bims-caglex 2025-08-31 papers

Cells. 2025 Aug 13. pii: 1249. [Epub ahead of print]14(16):

A Biophysics of Epigenetic Rejuvenation.

We present a synthesis based on epigenetics, machine learning and polymer physics from which emerges new relationships between the thermodynamic Flory-Huggins parameter (χ), epigenetic age (eAge) and Shannon entropy. Using a framework for the estimation of χ in the nuclear environment we show that χ∝eAge-1 and χ∝Shannon Entropy-1. As cells age, epigenetic drift results in "smoothing out" of the epigenetic landscape reducing the magnitude of χ. Epigenetic rejuvenation reverses epigenetic drift and restores χ to levels found in young cells with concomitant reduction in both eAge and Shannon entropy.

Keywords: Flory–Huggins parameter; H3K27me3; H3K9me3; Hi-C; Shannon entropy; age reprogramming; eAge; epigenetic rejuvenation; partial reprogramming

DOI: https://doi.org/10.3390/cells14161249

Cells. 2025 Aug 18. pii: 1278. [Epub ahead of print]14(16):

Cellular Models of Aging and Senescence.

Byunggik Kim, Dong I Lee, Nathan Basisty, Dao-Fu Dai.

Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from "steering" cells toward resilience to "reversing" age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging.

Keywords: cardiovascular aging; cellular aging; epigenetic reprogramming; in vitro models; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; neurodegeneration; progeroid syndromes; senescence; senolytics

DOI: https://doi.org/10.3390/cells14161278

Aging (Albany NY). 2025 Aug 21. 17

Sex-specific longitudinal reversal of aging in old frail mice.

Cameron Kato, Jessica Zheng, Cindy Quang, Sophia Siopack, Joana Cruz, Zachery R Robinson, Nicole Fong, Zhixin A Zhang, Patrick Young, Michael J Conboy, Irina M Conboy.

Important studies report acute rejuvenation of mammalian cells and tissues by blood heterochronicity, old plasma dilution, defined factors, and partial reprogramming. And extension of rodent lifespan via single-prong methods was tried in recent years. Here, we examined whether simultaneous calibration of pathways that change with aging in opposite directions would be more effective in increasing healthspan and lifespan. Moreover, we started with the challenging age group - frail 25-months-old mice that are equivalent to ~75-year-old people. We used an Alk5 inhibitor (A5i) of the age-elevated, pro-fibrotic transforming growth factor-beta (TGF-β) pathway that regulates inflammatory factors, including IL-11, and oxytocin (OT) that is diminished with age and controls tissue homeostasis via G-protein-coupled receptor and ERK signaling. Treatment of old frail male mice with OT+A5i resulted in a remarkable 73% life extension from that time, and a 14% increase in the overall median lifespan. Further, these animals had significantly increased healthspan, with improved physical performance, endurance, short term memory, and resilience to mortality. Intriguingly, these benefits manifested only in the male and not in the female mice, yet OT+A5i had positive effects on fertility of middle-aged female mice. Mechanistically, the bio-orthogonal metabolic proteomics on the blood serum demonstrated that the acute, 7-day, treatment of the old mice with OT+A5i youthfully restored systemic signaling determinants and reduced protein noise in old mice of both sexes. However, after 4 months of OT+A5i, only old male, but not female, mice remained responsive, showing the youthful normalization of systemic proteome. These findings establish the significant health-span extension capacity of OT+A5i and emphasize the differences in aging and in response to longevity therapeutics between the sexes.

Keywords: Alk5 inhibitor; healthspan; lifespan; oxytocin; sex-specific differences

DOI: https://doi.org/10.18632/aging.206304