bims-minfam 2024-06-30 papers

Issue of 2024–06–30
eight papers selected by
Ayesh Seneviratne, Western University

Int J Cardiol. 2024 Jun 20. pii: S0167-5273(24)00906-9. [Epub ahead of print]411 132284

Clonal hematopoiesis, NETosis and arterial thrombosis: A deadly combination.

Aldo Bonaventura, Luca Liberale.

Keywords: Acute coronary syndrome; CHIP; Endothelium; Inflammation; NETs; Neutrophils

DOI: https://doi.org/10.1016/j.ijcard.2024.132284

Science. 2024 Jun 28. 384(6703): 1404-1406

Neuronal senescence may drive brain aging.

Joseph R Herdy, Jerome Mertens, Fred H Gage.

Senescence of postmitotic neurons presents challenges and opportunities to modify brain aging.

DOI: https://doi.org/10.1126/science.adi3450

Nat Commun. 2024 Jun 26. 15(1): 5410

METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.

Chen Wang, Hideki Tanizawa, Connor Hill, Aaron Havas, Qiang Zhang, Liping Liao, Xue Hao, Xue Lei, Lu Wang, Hao Nie, Yuan Qi, Bin Tian, Alessandro Gardini, Andrew V Kossenkov, Aaron Goldman, Shelley L Berger, Ken-Ichi Noma, Peter D Adams, Rugang Zhang.

METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.

DOI: https://doi.org/10.1038/s41467-024-49745-5

Int J Mol Sci. 2024 Jun 14. pii: 6585. [Epub ahead of print]25(12):

Kidney Aging and Chronic Kidney Disease.

Yingying Zhang, Chen Yu, Xiaogang Li.

The process of aging inevitably leads to an increase in age-related comorbidities, including chronic kidney disease (CKD). In many aspects, CKD can be considered a state of accelerated and premature aging. Aging kidney and CKD have numerous common characteristic features, ranging from pathological presentation and clinical manifestation to underlying mechanisms. The shared mechanisms underlying the process of kidney aging and the development of CKD include the increase in cellular senescence, the decrease in autophagy, mitochondrial dysfunction, and the alterations of epigenetic regulation, suggesting the existence of potential therapeutic targets that are applicable to both conditions. In this review, we provide a comprehensive overview of the common characteristics between aging kidney and CKD, encompassing morphological changes, functional alterations, and recent advancements in understanding the underlying mechanisms. Moreover, we discuss potential therapeutic strategies for targeting senescent cells in both the aging process and CKD.

Keywords: cell senescence; chronic kidney disease; kidney aging

DOI: https://doi.org/10.3390/ijms25126585

Cell Stem Cell. 2024 Jun 21. pii: S1934-5909(24)00210-8. [Epub ahead of print]

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration.

Nathalie Saurat, Andrew P Minotti, Maliha T Rahman, Trisha Sikder, Chao Zhang, Daniela Cornacchia, Johannes Jungverdorben, Gabriele Ciceri, Doron Betel, Lorenz Studer.

Aging is the biggest risk factor for the development of Alzheimer's disease (AD). Here, we performed a whole-genome CRISPR screen to identify regulators of neuronal age and show that the neddylation pathway regulates both cellular age and AD neurodegeneration in a human stem cell model. Specifically, we demonstrate that blocking neddylation increased cellular hallmarks of aging and led to an increase in Tau aggregation and phosphorylation in neurons carrying the APPswe/swe mutation. Aged APPswe/swe but not isogenic control neurons also showed a progressive decrease in viability. Selective neuronal loss upon neddylation inhibition was similarly observed in other isogenic AD and in Parkinson's disease (PD) models, including PSENM146V/M146V cortical and LRRK2G2019S/G2019S midbrain dopamine neurons, respectively. This study indicates that cellular aging can reveal late-onset disease phenotypes, identifies new potential targets to modulate AD progression, and describes a strategy to program age-associated phenotypes into stem cell models of disease.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; cortical neurons; disease modeling; dopamine neurons; human pluripotent stem cells; neddylation; proteostasis; senescence

DOI: https://doi.org/10.1016/j.stem.2024.06.001

Drugs Aging. 2024 Jun 24.

Geriatric Assessment in the Era of Targeted and Immunotherapy.

Elizabeth Faour, Selynne Guo, Martine Puts.

Cancer is a disease that mostly affects older adults and because of the aging of the population, the number of older adults diagnosed with cancer will increase significantly around the world. With increasing age, more older adults are living with frailty, and this may impact the tolerability of cancer treatments. International guidelines, such as the American Society for Clinical Oncology geriatric oncology guideline, recommend a geriatric assessment and management for all older adults with cancer to support the treatment decision-making process as well as develop a plan for supportive care interventions to support the older adults during cancer treatments. While there is clinical trial evidence to support a geriatric assessment and management for older adults receiving chemotherapy, there is less evidence to support a geriatric assessment for older adults starting immunotherapy. There are increasing numbers of new immunotherapies and targeted therapies available for older adults with cancer but often few older adults have been included in the clinical trials, leaving less evidence for clinicians to guide treatment decisions. In this current opinion, we review the current evidence on the use of a geriatric assessment and management in the context of immunotherapy and targeted therapy. We review how a geriatric assessment could support older adults making treatment decisions for immunotherapy, review how geriatric assessment parameters are linked with outcomes and provide guidance on how geriatric assessment can guide the supportive care plan during immunotherapy treatment.

DOI: https://doi.org/10.1007/s40266-024-01126-9