bims-cesemi 2024-04-21 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–04–21
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Senescence and senolysis in cancer: The latest findings.
Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).
Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo.
A near-IR ratiometric fluorescent probe for the precise tracking of senescence: a multidimensional sensing assay of biomarkers in cell senescence pathways.
The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.
LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.
Role of β3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression.
Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs.

Cancer Sci. 2024 Apr 19.

Senescence and senolysis in cancer: The latest findings.

Yoshimi Imawari, Makoto Nakanishi.

  Aging is a life phenomenon that occurs in most living organisms and is a major risk factor for many diseases, including cancer. Cellular senescence is a cellular trait induced by various genomic and epigenetic stresses. Senescent cells are characterized by irreversible cell growth arrest and excessive secretion of inflammatory cytokines (senescence-associated secretory phenotypes, SASP). Chronic tissue microinflammation induced by SASP contributes to the pathogenesis of a variety of age-related diseases, including cancer. Senolysis is a promising new strategy to selectively eliminate senescent cells in order to suppress chronic inflammation, suggesting its potential use as an anticancer therapy. This review summarizes recent findings on the molecular basis of senescence in cancer cells and senolysis.

Keywords:  GLS1; aging; cancer; senescence; senolysis

DOI:  https://doi.org/10.1111/cas.16184
Aging Cell. 2024 Apr 16. e14118

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Paul M Coen, Zhiguang Huo, Gregory J Tranah, Haley N Barnes, Xiping Zhang, Christopher A Wolff, Kevin Wu, Peggy M Cawthon, Russell T Hepple, Frederico G S Toledo, Daniel S Evans, Olaya Santiago-Fernández, Ana Maria Cuervo, Stephen B Kritchevsky, Anne B Newman, Steven R Cummings, Karyn A Esser.

  Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

Keywords:  aging; autophagy; gene expression; mTor; mitochondria; mobility; oxidative metabolism

DOI:  https://doi.org/10.1111/acel.14118
Biogerontology. 2024 Apr 15.

Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo.

Kento Takaya, Kazuo Kishi.

  The skin's protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and sagging, a consequence of the senescence-associated secretory phenotype (SASP) that involves the accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling. Although therapeutic approaches for eliminating senescent cells from the skin are available, their efficacy remains unclear. Accordingly, we aimed to examine the effects of dasatinib in combination with quercetin (D + Q) on senescent human skin fibroblasts and aging human skin. Senescence was induced in human dermal fibroblasts (HDFs) using approaches such as long-term passaging, ionizing radiation, and doxorubicin treatment. The generated senescent cells were treated with D + Q or vehicle. Additionally, a mouse-human chimera model was generated by subcutaneously transplanting whole-skin grafts of aged individuals onto nude mice. Mouse models were administered D + Q or vehicle by oral gavage for 30 days. Subsequently, skin samples were harvested and stained for senescence-associated beta-galactosidase. Senescence-associated markers were assessed by western blotting, reverse transcription-quantitative PCR and histological analyses. Herein, D + Q selectively eliminated senescent HDFs in all cellular models of induced senescence. Additionally, D + Q-treated aged human skin grafts exhibited increased collagen density and suppression of the SASP compared with control grafts. No adverse events were observed during the study period. Collectively, D + Q could ameliorate skin aging through selective elimination of senescent dermal fibroblasts and suppression of the SASP. Our findings suggest that D + Q could be developed as an effective therapeutic approach for combating skin aging.

Keywords:  Chimeric model; Dasatinib; Quercetin; Senolytics; Skin rejuvenation

DOI:  https://doi.org/10.1007/s10522-024-10103-z
Chem Sci. 2024 Apr 17. 15(15): 5681-5693

A near-IR ratiometric fluorescent probe for the precise tracking of senescence: a multidimensional sensing assay of biomarkers in cell senescence pathways.

Haihong Liu, Ruidian Lv, Fuxiang Song, Yaqun Yang, Fei Zhang, Liantao Xin, Peng Zhang, Qian Zhang, Caifeng Ding.

Senescence is a complex physiological process that can be induced by a range of factors, and cellular damage caused by reactive oxygen species (ROS) is one of the major triggers. In order to learn and solve age-related diseases, tracking strategies through biomarkers, including senescence-associated β-galactosidase (SA-β-gal), with high sensitivity and accuracy, have been considered as a promising solution. However, endogenous β-gal accumulation is not only associated with senescence but also with other physiological processes. Therefore, additional assays are needed to define cellular senescence further. In this work, a fancy fluorescent probe SA-HCy-1 for accurately monitoring senescence is developed, with SA-β-gal and HClO as targets under high lysosomal pH conditions (pH > 6.0) specifically, on account of the role β-gal commonly played as an ovarian cancer biomarker. Therefore, precise tracking of cellular senescence could be achieved in view of these three dimensions, with response in dual fluorescence channels providing a ratiometric sensing pattern. This elaborate strategy has been verified to be suitable for biological applications by skin photo-aging evaluation and cellular passage tracing, displaying a significantly improved sensitivity compared with the commercial X-gal kit measurement.

DOI: https://doi.org/10.1039/d4sc00595c
Aging (Albany NY). 2024 Apr 12. 16

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Stephen A Banse, E Grace Jackson, Christine A Sedore, Brian Onken, David Hall, Anna Coleman-Hulbert, Phu Huynh, Theo Garrett, Erik Johnson, Girish Harinath, Delaney Inman, Suzhen Guo, Mackenzie Morshead, Jian Xue, Ron Falkowski, Esteban Chen, Christopher Herrera, Allie J Kirsch, Viviana I Perez, Max Guo, Gordon J Lithgow, Monica Driscoll, Patrick C Phillips.

  Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Keywords:  aging; compound intervention; genetic diversity; healthspan

DOI:  https://doi.org/10.18632/aging.205743
Cell Rep. 2024 Apr 15. pii: S2211-1247(24)00430-3. [Epub ahead of print] 114102

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.

Ryo Terao, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Keitaro Hase, Shinobu Yamaguchi, Daniel Du, Brian S Sohn, Yo Sasaki, Mitsukuni Yoshida, Rajendra S Apte.

  Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Keywords:  CD38; CP: Immunology; CP: Metabolism; NAD(+); NMN; age-related macular degeneration; cellular senescence; cholesterol efflux; neurodegeneration; nicotinamide adenine dinucleotide; nicotinamide mononucleotide

DOI:  https://doi.org/10.1016/j.celrep.2024.114102
Cell Cycle. 2024 Apr 16. 1-18

Role of β3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression.

J Bundy, J Shaw, M Hammel, J Nguyen, C Robbins, I Mercier, A Suryanarayanan.

  Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA β3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA β3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA β3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA β3 subunit decreases TNBC proliferation and migration. In addition, GABAA β3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the β3 subunit can be further developed as a potential novel target for the treatment of TNBC.

Keywords:  GABA type A receptor; breast cancer; cell cycle; migration; proliferation; triple negative

DOI:  https://doi.org/10.1080/15384101.2024.2340912
J Med Chem. 2024 Apr 18.

Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs.

Mengyang Chang, Feng Gao, Giri Gnawali, Hang Xu, Yue Dong, Xiang Meng, Wenpan Li, Zhiren Wang, Byrdie Lopez, Jennifer S Carew, Steffan T Nawrocki, Jianqin Lu, Qing-Yu Zhang, Wei Wang.

Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on senescence-associated β-galactosidase (SA-β-gal), have been developed to selectively eliminate senescent cells. However, chemotherapies relying on targeted molecular inhibitors as senolytic drugs can induce drug resistance. In the current investigation, we devised a new strategy for selective degradation of target proteins in senescent cancer cells that utilizes a prodrug composed of the SA-β-gal substrate galactose (galacto) and the proteolysis-targeting chimeras (PROTACs) as senolytic agents. Prodrugs Gal-ARV-771 and Gal-MS99 were found to display senolytic indexes higher than those of ARV-771 and MS99. Significantly, results of in vivo studies utilizing a human lung A549 xenograft mouse model demonstrated that concomitant treatment with etoposide and Gal-ARV-771 leads to a significant inhibition of tumor growth without eliciting significant toxicity.

DOI: https://doi.org/10.1021/acs.jmedchem.4c00152