bims-minfam 2025-11-02 papers

Issue of 2025–11–02
seven papers selected by
Ayesh Seneviratne, McMaster University

Development. 2025 Oct 15. pii: dev205103. [Epub ahead of print]152(20):

The systemic costs of hematopoietic stem cell aging.

Stem cell behavior is tightly regulated by signals from the surrounding immune environment. Immune cells play an indispensable role in the maintenance, activation and differentiation of tissue-resident stem cells (TSCs). These interactions are dynamic and adapt across the lifespan, profoundly influencing regenerative capacity under both physiological and pathological conditions. Notably, immune dysfunction originating from aging hematopoietic stem cells (HSCs) disrupts tissue regeneration across distant organs, including the brain, muscle and skin. In this Review, we synthesize current knowledge on the interplay between HSC aging and TSC function, emphasizing how age-related changes in HSC-derived immune outputs impair local tissue homeostasis. We explore potential mechanisms underlying HSC-TSC communication, including inflammaging, cytokine signaling and the secretion of bioactive factors. Finally, we discuss emerging strategies aimed at rejuvenating aged HSCs, restoring immune equilibrium and enhancing systemic tissue regeneration. By linking systemic immune remodeling to local niche dysfunction, this Review proposes a hierarchical model in which HSC aging acts as a central regulator of tissue regenerative decline.

Keywords: Bone marrow; Hematopoietic stem cell; Immunomodulation; Immunosenescence; Inflammation; Systemic aging

DOI: https://doi.org/10.1242/dev.205103

EMBO J. 2025 Oct 29.

Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues.

Dominik Saul, Diana Jurk, Madison L Doolittle, Robyn Laura Kosinsky, Yeaeun Han, Xu Zhang, Ana Catarina Franco, Sung Y Kim, Saranya P Wyles, Y S Prakash, David G Monroe, Luigi Ferrucci, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Sundeep Khosla, João F Passos.

Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21Cip1 and p16Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated, particularly in vivo. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing datasets spanning both murine and human tissues during aging. Our analysis revealed that p21Cip1 and p16Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21Cip1 or p16Ink4a expression. Using RNA velocity and pseudotime analyses, we discovered that p21+ and p16+ cells follow independent trajectory dynamics, with no evidence of direct transitions between these two states. Despite this heterogeneity, we identified a limited set of shared "core" SASP factors that may drive common senescence-related functions. Our study underscores the substantial diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent.

Keywords: Aging; Cellular Senescence; Heterogeneity; Senescence-Associated Secretory Phenotype (SASP); Single-Cell Mapping

DOI: https://doi.org/10.1038/s44318-025-00601-2

Med Rev (2021). 2025 Oct;5(5): 400-411

Transcript diversity in aging: cryptic transcription and splicing.

Brenna S McCauley, Nicholas Nikoloutsos, Weiwei Dang.

Increased transcript diversity, which is caused in part by alternative splicing and cryptic transcription, is an underappreciated aspect of age-associated transcriptome remodeling. Recent work has revealed that structurally novel transcripts increase during aging in many tissues. Genes with cryptic and alternatively spliced transcripts with age are enriched for functional categories relevant to tissue function and aging, and have been implicated in cognitive decline, decreased muscle strength, reduced oocyte quality, immune aging, altered stem cell properties, and senescence. Indeed, there is emerging evidence that alternatively spliced transcripts and elevated cryptic transcription directly contribute to aging phenotypes in multiple tissues. The full impact of the increased transcript diversity on the aging process has yet to be explored. The increased transcript diversity engendered by alternative splicing and cryptic transcription is emerging as a potent driver of aging and aging phenotypes, adding another layer to our understanding of the transcriptional regulation of aging.

Keywords: aging; alternative splicing; cryptic transcription; epigenetics

DOI: https://doi.org/10.1515/mr-2025-0032

EMBO Mol Med. 2025 Oct 30.

Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients.

Juan Ignacio Jiménez-Loygorri, Peng Shang, Ibrahim Bayramoglu, Raquel Gómez-Sintes, Adrián Martín-Segura, Helena Ambrosino, Johnson Hoang, Antonio Díaz, Zhaohui Geng, Evripidis Gavathiotis, James R Dutton, Jörn Dengjel, Ana Maria Cuervo, Deborah A Ferrington, Patricia Boya.

Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.

Keywords: Age-related Macular degeneration; Chaperone-mediated Autophagy; Oxidative Stress; Proteostasis; RPE

DOI: https://doi.org/10.1038/s44321-025-00329-w

Int J Radiat Oncol Biol Phys. 2025 Oct 23. pii: S0360-3016(25)06386-2. [Epub ahead of print]

Clonal Hematopoiesis of Indeterminate Potential after Radiation Therapy.

Shelby A Crants, Sydney S Olson, Yajing Li, Cosmin A Bejan, Caitlyn Vlasschaert, Taralynn M Mack, Yash Pershad, Ashwin Kishtagari, Sarah C Reed, Sarah Croessmann, Dan M Roden, Travis J Osterman, Eric T Shinohara, Alexander G Bick, Ben H Park, Leo Y Luo.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a condition associated with increased risk of hematologic malignancies and cardiovascular diseases. While radiation therapy has been identified as a risk factor for CHIP, specific radiation factors that influence the development of CHIP remain unclear.
METHODS AND MATERIALS: We identified 489 cancer patients who underwent radiation therapy (RT) at least 6 months prior to blood samples deposited in an institutional biorepository. Patients with prior hematologic malignancy diagnosis or cytotoxic chemotherapy exposure were excluded. Targeted DNA sequencing of the blood samples was performed to detect mutations in CHIP-associated genes. CHIP prevalence was compared with a control cohort of 854 cancer patients without exposure to RT or chemotherapy. RT parameters, including dose, technique, and irradiated site, were characterized and examined for association with CHIP prevalence.
RESULTS: CHIP was detected in 23% of patients who received RT. The probability of CHIP was increased in patients who received RT compared to the patients who did not (odds ratio 1.49, 95% confidence interval 1.08-2.05), after adjusting for age, sex, race, smoking status, and metastatic disease status. The risk of CHIP positively correlated with the biologically equivalent dose (Pearson correlation coefficient r=0.64, p<0.001). CHIP was associated with stereotactic technique (OR 2.56, 95% CI 1.01-6.34) and more prevalent in patients with primary lung cancer and patients who received radiation to spine. We observed five cases of subsequent myelodysplastic syndrome and one case of subsequent acute myeloid leukemia in the RT cohort with a median interval of 6.3 years between RT and diagnosis, and one case of myelodysplastic syndrome in the control cohort, 7.5 years after blood sample collection.
CONCLUSIONS: In this cohort study, prior radiation therapy was associated with an increased risk of clonal hematopoiesis, particularly among patients receiving higher biologically equivalent radiation doses, stereotactic techniques, or treatment to the spine.

DOI: https://doi.org/10.1016/j.ijrobp.2025.10.006