bims-minfam 2024-12-15 papers

Issue of 2024–12–15
eight papers selected by
Ayesh Seneviratne, McMaster University

Nat Aging. 2024 Dec 10.

IL-23R is a senescence-linked circulating and tissue biomarker of aging.

Chase M Carver, Sonia L Rodriguez, Elizabeth J Atkinson, Andrew J Dosch, Niels C Asmussen, Paul T Gomez, Ethan A Leitschuh, Jair M Espindola-Netto, Karthik B Jeganathan, Madison G Whaley, Theodore M Kamenecka, Darren J Baker, Andrew J Haak, Nathan K LeBrasseur, Marissa J Schafer.

Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.

DOI: https://doi.org/10.1038/s43587-024-00752-7

bioRxiv. 2024 Nov 27. pii: 2024.11.25.625252. [Epub ahead of print]

Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.

Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
Key Points: Age-related attrition of the megakaryocytic niche and associated PF4 downregulation is a central mechanism in HSC aging.PF4 supplementation, acting on LDLR and CXCR3 receptors, rejuvenates the function of aged HSCs.

DOI: https://doi.org/10.1101/2024.11.25.625252

Nat Aging. 2024 Dec;4(12): 1658-1659

Healthy longevity requires bridging reproductive medicine, aging research and public engagement.

NUS Bia-Echo Asia Centre for Reproductive Longevity and Equality (ACRLE)

DOI: https://doi.org/10.1038/s43587-024-00713-0

Curr Opin Clin Nutr Metab Care. 2025 Jan 01. 28(1): 1-5

Nutritional specificity of frailty: from epidemiological and clinical evidence to potential mechanisms.

Laetitia Lengelé, Natasha A Grande de França, Philipe de Souto Barreto, Yves Rolland.

PURPOSE OF REVIEW: Considering the ageing of the population, age-related syndromes, such as frailty, are prominent. In this context, nutrition is a modifiable factor considered a key nonpharmacological approach to prevention and treatment. Yet, its contribution to the frailty pathophysiology is conflicting in the literature. This paper discusses the recent literature (January 2023-June 2024) on the implication of nutrition in frailty management.
RECENT FINDINGS: Malnutrition is one of the main frailty risk factors. Proteins are the targeted macronutrient for their effects on muscle anabolism, not only in terms of quantity consumed but also in terms of sources. The diversity in plant and animal sources demonstrates better results than relying on a single source. More globally, anti-inflammatory and antioxidant diets are associated with a lower risk of frailty, like the Mediterranean Diet and specific food groups, like seafood, nuts, and seeds. Nutrition is pivotal in frailty prevention and treatment, and multidomain interventions providing exercises seem to yield even better results.
SUMMARY: Diverse protein sources and anti-inflammatory and antioxidant diets associated with exercises are the primary recommendations for frailty prevention and treatment. However, there is a need to evaluate how to achieve and maintain this healthy behaviour in real life.

DOI: https://doi.org/10.1097/MCO.0000000000001079

Crit Rev Oncol Hematol. 2024 Dec 10. pii: S1040-8428(24)00332-9. [Epub ahead of print] 104589

Clonal hematopoiesis of indeterminate potential (CHIP): A potential contributor to lymphoma.

QingQing Luo, LiLi Zhou, DaYa Luo, Li Yu.

Clonal hematopoiesis (CH) typically refers to the clonal expansion of hematopoietic stem cells (HSCs) due to genetic mutations, serving as the pathogenic basis for various diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a subtype of CH, emerging as a significant risk factor for myeloid malignancies and cardiovascular diseases, which has attracted increasing attention. However, recent research has unveiled previously overlooked links between CHIP and lymphoma. This paper reviews the relationship between CHIP and lymphoma, focusing on the role and mechanism of TET2 and DNMT3A-mediated CHIP in lymphoma from the perspective of laboratory research and clinical observation. Additionally, we explore the therapeutic implications of targeting CHIP genes and inflammatory pathways in lymphoma. Our findings underscore the multifaceted influence of CHIP on lymphoma development and provide a promising avenue for therapeutic interventions in CHIP mediated lymphoma.

Keywords: Clonal Hematopoiesis of Indeterminate Potential; DNMT3A; TET2; lymphoma

DOI: https://doi.org/10.1016/j.critrevonc.2024.104589