Systems toxicology study reveals reduced impact of heated tobacco product aerosol extract relative to cigarette smoke on premature aging and exacerbation effects in aged aortic cells in vitro

Poussin, Carine; Toorn, Marco van der; Scheuner, Sophie; Piault, Romain; Kondylis, Athanasios; Savioz, Rebecca; Dulize, Rémi; Peric, Dariusz; Guedj, Emmanuel; Maranzano, Fabio; Merg, Céline; Morelli, Moran; Egesipe, Anne-Laure; Johne, Stephanie; Majeed, Shoaib; Pak, Claudius; Schneider, Thomas; Schlage, Walter K.; Ivanov, Nikolai V.; Peitsch, Manuel C.; Hoeng, Julia

doi:10.1007/s00204-021-03123-y

Cited by 13 publications

(10 citation statements)

References 86 publications

(112 reference statements)

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“…A study from India in 699,686 women showed that the risk of multimorbidity was 87% higher in women who smoked or chewed tobacco and was 18% higher in those who consumed alcohol than in women who did not smoke or chew tobacco or consume alcohol, respectively 155 . Factors such as smoking promote cellular senescence through inflammatory effects, oxidative stress and DNA damage 156 , whereas exercise prevents cellular senescence 156,157 , highlighting the probable interplay between socioeconomic, psychosocial and behavioural determinants and the hallmarks of ageing.…”

Section: Allostasismentioning

confidence: 99%

Multimorbidity

Skou

Mair

Fortin

et al. 2022

Nat Rev Dis Primers

367

283

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Interest in multimorbidity -commonly defined as the co-occurrence of at least two chronic conditions in the same individual 1 -has increased in the past few years owing to its substantial effect on the individual and the individual's family, as well as on health systems and on society, particularly in resource-poor settings 2-4 . Multimorbidity is distinct from the related concept of comorbidity, which refers to the combined effects of additional conditions in relation to the index condition in an individual [5][6][7][8] . By contrast, care for multimorbidity is patient-centred and does not routinely give priority to any single condition, although in clinical care, patients and clinicians will usually focus on the most pressing problems that the patient is experiencing.People with multimorbidity are more likely to die prematurely, be admitted to hospital and have an increased length of stay than people with a single chronic condition 9,10 . Multimorbidity is also associated with poorer function and health-related quality of life (HRQOL), depression and intake of multiple drugs (polypharmacy) and greater socioeconomic costs [11][12][13][14][15][16][17][18] . Most health care is designed to treat individual conditions rather than providing comprehensive, person-centred care 2,19,20 , which often leads to fragmented and sometimes contradictory care for people with multimorbidity and increases their treatment burden 21 Moreover, treating one condition at a time is inefficient and unsatisfactory for both people with multimorbidity and their health-care providers [22][23][24] .Multimorbidity is increasingly common owing to changes in lifestyle risk factors, notably physical inactivity and obesity, and population ageing that in part reflects improvements in survival from acute and chronic conditions 2,19,25,26 . Multimorbidity is associated with socioeconomic status and age 3,19,25,27 . However, although age is the strongest driver of multimorbidity, in absolute numbers, more people <65 years of age have multimorbidity than people ≥65 years of age, partly because more people in the general population are in that age group. Moreover, this emphasizes that multimorbidity is not just a feature of ageing 19,26 .Multimorbidity is further complicated in low-income and middle-income countries (LMICs) by the overlap of compounding factors, including adverse environmental and early life stressors linked to poverty, limited social infrastructure and poorer family coping mechanisms, that translate into chronic diseases occurring at earlier ages [28][29][30][31] . LMICs also have a higher prevalence of multimorbidity-related financial burden 32,33 and have weaknesses in health systems including a greater focus Treatment burdenThe workload associated with managing treatments and health-care recommendations and the impact of this on an individual and their supporters.

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Section: Allostasismentioning

confidence: 99%

Multimorbidity

Skou

Mair

Fortin

et al. 2022

Nat Rev Dis Primers

367

283

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“…Previous studies have demonstrated that aging-related senescence in vascular cells is responsible for AAA development in aging mice [ 33 ], which, combined with our results, could support the important role of cellular senescence in AAA formation. Notably, in contrast to age-related senescence, SIPS was closely associated with risk factors [ 13 ] for AAA, such as hypertension [ 10 ], hyperlipidemia [ 12 ] and cigarettes [ 11 ]. The above results indicated that SIPS might mediate the effect of risk factors on initiating the pathogenic process of AAA.…”

Section: Discussionmentioning

confidence: 99%

“…Chronic exposure to risk factors for vascular diseases, such as hypertension [ 10 ], nicotine [ 11 ], and hyperlipidemia [ 12 ], promotes premature senescence in vascular cells by generating stress-dependent damage [ 13 ]. Stress-induced premature senescence (SIPS) has been found to be one of the main contributors to the formation of vascular diseases, including aortic atherosclerosis [ 14 ] and vascular calcification [ 15 ], indicating its relationship to AAA.…”

Section: Introductionmentioning

confidence: 99%

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Xie¹,

Tang²,

Chen³

et al. 2023

Aging and disease

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Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRβ/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRβ/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

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“…It is interesting to note that there is a consensus about age-promoting properties of exposures to some compounds, also called “gerontogenic,” such as tobacco. Cigarette smoking has been involved with premature aging, accelerating aging, and, consequently, is a risk of age-related diseases and a link between cigarette smoking and cellular senescence has been widely raised ( Poussin et al, 2021 ). In accordance with our findings and hypothesis, Shi et al (2016) reported that miR-16-5p (a synonym of miR-15b-5p) had increased levels in plasma from healthy smokers, since miR-15b-5p (miR-16-5p is a synonym of miR-15b-5p) was the top one upstream regulator, indicating its potential role on several biological processes, including cell cycle deregulation.…”

Section: Discussionmentioning

confidence: 99%

Circulating Extracellular Vesicles and Particles Derived From Adipocytes: The Potential Role in Spreading MicroRNAs Associated With Cellular Senescence

et al. 2022

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Aging is associated with adipose tissue dysfunction and is recognized as a risk factor for shortened life span. Considering that in vitro findings have shown the involvement of microRNA in extracellular vesicles and particles (EVPs) on senescence, we hypothesized that circulating EVPs derived from adipocytes can be involved in the aging process via their microRNA cargo. We aimed to determine the microRNA profiles of circulating EVPs derived from adipocytes (FABP4+) from aged and young adult animals and to perform in silico prediction of their downstream signaling effects. Plasma was obtained from Wistar rats (3 and 21 months old), and adipocyte-derived EVPs were isolated using the commercially available kit. Fatty acid-binding protein 4 (FABP4) was used for adipocyte-derived EVPs isolation; microRNA isolation and microarray expression analysis were performed. The analysis revealed 728 miRNAs, 32 were differentially between groups (p < 0.05; fold change ≥ |1.1|), of which 15 miRNAs were upregulated and 17 were downregulated in circulating EVPs from aged animals compared to young adults. A conservative filter was applied, and 18 microRNAs had experimentally validated and highly conserved predicted mRNA targets, with a total of 2,228 mRNAs. Canonical pathways, disease and functions, and upstream regulator analyses were performed using IPA-QIAGEN, allowing a global and interconnected evaluation. IPA categories impacted negatively were cell cycle, cellular development, cellular growth and proliferation, and tissue development, while those impacted positively were “digestive system cancer” and “endocrine gland tumor.” Interestingly, the upregulated miR-15-5p targets several cyclins, such as CCND1 and CCND2, and miR-24-3p seems to target CDK4 (cyclin-dependent kinase 4); then potentially inhibiting their expression, both miRNAs can induce a negative regulation of cell cycle progression. In contrast, silencing of negative cell cycle checkpoint regulators, such as p21 and p16, can be predicted, which can induce impairment in response to genotoxic stressors. In addition, predicted targets, such as SMAD family members, seem to be involved in the positive control of digestive and endocrine tumors. Taken together, this exploratory study indicates that miRNA signature in circulating adipocyte-derived EVPs may be involved with the double-edged sword of cellular senescence, including irreversible proliferation arrest and tissue-dependent cancer, and seems to be suitable for further validation and confirmatory studies.

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Systems toxicology study reveals reduced impact of heated tobacco product aerosol extract relative to cigarette smoke on premature aging and exacerbation effects in aged aortic cells in vitro

Cited by 13 publications

References 86 publications

Multimorbidity

Multimorbidity

Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Circulating Extracellular Vesicles and Particles Derived From Adipocytes: The Potential Role in Spreading MicroRNAs Associated With Cellular Senescence

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