Longevity Papers

Gait is increasingly recognized as a vital sign, yet current approaches treat it as a symptom of specific pathologies rather than a systemic biomarker. We developed a gait foundation model for 3D skeletal motion from 3,414 deeply phenotyped adults, recorded via a depth camera during five motor tasks. Learned embeddings outperformed engineered features, predicting age (Pearson r = 0.69), BMI (r = 0.90), and visceral adipose tissue area (r = 0.82). Embeddings significantly predicted 1,980 of 3,210 phenotypic targets; after adjustment for age, BMI, VAT, and height, gait provided independent gains in all 18 body systems in males and 17 of 18 in females, and improved prediction of clinical diagnoses and medication use. Anatomical ablation revealed that legs dominated metabolic and frailty predictions while torso encoded sleep and lifestyle phenotypes. These findings establish gait as an independent multi-system biosignal, motivating translation to consumer-grade video and its integration as a scalable, passive vital sign.

The integration of environmental cues into cellular programs is crucial for cell function. Yet, how this integration is modulated due to cellular aging remains unclear. We propose that the 3D chromatin organization filters these signals and investigated how age-related chromatin changes in human dermal fibroblasts affect responses to mechanical tension and TGF-β. Young fibroblasts exhibited synergistic gene expression enhancement in response to combined stimuli, a response that was markedly blunted or divergent in aged cells. These distinct outcomes correlated with significant age-related differences in chromatin accessibility. We identified the AP-1 complex and other transcription factors with age-specific activity as pivotal in remodeling chromatin and orchestrating these divergent mechanochemical responses during cellular aging. We validated that disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery. Our findings establish chromatin as a key integrator of mechanochemical signals and characterize the age-related alterations to this integration that modify the cellular responsiveness of aged cells, highlighting AP-1 and its network as potential therapeutic targets against age-related decline.

Introduction: The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes. Methods: We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort. Results: The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months. Discussion: Our findings support the potential of a deep learning-derived SASP Score as a biomarker for systemic cellular senescence burden. Our statistical approach can offer enhanced interpretability and cross-platform utility, providing a valuable tool for aging research and the evaluation of geroscience-guided interventions.

To improve senolytic efficacy and selectivity, we designed gemcitabine (Gem)-based galactoside prodrugs activated by senescence-associated β-galactosidase (SA-β-gal), bearing lysosome-targeting groups at the 3- and 5-positions of the self-immolative linker aromatic ring. This strategy avoids stereocenter formation and promotes faster, electron-donating-effect-driven drug release. Gal-dMor-Gem, with two morpholine groups, showed the strongest activity. Its senolytic index reached 16.1-56.7 across six senescent cell (SnC) models, a 2.8- to 3.7-fold improvement over the nontargeted SSK1. Gal-dMor-Gem released Gem faster and preferentially induced SnC apoptosis, as validated in a coculture model. Biodistribution studies confirmed its preferential accumulation and activation in senescent tissues. In senescent mice, Gal-dMor-Gem (0.5 mg/kg) surpassed SSK1 in restoring body weight, improving biochemical parameters, and reducing SA-β-gal, IL-6, and lamin B1 abnormalities in multiple organs. At 1.0 mg/kg, most markers returned to healthy levels. This work identifies Gal-dMor-Gem as a potent senolytic and highlights a generalizable strategy for developing targeted SA-β-gal-responsive prodrugs.

Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases. The role of ferroptosis in age-related HF remains unclear. Here, we show that aged rats exhibit impaired cardiac function accompanied by hallmark features of ferroptosis, including reduced glutathione peroxidase 4 (GPX4) expression and excessive lipid peroxidation. Consistently, cardiomyocyte-specific GPX4 knockout mice develop exacerbated cardiac ferroptosis and pronounced cardiac dysfunction. Iron overload further aggravates ferroptotic injury and cardiac dysfunction in aged rats, whereas pharmacological inhibition of ferroptosis markedly alleviates these effects. Conversely, cardiomyocyte-specific overexpression of GPX4 via rAAV9 attenuates ferroptosis and preserves cardiac function in D-galactose-induced aging mice. Proteomic analysis identifies hydroxyacyl-CoA dehydrogenase subunit A (HADHA) as a key protein markedly downregulated in aging hearts, particularly under iron overload. Mechanistically, HADHA deficiency induces mitochondrial dysfunction and excessive reactive oxygen species production, leading to glutathione depletion, GPX4 suppression, and subsequent ferroptosis. Accordingly, cardiomyocyte-specific knockdown of HADHA in young mice recapitulates ferroptosis-associated cardiac remodeling, which is reversed by ferrostatin-1 treatment. Furthermore, we identify SIRT1 (sirtuin 1) as an upstream regulator of HADHA during cardiac aging. Reduced SIRT1 expression in aging hearts suppresses HADHA transcription through inhibition of GATA4. Importantly, both cardiomyocyte-specific SIRT1 overexpression via rAAV9 in D-galactose-induced aging mice and pharmacological SIRT1 activation by resveratrol in aging rats restore HADHA expression, suppress ferroptosis, and protect against HF. Collectively, these findings establish ferroptosis as a critical contributor to age-related HF and identify the SIRT1-GATA4-HADHA axis as a potential therapeutic target.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene, leading to the production of progerin, an aberrant and toxic form of lamin A. Due to its hydrophobic nature, progerin accumulates at the nuclear membrane, disrupting nuclear architecture, impairing cellular functions, and ultimately resulting in death around adolescence. Reducing progerin levels is considered the most effective strategy to improve disease progression. To date, small-molecule approaches have primarily targeted progerin upstream mechanisms to indirectly reduce its levels. In this study, we report the development of first-generation proteolysis targeting chimeras (PROTACs) designed to directly degrade progerin, establishing a novel therapeutic paradigm for HGPS. We identify UCM-18142 (compound 2) as the first PROTAC capable of selectively degrading progerin. Treatment with UCM-18142 results in significant improvements in cellular phenotype in both HGPS patient-derived cells and a murine model, including enhanced proliferation, reduced senescence markers, and normalization of nuclear and mitochondrial abnormalities. Additionally, transcriptomic analysis of treated human cells reveals the cellular pathways modulated by compound. Remarkably, PROTAC 2 reduces progerin levels in vivo, supporting the therapeutic potential of this direct-targeting approach and opening new avenues for intervention in HGPS and related laminopathies.