bims-caglex 2025-08-17 papers

Cell. 2025 Aug 11. pii: S0092-8674(25)00853-0. [Epub ahead of print]

Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.

Jinlong Y Lu, William B Tu, Ronghui Li, Mingxi Weng, Bhargav D Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.

The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a "mesenchymal drift" (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.

Keywords: Yamanaka factors; aging; chronic kidney disease; epithelial-mesenchymal transition; fibrosis; heart failure; idiopathic pulmonary fibrosis; metabolic dysfunction-associated steatohepatitis; partial reprogramming; rejuvenation

DOI: https://doi.org/10.1016/j.cell.2025.07.031

Life Sci. 2025 Aug 12. pii: S0024-3205(25)00539-9. [Epub ahead of print]379 123904

Telomere-targeted medicine: Bridging molecular mechanisms and clinical applications in age-related diseases.

Sarfaraz K Niazi.

Telomeres, the nucleoprotein structures at the ends of chromosomes, have emerged as critical regulators of cellular aging and key contributors to the pathogenesis of age-related diseases. This comprehensive review examines the evolution of telomere biology from fundamental research to therapeutic applications, analyzing molecular mechanisms of telomere dysfunction across diverse disease categories, including autoimmune disorders, cardiovascular diseases, neurodegeneration, respiratory diseases, metabolic disorders, chronic kidney disease, cancer, and premature aging syndromes. We explore current therapeutic strategies ranging from telomerase modulation to senolytic approaches, highlighting emerging technologies in drug discovery, including CRISPR-based interventions, nanomedicine, mRNA-based therapies, partial cellular reprogramming, and artificial intelligence applications. The convergence of mechanistic understanding with innovative therapeutic approaches positions telomere biology as a promising frontier for addressing multiple age-related conditions simultaneously, potentially shifting medicine from reactive disease treatment toward proactive aging-focused prevention. However, significant challenges remain, including safety considerations, biomarker development, and establishing regulatory frameworks for aging-targeted therapeutics. The success of telomere-targeted interventions could herald a paradigm shift toward geroscience-based medicine, extending lifespan and health span by targeting fundamental biological aging processes.

Keywords: Aging; Cellular reprogramming; Cellular senescence; Geroscience; Precision medicine; Telomerase; Telomeres; Therapeutic targets; mRNA therapy

DOI: https://doi.org/10.1016/j.lfs.2025.123904

Ageing Res Rev. 2025 Aug 12. pii: S1568-1637(25)00217-X. [Epub ahead of print] 102871

From Clock to Clock: Therapeutic Target Discovery for Aging and Age-Related Diseases.

Jianjiu Chen, Geoffrey Ho Duen Leung, Howell Leung, Alina Ustiugova, Anastasia Shneyderman, Mike Korzinkin, David Gennert, Frank W Pun, Alex Aliper, Feng Ren, Alex Zhavoronkov.

The aging population worldwide necessitates the development of novel therapeutics that enhance the quality of life by preventing and treating age-related diseases. In this review, we first discuss the advantages of a dual-purpose target identification strategy for aging and age-related diseases, with assessment of the hallmark of aging as an approach to identify such dual-purpose targets. Resulting from a convergence of aging research with machine learning (ML) and other artificial intelligence (AI) models, aging clocks were initially developed as aging biomarkers, but its value in identifying therapeutic targets is also increasingly recognized. Building on recently published aging clocks, we reestablish a significant proportion of known drug targets by identifying clock-associated genes, highlighting the potential of these clocks for target identification. Lastly, we discuss other applications of aging clocks in drug development such as population stratification and disease and treatment monitoring. With the growing availability of multi-omics data and rapid advancements in ML and AI, we anticipate accelerated progress in aging clock research, paving the way for innovative treatments to meet the healthcare needs of a global aging population.

Keywords: aging; aging clock; dual-purpose target; hallmark of aging; target identification

DOI: https://doi.org/10.1016/j.arr.2025.102871

Aging Cell. 2025 Aug 14. e70193

T-CLASS: An Online Tool for the Identification and Classification of Aging and Senescence Using Transcriptome Data.

Seung-Chul J Lee, Gee-Yoon Lee, Sieun S Kim, Yunkyu Bae, Seokjin Ham, Jooyeon Sohn, Seong Kyu Han, Seung-Jae V Lee.

Transcriptome analysis has become increasingly utilized in aging research. However, the identification of the key molecular changes underlying aging processes and longevity-promoting regimens from transcriptome data remains challenging. Here, we present Transcriptomic CLassification via Adaptive learning of Signature States (T-CLASS), an online tool that identifies, from transcriptome data, gene sets of several hundred genes that provide an optimal representation of longevity and aging paradigms. We systematically evaluated the effectiveness of T-CLASS with diverse datasets, including longevity-promoting regimens in Caenorhabditis elegans, cellular senescence by different means in both cultured mouse primary cells and cultured human cells, and human sarcopenia. We found that T-CLASS exhibited robust and high classification performance across datasets compared to preexisting machine/deep learning-based gene selection tools. By focusing our further analysis on longevity-promoting regimens in C. elegans, we showed that T-CLASS successfully classified transcriptomic changes caused by ten lifespan-extending small molecules, among which we experimentally validated the effect of rifampicin and atracurium as a proof of principle. Overall, T-CLASS is an effective and practical tool for uncovering and classifying physiological changes caused by genetic and pharmacological interventions that affect aging.

Keywords: C. elegans ; aging; classification; longevity; transcriptome; web‐based tool

DOI: https://doi.org/10.1111/acel.70193

Aging Cell. 2025 Aug 10. e70190

Associations of Skin Biomechanical Properties With Biological Aging Clocks and Longitudinal Changes in Intrinsic Capacity in Adults Aged 20-93: The INSPIRE-T Project.

IHU HealthAge INSPIRE/Open Science study group

Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological aging clocks (epigenetic and inflammatory clocks) and potential moderating effects on the skin-IC relationship. Baseline skin elasticity and viscoelasticity were measured in 441 INSPIRE-T participants aged 20 to 93 (59.9% women) using Cutometer parameters. IC was evaluated over 3 years as a five-domain score covering cognition, locomotion, psychology, vitality, and sensory (a higher score indicated better). Biological aging was measured at baseline using six epigenetic clocks (Horvath pan-tissue, Horvath skin & blood, Hannum, PhenoAge, GrimAge, and DunedinPACE) and inflammatory clock (iAge). Poor skin elasticity and viscoelasticity in older adults were associated with lower baseline IC after controlling for demographic, medical, and lifestyle factors. Longitudinally, older men with a higher viscoelastic ratio (R6) experienced a faster decline in IC (a standardized coefficient [95% CI] ranged from -0.37 [-0.72, -0.03] at age 62 to -1.32 [-1.91, -0.73] at age 93). Accelerated iAge was associated with reduced skin elasticity (R2, R5, R7). Moreover, the association between parameters related to elastic recovery (R5, R7) and baseline IC became more pronounced as accelerated iAge increased. This is the first study demonstrating the association between skin-aging biomechanics and IC. Poor skin elasticity was associated with higher systemic inflammation. Therefore, skin biomechanical properties may reflect overall functional aging, with inflammation serving as a common underlying factor.

Keywords: biomarkers; biomechanical phenomena; epigenesis; healthy aging; inflammation; intrinsic capacity; skin aging

DOI: https://doi.org/10.1111/acel.70190