ハッチンソン・ギルフォード症候群

Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation of STING at Ser366 by CK2α, which promotes STING turnover and restricts its accumulation, thereby attenuating pathway activation and mitigating senescence in myeloid cells as well as systemic aging. Strikingly, pharmacologic STING inhibition in vivo robustly rescues progeroid phenotypes-including loss of bone density and multi-tissue senescence-and extends lifespan in progeroid mouse models. Moreover, H-151 treatment also ameliorates the premature aging phenotypes induced by myeloid-specific CK2α ablation. In contrast, constitutive STING ablation yields limited survival benefits, revealing that controlled attenuation of STING signaling, rather than complete elimination, drives therapeutic efficacy. Our findings establish the LMNA-CK2-STING axis as a key biochemical mechanism that suppresses innate immune activation at the NE, offering a promising strategy for ameliorating aging and progeroid pathologies.

Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of LmnaG609G/G609G, a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and naturally aging mice, and HP1β was decreased in Hmga1-/- mice. We further demonstrate that HMGA1 mitigates HGPS cellular senescence in a HP1β-dependent manner. Multi-omics reveals that HP1β downregulates angiopoietin-like protein 2 (ANGPTL2) by reducing chromatin accessibility, thereby suppressing SASP factors, and thus, alleviating senescence. Furthermore, HMGA1 stabilizes HP1β by recruiting de-ubiquitinating enzyme USP7. Based on the binding region of HMGA1 with HP1β and USP7, we develop a unique HMGA1 peptide (UHP) that prevents HP1β degradation, thereby ameliorating HGPS cellular senescence and significantly extending the lifespan of LmnaG609G/G609G mice. Our findings elucidate a critical HMGA1-HP1β axis in premature aging and suggest that therapeutic strategies based on UHP may hold promise for HGPS.

Preclinical research traditionally advances through hypothesis-driven experimentation that establishes mechanistic pathways to support translational development. While this approach has generated major biological insights, it may underemphasize alternative organizational patterns embedded within complex datasets, particularly in rare diseases where opportunities for experimental reiteration are limited. Recent advances in conversational artificial intelligence (AI) provide an opportunity to support structured analytical dialogue as a complementary approach for re-examining validated experimental observations. Here, we evaluated the feasibility and informative value of an investigator-led structured analytical dialogue to reinterpret a previously published preclinical study of Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disorder characterized by accelerated cardiovascular aging. Investigators defined the analytical questions, established interpretative boundaries, and critically evaluated successive AI-generated outputs, while the AI platform functioned exclusively as an analytical support tool for exploring complementary conceptual organization of experimentally validated findings. The original study showed that delivery of the longevity-associated LAV-BPIFB4 gene preserved left ventricular diastolic function, reduced perivascular fibrosis, increased coronary arteriole density, and attenuated cellular senescence without modifying progerin accumulation. Structured analytical dialogue generated complementary hierarchical interpretations of these observations. By integrating graphical dispersion with individual-level numerical data, the investigator-led dialogue identified heterogeneous response trajectories and suggested that cardiovascular protection may be viewed as emerging from coordinated interactions between nuclear stress adaptation and vascular remodelling within a broader resilience framework. These interpretations are presented as hypothesis-generating conceptual extensions rather than new experimental findings. This study demonstrates the feasibility of structured investigator-led analytical dialogue as a complementary methodological approach for broadening interpretation of existing preclinical datasets while preserving the original experimental evidence. By making analytical reasoning more transparent and explicitly distinguishing validated observations from conceptual reinterpretation, this framework may assist prioritization of future mechanistic investigations, particularly in rare cardiovascular diseases where maximizing insight from existing datasets is especially important.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare systemic laminopathy caused by a heterozygous point mutation in the LMNA gene encoding Lamin A/C (c.1824C > T, p.G608G). This synonymous mutation causes the production of a toxic form of Lamin A called Progerin. Integration of Progerin within the nuclear lamina disrupts cellular processes such as chromatin organization and gene transcription. Here we generated and characterized the induced isogenic pluripotency stem cell control line generated by correcting the c.1824C > T mutation. Used together with its parental line, this isogenic line excludes differences in genetic background while studying the pathophysiology of HGPS.

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.