bims-cesemi 2024-03-10 papers

Issue of 2024–03–10
five papers selected by
Julio Cesar Cardenas, Universidad Mayor

Cell Biochem Funct. 2024 Mar;42(2): e3970

Exploring the emerging bidirectional association between inflamm-aging and cellular senescence in organismal aging and disease.

Rohit Sharma.

There is strong evidence that most individuals in the elderly population are characterized by inflamm-aging which refers to a subtle increase in the systemic pro-inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm-aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm-aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro-inflammatory tissue environment that provides a rationale for immune system-independent activation of inflamm-aging and associated diseases. There is also accumulating evidence that inflamm-aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence-based molecular etiology of inflamm-aging as well as the dynamic reciprocal interactions between inflamm-aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm-aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm-aging with cellular senescence both as an underlying cause and therapeutic target for further studies.

Keywords: aging; cellular senescence; inflamm-aging; inflammation; senescent cells

DOI: https://doi.org/10.1002/cbf.3970

Cell Biol Int. 2024 Mar 04.

Dihydroartemisinin eliminates senescent cells by promoting autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.

Xing Wan, Can Li, Yue Hao Tan, Shi Qi Zuo, Feng Mei Deng, Jing Sun, Yi Lun Liu.

Cellular senescence is an irreversible cell-cycle arrest in response to a variety of cellular stresses, which contribute to the pathogenesis of a variety of age-related degenerative diseases. However, effective antisenescence strategies are still lacking. Drugs that selectively target senescent cells represent an intriguing therapeutic strategy to delay aging and age-related diseases. Thus, we thought to investigate the effects of dihydroartemisinin (DHA) on senescent cells and elucidated its mechanisms underlying aging. Stress-induced premature senescence (SIPS) model was built in NIH3T3 cells using H2 O2 and evaluated by β-galactosidase staining. Cells were exposed to DHA and subjected to cellular activity assays including viability, ferroptosis, and autophagy. The number of microtubule-associated protein light-chain 3 puncta was detected by immunofluorescence staining. The iron content was assessed by spectrophotometer and intracellular reactive oxygen species (ROS) was measured by fluorescent probe dichlorodihydrofluorescein diacetate. We found that DHA triggered senescent cell death via ferroptosis. DHA accelerated ferritin degradation via promoting autophagy, increasing the iron contents, promoting ROS accumulation, thus leading to ferroptotic cell death in SIPS cells. In addition, autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. Moreover, Atg5 silencing and autophagy inhibitor BafA1 preconditioning inhibited ferroptosis induced by DHA. We also revealed that the expression of p-AMP-activated protein kinase (AMPK) and p-mammalian target of rapamycin (mTOR) in senescent cells was downregulated. These results suggested that DHA may be a promising drug candidate for clearing senescent cells by inducing autophagy-dependent ferroptosis via AMPK/mTOR signaling pathway.

Keywords: AMPK/mTOR signaling pathways; autophagy; dihydroartemisinin; ferroptosis; senescence

DOI: https://doi.org/10.1002/cbin.12143

Front Physiol. 2024 ;15 1344116

Cellular senescence and wound healing in aged and diabetic skin.

Arisa Kita, Sena Yamamoto, Yuki Saito, Takako S Chikenji.

Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it is often accompanied by the secretion of various factors, such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes tissue repair, regeneration, and development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, tissue dysfunction, and intractable wounds. The effects of cellular senescence on skin wound healing can be both beneficial and detrimental, depending on the condition. Here, we reviewed the functional differences in cellular senescence that emerge during wound healing, chronic inflammation, and skin aging. We also review the latest mechanisms of wound healing in the epidermis, dermis, and subcutaneous fat, with a focus on cellular senescence, chronic inflammation, and tissue regeneration. Finally, we discuss the potential clinical applications of promoting and inhibiting cellular senescence to maximize benefits and minimize detrimental effects.

Keywords: aged-skin; cellular senescence; diabetic skin; senescence-associated secretory phenotypes (SASP); woundhealing

DOI: https://doi.org/10.3389/fphys.2024.1344116

Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]

Metabolic remodeling in cancer and senescence and its therapeutic implications.

Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.

Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.

Keywords: aging; cancer; metabolism; senescence; senotherapy

DOI: https://doi.org/10.1016/j.tem.2024.02.008

J Clin Invest. 2024 Mar 07. pii: e173371. [Epub ahead of print]

An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis.

Jin Young Lee, Nabora S Reyes, Supriya Ravishankar, Minqi Zhou, Maria Krasilnikov, Christian Ringler, Grace Pohan, Chris Wilson, Kenny Kean-Hooi Ang, Paul J Wolters, Tatsuya Tsukui, Dean Sheppard, Michelle R Arkin, Tien Peng.

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.

Keywords: Aging; Cellular senescence; Drug screens; Fibrosis; Pulmonology

DOI: https://doi.org/10.1172/JCI173371