Moshi Song

A growing body of evidence suggests that aging is not simply the accumulation of damage, but a systemic progression of increasing entropy across biological scales. Synthesizing concepts from thermodynamics and information theory, we propose a three-stage entropy model of the lifespan: order-building development, homeostatic adulthood, and disorder-dominant aging. Within this model, we reframe the established hallmarks of aging as interconnected nodes in an entropy-centered network and detail the multiscale manifestations of disorder from molecules to systems. To quantify this trajectory, we introduce a Multiscale Entropic Aging Index (MEAI) as a proof-of-concept conceptual framework, designed to integrate measurements of disorder across biological levels. This framework offers a potential unifying, quantitative language for aging research and positions entropy reduction as a testable mechanism underlying interventions, laying a principled foundation for the future development of biomarkers and rejuvenative strategies.

Accumulating evidence emphasizes the importance of microbiota–immune interactions in health and disease development, and identified bacteria‐derived small‐molecule metabolites as well as macromolecules such as peptides and proteins as promising therapeutic approaches. Here, we identify cytokine motif‐containing, immunomodulatory bacterial proteins (CMCPs) as a special category of bacterial proteins in both bacterial genomes and gut metagenomes using Hidden Markov Models (HMMs). We further find eight colorectal cancer‑associated CMCPs differentially enriched in patients or healthy controls. Engineered E. coli Nissle 1917 (EcN) expressing selected CMCPs administered to Apc ^min/+ mice selectively colonize intestinal tumors, deliver functional CMCPs in situ, and elicit significant antitumor immune responses while reducing tumor burden. In vitro, purified CMCPs modulate mouse splenic T cells, bone marrow‑derived macrophages and dendritic cells. Our findings indicate that bacterially encoded CMCPs can directly modulate tumor immunity and serve as microbiota‑derived proteins as candidate immunomodulators, which can further be applied in microbiome‐mediated immune therapies for CRC.

Myocardial ischemia/reperfusion (I/R) injury is exacerbated by inflammation, yet the upstream triggers of this cascade and their amenability to therapeutic intervention remain unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a driver of sterile inflammation in I/R injury, but whether its activation can be suppressed via enhanced mitochondrial quality control has not been explored. We hypothesized that augmenting PARKIN-mediated mitophagy would limit cGAS-STING activation and attenuate I/R injury by clearing damaged mitochondria and preventing the release of its agonist, mitochondrial DNA (mtDNA). Cardiomyocyte-specific PARKIN overexpression in mice was well tolerated at baseline and conferred cardioprotection following I/R injury, attenuating adverse remodeling and preserving cardiac function. Mechanistically, PARKIN overexpression enhanced mitophagy, which limited cytosolic mtDNA accumulation, thereby inhibiting cGAS-STING activation and its downstream inflammatory response. The therapeutic potential of this pathway was further supported by lentiviral PARKIN delivery in wild-type mouse hearts, which also improved cardiac outcomes following I/R injury. Taken together, our findings delineate a PARKIN-mtDNA-cGAS-STING axis as a regulatory mechanism of I/R injury and support PARKIN augmentation as a potential therapeutic strategy.

Cardiac aging is a major driver of cardiovascular diseases and associated mortality, yet its therapeutic options are limited. While long interspersed nuclear element-1 (LINE-1) retrotransposons are known to drive cellular senescence, their role in cardiac aging is poorly defined. Here we showed that LINE-1 expression increased in the heart with age. To investigate their role in cardiac aging, we generated cardiomyocyte-specific Mov10-knockout mice, which failed to suppress LINE-1. These mice developed LINE-1 derepression, cardiac dysfunction and premature cardiac aging by 3 months of age, accompanied by cGAS–STING activation. Pharmacological inhibition of LINE-1 reverse transcription (with 3TC) or STING (with H-151) suppressed cGAS–STING activation and attenuated senescence in Mov10-knockout H9C2 cells. Notably, both inhibitors improved cardiac function and reduced cardiac inflammation and senescence phenotypes in naturally aged mice. Together, our findings establish LINE-1 as a driver of cardiac aging via cGAS–STING activation, highlighting LINE-1 and its downstream effectors as therapeutic targets for age-related cardiac dysfunction.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age‐related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual’s physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions.