth, patients develop symptoms within the first year of life when they begin to display accelerated aging and suffer from growth retardation, and severe cardiovascular complications including loss of vascular smooth muscle cells (VSMCs). Recent works reported the loss of VSMCs as a major factor triggering atherosclerosis in HGPS. Here, we investigated the mechanisms by which progerin expression leads to massive VSMCs loss. Using aorta tissue and primary cultures of murine VSMCs from a mouse model of HGPS, we showed increased VSMCs death associated with increased poly(ADP-Ribosyl)ation. Poly(ADP-Ribosyl)ation is recognized as a post-translational protein modification that coordinates the repair at DNA damage sites. Poly-ADP-ribose polymerase (PARP) catalyzes protein poly(ADP-Ribosyl)ation by utilizing nicotinamide adenine dinucleotide (NAD+). Our results provided the first demonstration linking progerin accumulation, augmented poly(ADP-Ribosyl)ation and decreased nicotinamide adenine dinucleotide (NAD+) level in VSMCs. Using high-throughput screening on VSMCs differentiated from iPSCs from HGPS patients, we identified a new compound, trifluridine able to increase NAD+ levels through decrease of PARP-1 activity. Lastly, we demonstrate that trifluridine treatment in vivo was able to alleviate aortic VSMCs loss and clinical sign of progeria, suggesting a novel therapeutic approach of cardiovascular disease in progeria.

The syntaxin-binding protein STXBP5 regulates progerin expression.

Hutchinson-Gilfor progeria syndrome (HGPS) is caused by a mutation in Lamin A resulting in the production of a protein called progerin. The accumulation of progerin induces inflammation, cellular senescence and activation of the P53 pathway. In this study, through public dataset analysis, we identified Syntaxin Binding Protein 5 (STXBP5) as an influencing factor of progerin expression. STXBP5 overexpression accelerated the onset of senescence, while STXBP5 deletion suppressed progerin expression, delayed senility, and decreased the expression of senescence-related factors. STXBP5 and progerin have synergistic effects and a protein-protein interaction. Through bioinformatics analysis, we found that STXBP5 affects ageing-related signalling pathways such as the mitogen-activated protein kinase (MAPK) pathway, the hippo pathway and the interleukin 17 (IL17) signalling pathway in progerin-expressing cells. In addition, STXBP5 overexpression induced changes in transposable elements (TEs), such as the human endogenous retrovirus H internal coding sequence (HERVH-int) changes. Our protein coimmunoprecipitation (Co-IP) results indicated that STXBP5 bound directly to progerin. Therefore, decreasing STXBP5 expression is a potential new therapeutic strategy for treating ageing-related phenotypes in patients with HGPS.

Nuclear envelope budding inhibition slows down progerin-induced aging process.

Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti-aging, and provide a distinct avenue for treating HGPS.

Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging.

Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell-specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle-related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.

Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes.

Lipodystrophic laminopathies are a group of ultra-rare disorders characterised by the presence of pathogenic variants in the same gene (LMNA) and other related genes, along with an impaired adipose tissue pattern and other features that are specific of each of these disorders. The most fascinating traits include their complex genotype-phenotype associations and clinical heterogeneity, ranging from Dunnigan disease, in which the most relevant feature is precisely adipose tissue dysfunction and lipodystrophy, to the other laminopathies affecting adipose tissue, which are also characterised by the presence of signs of premature ageing (Hutchinson Gilford-progeria syndrome, LMNA-atypical progeroid syndrome, mandibuloacral dysplasia types A and B, Nestor-Guillermo progeria syndrome, LMNA-associated cardiocutaneous progeria). This raises several questions when it comes to understanding how variants in the same gene can lead to similar adipose tissue disturbances and, at the same time, to such heterogeneous phenotypes and variable degrees of metabolic abnormalities. The present review aims to gather the molecular basis of adipose tissue impairment in lipodystrophic laminopathies, their main clinical aspects and recent therapeutic strategies. In addition, it also summarises the key aspects for their differential diagnosis.

Inflammation and Fibrosis in Progeria: Organ-Specific Responses in an HGPS Mouse Model.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina's structure. In our study, we conducted a histopathological analysis of various organs in the LmnaG609G/G609G mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage.

Premature aging effects on COVID-19 pathogenesis: new insights from mouse models.

Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using an Hutchinson-Gilford progeria syndrome (HGPS) mouse model, a premature aging disease model, with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SARS-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract hemorrhage, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a useful tool for investigating COVID-19 pathogenesis in individuals with premature aging.

Navigating Lipodystrophy: Insights from Laminopathies and Beyond.

Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.

The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.

The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24-/- mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a LmnaG609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3-inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile further improved the effect of lonafarnib, the only FDA-approved drug for the progeria. The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co-adjuvant treatment with lonafarnid in HGPS.

Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence.

Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H2O2), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.

Cardiac and skeletal muscle manifestations in the G608G mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence-associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS.

mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.

The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24-/- progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24-/- myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24-/- myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24-/- myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24-/- myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.

Progerin forms an abnormal meshwork and has a dominant-negative effect on the nuclear lamina.

Progerin, the protein that causes Hutchinson-Gilford progeria syndrome, triggers nuclear membrane (NM) ruptures and blebs, but the mechanisms are unclear. We suspected that the expression of progerin changes the overall structure of the nuclear lamina. High-resolution microscopy of smooth muscle cells (SMCs) revealed that lamin A and lamin B1 form independent meshworks with uniformly spaced openings (~0.085 µm2). The expression of progerin in SMCs resulted in the formation of an irregular meshwork with clusters of large openings (up to 1.4 µm2). The expression of progerin acted in a dominant-negative fashion to disrupt the morphology of the endogenous lamin B1 meshwork, triggering irregularities and large openings that closely resembled the irregularities and openings in the progerin meshwork. These abnormal meshworks were strongly associated with NM ruptures and blebs. Of note, the progerin meshwork was markedly abnormal in nuclear blebs that were deficient in lamin B1 (~50% of all blebs). That observation suggested that higher levels of lamin B1 expression might normalize the progerin meshwork and prevent NM ruptures and blebs. Indeed, increased lamin B1 expression reversed the morphological abnormalities in the progerin meshwork and markedly reduced the frequency of NM ruptures and blebs. Thus, progerin expression disrupts the overall structure of the nuclear lamina, but that effect-along with NM ruptures and blebs-can be abrogated by increased lamin B1 expression.

Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate.

Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue specific and not simply driven by protein expression differences. Experimental interrogation in killifish and yeast, combined with machine learning, indicates that this specificity is linked to protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during vertebrate aging and identify strong, tissue-specific associations with dysfunction and disease.

LEMD2-associated progeroid syndrome: Expanding the phenotype of the nuclear envelopathy caused by a defect in LEMD2 gene.

Nuclear envelopathies are rare genetic diseases that compromise the integrity of the nuclear envelope. Patients with a defect in LEM domain nuclear envelope protein 2 (LEMD2) leading to LEMD2-associated progeroid syndrome are exceedingly scarce in number, yet they exhibit shared clinical features including skeletal abnormalities and a prematurely-aged appearance. Our study broadens the understanding of LEMD2-associated progeroid syndrome by detailing its phenotypic and molecular characteristics in the first female and fourth reported case, highlighting a distinct impact on metabolic functions. The patient's history revealed growth delay, facial and skeletal abnormalities, and recurrent abdominal pain crises caused by hepatomegaly. Comparisons with the previously documented cases emphasized similarities in skeletal and facial features while showcasing unique variations, notably in cardiac and hepatic manifestations. In vitro experiments conducted on patient-derived peripheral blood and urinary epithelial cells and LEMD2-downregulated HepG2 cells confirmed abnormalities in the structure of the nuclear envelope in all three tissue-types. Overall, our work offers a comprehensive profile of a patient with LEMD2-related syndrome, emphasizing the hepatic involvement in the disease and broadening our understanding of clinical and molecular implications. This study not only contributes specific insights into LEMD2-related conditions but also underscores potential therapeutic paths for disorders affecting nuclear envelope dynamics.

Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and precipitates death. Given that atherosclerosis complications are the main cause of death in progeria, here, we investigated whether progerin-induced atherosclerosis is prevented in HGPSrev-Cdh5-CreERT2 and HGPSrev-SM22α-Cre mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. HGPSrev-Cdh5-CreERT2 mice were undistinguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of HGPSrev-SM22α-Cre mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain-of-function mutant. While HGPSrev-Cdh5-CreERT2 and HGPSrev mice developed a similar level of excessive atherosclerosis, plaque development in HGPSrev-SM22α-Cre mice was reduced to wild-type levels. Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents exacerbated atherosclerosis in progeroid mice.

Doxycycline decelerates aging in progeria mice.

Beyond the antimicrobial activity, doxycycline (DOX) exhibits longevity-promoting effect in nematodes, while its effect on mammals is unclear. Here, we applied a mouse model of Hutchinson-Gilford progeria syndrome (HGPS), Zmpste24 knockout (KO) mice, and analyzed the antiaging effect of DOX. We found that the DOX treatment prolongs lifespan and ameliorates progeroid features of Zmpste24 KO mice, including the decline of body and tissue weight, exercise capacity and cortical bone density, and the shortened colon length. DOX treatment alleviates the abnormal nuclear envelope in multiple tissues, and attenuates cellular senescence and cell death of Zmpste24 KO and HGPS fibroblasts. DOX downregulates the level of proinflammatory IL6 in both serum and tissues. Moreover, the elevated α-tubulin (K40) acetylation mediated by NAT10 in progeria, is rescued by DOX treatment in the aorta tissues in Zmpste24 KO mice and fibroblasts. Collectively, our study uncovers that DOX can decelerate aging in progeria mice via counteracting IL6 expression and NAT10-mediated acetylation of α-tubulin.

Progeria-based vascular model identifies networks associated with cardiovascular aging and disease.

Hutchinson-Gilford Progeria syndrome (HGPS) is a lethal premature aging disorder caused by a de novo heterozygous mutation that leads to the accumulation of a splicing isoform of Lamin A termed progerin. Progerin expression deregulates the organization of the nuclear lamina and the epigenetic landscape. Progerin has also been observed to accumulate at low levels during normal aging in cardiovascular cells of adults that do not carry genetic mutations linked with HGPS. Therefore, the molecular mechanisms that lead to vascular dysfunction in HGPS may also play a role in vascular aging-associated diseases, such as myocardial infarction and stroke. Here, we show that HGPS patient-derived vascular smooth muscle cells (VSMCs) recapitulate HGPS molecular hallmarks. Transcriptional profiling revealed cardiovascular disease remodeling and reactive oxidative stress response activation in HGPS VSMCs. Proteomic analyses identified abnormal acetylation programs in HGPS VSMC replication fork complexes, resulting in reduced H4K16 acetylation. Analysis of acetylation kinetics revealed both upregulation of K16 deacetylation and downregulation of K16 acetylation. This correlates with abnormal accumulation of error-prone nonhomologous end joining (NHEJ) repair proteins on newly replicated chromatin. The knockdown of the histone acetyltransferase MOF recapitulates preferential engagement of NHEJ repair activity in control VSMCs. Additionally, we find that primary donor-derived coronary artery vascular smooth muscle cells from aged individuals show similar defects to HGPS VSMCs, including loss of H4K16 acetylation. Altogether, we provide insight into the molecular mechanisms underlying vascular complications associated with HGPS patients and normative aging.

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder.

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1's physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging.