bims-minfam 2024-06-09 papers

Issue of 2024–06–09
nine papers selected by
Ayesh Seneviratne, Western University

J Clin Invest. 2024 Jun 03. pii: e181064. [Epub ahead of print]134(11):

CHIPing away at immunity: the role of clonal hematopoiesis of indeterminate potential in bacterial pneumonia.

The occurrence of clonal hematopoiesis of indeterminate potential (CHIP), in which advantageous somatic mutations result in the clonal expansion of blood cells, increases with age, as do an increased risk of mortality and detrimental outcomes associated with CHIP. However, the role of CHIP in susceptibility to pulmonary infections, which also increase with age, is unclear. In this issue of the JCI, Quin and colleagues explored the role of CHIP in bacterial pneumonia. Using characterization of immune cells from human donors and mice lacking tet methylcytosine dioxygenase 2 (Tet2), the authors mechanistically link myeloid immune cell dysfunction to CHIP-mediated risk of bacterial pneumonia. The findings suggest that CHIP drives inflammaging and immune senescence, and provide Tet2 status in older adults as a potential prognostic tool for informing treatment options related to immune modulation.

DOI: https://doi.org/10.1172/JCI181064

Curr Osteoporos Rep. 2024 Jun 03.

Marrow Adipocyte Senescence in the Pathogenesis of Bone Loss.

Mitchell N Froemming, Sundeep Khosla, Joshua N Farr.

PURPOSE OF REVIEW: Beyond aging, senescent cells accumulate during multiple pathological conditions, including chemotherapy, radiation, glucocorticoids, obesity, and diabetes, even earlier in life. Therefore, cellular senescence represents a unifying pathogenic mechanism driving skeletal and metabolic disorders. However, whether senescent bone marrow adipocytes (BMAds) are causal in mediating skeletal dysfunction has only recently been evaluated.
RECENT FINDINGS: Despite evidence of BMAd senescence following glucocorticoid therapy, additional evidence for BMAd senescence in other conditions has thus far been limited. Because the study of BMAds presents unique challenges making these cells difficult to isolate and image, here we review issues and approaches to overcome such challenges, and present advancements in isolation and histological techniques that may help with the future study of senescent BMAds. Further insights into the roles of BMAd senescence in the pathogenesis of skeletal dysfunction may have important basic science and clinical implications for human physiology and disease.

Keywords: Aging; Chemotherapy; Marrow Fat; Obesity; Radiotherapy

DOI: https://doi.org/10.1007/s11914-024-00875-1

Nat Rev Mol Cell Biol. 2024 Jun 03.

SenNet recommendations for detecting senescent cells in different tissues.

Vidyani Suryadevara, Adam D Hudgins, Adarsh Rajesh, Alberto Pappalardo, Alla Karpova, Amit K Dey, Ann Hertzel, Anthony Agudelo, Azucena Rocha, Bikem Soygur, Birgit Schilling, Chase M Carver, Cristina Aguayo-Mazzucato, Darren J Baker, David A Bernlohr, Diana Jurk, Dilyana B Mangarova, Ellen M Quardokus, Elizabeth Ann L Enninga, Elizabeth L Schmidt, Feng Chen, Francesca E Duncan, Francesco Cambuli, Gagandeep Kaur, George A Kuchel, Gung Lee, Heike E Daldrup-Link, Helene Martini, Hemali Phatnani, Iman M Al-Naggar, Irfan Rahman, Jia Nie, João F Passos, Jonathan C Silverstein, Judith Campisi, Julia Wang, Kanako Iwasaki, Karina Barbosa, Kay Metis, Kerem Nernekli, Laura J Niedernhofer, Li Ding, Lichao Wang, Lisa C Adams, Liu Ruiyang, Madison L Doolittle, Marcos G Teneche, Marissa J Schafer, Ming Xu, Mohammadjavad Hajipour, Mozhgan Boroumand, Nathan Basisty, Nicholas Sloan, Nikolai Slavov, Olena Kuksenko, Paul Robson, Paul T Gomez, Periklis Vasilikos, Peter D Adams, Priscila Carapeto, Quan Zhu, Ramalakshmi Ramasamy, Rolando Perez-Lorenzo, Rong Fan, Runze Dong, Ruth R Montgomery, Sadiya Shaikh, Sanja Vickovic, Shanshan Yin, Shoukai Kang, Sonja Suvakov, Sundeep Khosla, Vesna D Garovic, Vilas Menon, Yanxin Xu, Yizhe Song, Yousin Suh, Zhixun Dou, Nicola Neretti.

Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.

DOI: https://doi.org/10.1038/s41580-024-00738-8

Cell. 2024 May 30. pii: S0092-8674(24)00492-6. [Epub ahead of print]

Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Keywords: DNMT3A; T cells; arthritis; bone marrow; clonal hematopoiesis of indeterminate potential; hematopoietic stem and progenitor cells; inflammation; neutrophils; osteoclastogenesis; periodontitis

DOI: https://doi.org/10.1016/j.cell.2024.05.003

Inflamm Regen. 2024 Jun 03. 44(1): 28

Role of cellular senescence in inflammation and regeneration.

Yuki Saito, Sena Yamamoto, Takako S Chikenji.

Cellular senescence is the state in which cells undergo irreversible cell cycle arrest and acquire diverse phenotypes. It has been linked to chronic inflammation and fibrosis in various organs as well as to individual aging. Therefore, eliminating senescent cells has emerged as a potential target for extending healthy lifespans. Cellular senescence plays a beneficial role in many biological processes, including embryonic development, wound healing, and tissue regeneration, which is mediated by the activation of stem cells. Therefore, a comprehensive understanding of cellular senescence, including both its beneficial and detrimental effects, is critical for developing safe and effective treatment strategies to target senescent cells. This review provides an overview of the biological and pathological roles of cellular senescence, with a particular focus on its beneficial or detrimental functions among its various roles.

Keywords: Aging; Cell cycle arrest; Cellular senescence; Fibrosis; Senescence-associated secretory phenotype (SASP); Tissue remodeling

DOI: https://doi.org/10.1186/s41232-024-00342-5

Cell Rep Med. 2024 Jun 03. pii: S2666-3791(24)00285-4. [Epub ahead of print] 101593

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.

Diego Acuña-Catalán, Samah Shah, Cameron Wehrfritz, Mitsunori Nomura, Alejandro Acevedo, Cristina Olmos, Gabriel Quiroz, Hernán Huerta, Joanna Bons, Estibaliz Ampuero, Ursula Wyneken, Magdalena Sanhueza, Felipe Arancibia, Darwin Contreras, Julio César Cárdenas, Bernardo Morales, Birgit Schilling, John C Newman, Christian González-Billault.

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.

Keywords: BDNF; LTP; PKA; aging; brain-derived neurotrophic factor; ketogenic diet; long-term potentiation; protein kinase A; proteomics; β-hydroxybutyrate

DOI: https://doi.org/10.1016/j.xcrm.2024.101593

Mol Cell Biochem. 2024 Jun 04.

Mitophagy in relation to chronic inflammation/ROS in aging.

Liang Kong, Shuhao Li, Yu Fu, Qinyun Cai, Xinyun Du, Jingyan Liang, Tan Ma.

Various assaults on mitochondria occur during the human aging process, contributing to mitochondrial dysfunction. This mitochondrial dysfunction is intricately connected with aging and diseases associated with it. In vivo, the accumulation of defective mitochondria can precipitate inflammatory and oxidative stress, thereby accelerating aging. Mitophagy, an essential selective autophagy process, plays a crucial role in managing mitochondrial quality control and homeostasis. It is a highly specialized mechanism that systematically removes damaged or impaired mitochondria from cells, ensuring their optimal functioning and survival. By engaging in mitophagy, cells are able to maintain a balanced and stable environment, free from the potentially harmful effects of dysfunctional mitochondria. An ever-growing body of research highlights the significance of mitophagy in both aging and age-related diseases. Nonetheless, the association between mitophagy and inflammation or oxidative stress induced by mitochondrial dysfunction remains ambiguous. We review the fundamental mechanisms of mitophagy in this paper, delve into its relationship with age-related stress, and propose suggestions for future research directions.

Keywords: Aging; Chronic inflammation; Mitophagy; ROS

DOI: https://doi.org/10.1007/s11010-024-05042-9