Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types

Limbad, Chandani; Doi, Ryosuke; McGirr, Julia; Ciotlos, Serban; Pérez, Kevin; Clayton, Zachary S.; Daya, Radha; Seals, Douglas R.; Campisi, Judith; Melov, Simon

doi:10.1016/j.isci.2022.103848

Cited by 27 publications

(22 citation statements)

References 82 publications

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“…40 Recently, CRYAB and HMOX1 have been proposed to be senolytic targets in humans cell models. 41 Interestingly, it was also demonstrated that HMOX1 expression levels were increased during differentiation, which supports a similar correlation as measured in our study. 42 As reported here, we observe a significant increase in the expression patterns of these genes starting in the 30’s and continuing into the 70’s in photoexposed facial epidermis sites.…”

Section: Discussionsupporting

confidence: 92%

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades

Jarrold

Tan

et al. 2022

Preprint

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Inflammaging is a theory of aging which purports that low-level chronic inflammation leads to cellular dysfunction and premature aging of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defense from the environment, particularly solar radiation. To better understand the impact of aging and photoexposure on epidermal biology we performed a systems biology-based analysis of photoexposed face and arm and photoprotected buttock sites from women between the ages of 20s to 70s. Biopsies were analyzed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss, and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-alpha were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic aging was accelerated. Genes associated with differentiation and senescence show increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increase in the 50s. Proteomics comparing 60s vs 20s confirmed elevated levels of differentiation and glycolytic related proteins. Representative immunostaining for proteins of differentiation, senescence, and oxygen sensing/hypoxia shows similar relationships. This systems biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

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Section: Discussionsupporting

confidence: 92%

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades

Jarrold

Tan

et al. 2022

Preprint

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“…In this context, the compound 25HC—an oxygenated derivate of cholesterol that inhibits the CRYAB (Alpha beta-crystallin) protein, which is upregulated in senescent cells—showed significant effects in skeletal muscle. 25HC inhibits the expression of IL-6, a known contributor to muscle atrophy in sarcopenia, attenuating the loss of muscle mass associated with aging in mice and human cultures ( Table 1 ) [ 70 ]. Another preliminary report suggested the use of a 5-fluorouridine (5FUR) derivate; 5FURGal kills human senescent cells with multiple benefits such as enhancing cognitive function, lifespan extension, and improvement of muscle tissue and satellite cells ( Table 1 ) [ 71 ].…”

Section: Inflammation In Sarcopeniamentioning

confidence: 99%

Molecular Mechanisms of Inflammation in Sarcopenia: Diagnosis and Therapeutic Update

Jiménez-Gutiérrez

Martínez-Gómez

Martínez-Armenta

et al. 2022

Cells

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Sarcopenia is generally an age-related condition that directly impacts the quality of life. It is also related to chronic diseases such as metabolic dysfunction associated with diabetes and obesity. This means that everyone will be vulnerable to sarcopenia at some point in their life. Research to find the precise molecular mechanisms implicated in this condition can increase knowledge for the better prevention, diagnosis, and treatment of sarcopenia. Our work gathered the most recent research regarding inflammation in sarcopenia and new therapeutic agents proposed to target its consequences in pyroptosis and cellular senescence. Finally, we compared dual X-ray absorptiometry (DXA), magnetic resonance imaging (MRI), and ultrasound (US) as imaging techniques to diagnose and follow up on sarcopenia, indicating their respective advantages and disadvantages. Our goal is for the scientific evidence presented here to help guide future research to understand the molecular mechanisms involved in sarcopenia, new treatment strategies, and their translation into clinical practice.

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“…Recently, it has been shown that 25-HC has the senolytic properties in skeletal muscle, preventing the appearance of signs of aging (e.g., CRYAB aggregation) and infl ammation [98]. Increased production of 25-HC (through the activation of LXRs) may improve the conditions in a model of non-alcoholic fatty liver disease [99], which is accompanied by neuromuscular disorders and neurodegeneration.…”

Section: Hydroxycholesterol As a Molecule Of Intercellular Interacti...mentioning

confidence: 99%

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

Odnoshivkina

Kuznetsova

Petrov

2022

Biochemistry Moscow

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Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol; they can pass across the membrane and vascular barriers and act distantly as para-and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the infl ammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to aff ect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the eff ects of 25-HC as a signaling molecule mediating the infl uence of infl ammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinfl ammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic eff ects.

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Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types

Cited by 27 publications

References 82 publications

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades

Molecular Mechanisms of Inflammation in Sarcopenia: Diagnosis and Therapeutic Update

25-Hydroxycholesterol as a Signaling Molecule of the Nervous System

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