bims-cesemi 2024-03-17 papers

Issue of 2024‒03‒17
four papers selected by
Julio Cesar Cardenas, Universidad Mayor

Pathol Oncol Res. 2024 ;30 1611623

Geroscience and pathology: a new frontier in understanding age-related diseases.

Monika Fekete, David Major, Agnes Feher, Vince Fazekas-Pongor, Andrea Lehoczki.

Geroscience, a burgeoning discipline at the intersection of aging and disease, aims to unravel the intricate relationship between the aging process and pathogenesis of age-related diseases. This paper explores the pivotal role played by geroscience in reshaping our understanding of pathology, with a particular focus on age-related diseases. These diseases, spanning cardiovascular and cerebrovascular disorders, malignancies, and neurodegenerative conditions, significantly contribute to the morbidity and mortality of older individuals. We delve into the fundamental cellular and molecular mechanisms underpinning aging, including mitochondrial dysfunction and cellular senescence, and elucidate their profound implications for the pathogenesis of various age-related diseases. Emphasis is placed on the importance of assessing key biomarkers of aging and biological age within the realm of pathology. We also scrutinize the interplay between cellular senescence and cancer biology as a central area of focus, underscoring its paramount significance in contemporary pathological research. Moreover, we shed light on the integration of anti-aging interventions that target fundamental aging processes, such as senolytics, mitochondria-targeted treatments, and interventions that influence epigenetic regulation within the domain of pathology research. In conclusion, the integration of geroscience concepts into pathological research heralds a transformative paradigm shift in our understanding of disease pathogenesis and promises breakthroughs in disease prevention and treatment.

Keywords: ageing; cancer; cardiovascular disease; geroscience; senescence

DOI: https://doi.org/10.3389/pore.2024.1611623

Cell Cycle. 2024 Mar 10. 1-20

Sustained activation of NF-κB through constitutively active IKKβ leads to senescence bypass in murine dermal fibroblasts.

Masayuki Harada, Kanae Su-Harada, Takeshi Kimura, Koh Ono, Noboru Ashida.

Although the transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-κB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-κB pathway suppresses senescence in murine dermal fibroblasts. IκB kinase β (IKKβ)-depleted dermal fibroblasts showed ineffective NF-κB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated β-galactosidase (SA-β-gal) staining and p16INK4a mRNA levels. Conversely, the expression of constitutively active IKKβ (IKKβ-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of κB (IκB), which inhibits NF-κB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKβ-CA on senescence is largely mediated by NF-κB. We also found that IKKβ-CA expression suppressed the derepression of INK4/Arf genes and counteracted the senescence-associated loss of Ezh2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2). Moreover, pharmacological inhibition of Ezh2 abolished IKKβ-CA-induced senescence bypass. We propose that NF-κB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression.

Keywords: IκB kinase β; Senescence bypass; nuclear factor κb

DOI: https://doi.org/10.1080/15384101.2024.2325802

J Alzheimers Dis. 2024 Mar 02.

A Need for Refined Senescence Biomarkers and Measures of Senolytics in the Brain.

Miranda E Orr.

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. Treatments that remove senescent cells, senolytics, improve brain outcomes in AD mice with amyloid-β or tau deposition. 3xTgAD mice develop both AD neuropathologies; however, Ng et al. report low p16INK4a-associated senescence in the brain. Senolytic treatment by genetic removal; dasatinib with quercetin (D+Q), which enter the brain; and ABT-263 with limited brain penetrance all reduced AD neuropathology. Refined measures of senescence and brain exposure would help clarify the benefits of senolytics despite low p16INK4a-associated senescence and potential limited brain penetrance.

Keywords: Alzheimer’s disease; D+Q; amyloid; blood-brain barrier; brain; cellular senescence; geroscience; senolytics; tau; transgenic mice

DOI: https://doi.org/10.3233/JAD-231462

J Biol Chem. 2024 Mar 07. pii: S0021-9258(24)01640-5. [Epub ahead of print] 107145

Purinergic signaling promotes premature senescence.

Daniela Volonte, Cory J Benson, Stephanie L Daugherty, Jonathan M Beckel, Mohamed Trebak, Ferruccio Galbiati.

Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that oxidative stress induced release of ATP and caused senescence in human lung fibroblasts. Inhibition of P2 receptors limited oxidative stress-induced senescence, while stimulation with exogenous ATP promoted premature senescence. Pharmacological inhibition of P2Y11 receptor (P2Y11R) inhibited premature senescence induced by either oxidative stress or ATP, while stimulation with a P2Y11R agonist was sufficient to induce cellular senescence. Our data show that both extracellular ATP and a P2Y11R agonist induced calcium (Ca++) release from the endoplasmic reticulum (ER) and that either inhibition of phospholipase C (PLC) or intracellular Ca++ chelation impaired ATP-induced senescence. We also find that Ca++ that was released from the ER, following ATP-mediated activation of PLC, entered mitochondria in a manner dependent on P2Y11R activation. Once in mitochondria, excessive Ca++ promoted the production of reactive oxygen species (ROS) in a P2Y11R-dependent fashion, which drove development of premature senescence of lung fibroblasts. Finally, we show that conditioned medium derived from senescent lung fibroblasts, which were induced to senesce through the activation of ATP/P2Y11R-mediated signaling, promoted the proliferation of triple-negative breast cancer cells and their tumorigenic potential by secreting amphiregulin. Our study identifies the existence of a novel purinergic signaling pathway that links extracellular ATP to the development of a pro-tumorigenic premature senescent phenotype in lung fibroblasts that is dependent on P2Y11R activation and ER-to-mitochondria calcium signaling.

Keywords: ATP; purinergic signaling; reactive oxygen species; senescence

DOI: https://doi.org/10.1016/j.jbc.2024.107145