Obesity, Senescence, and Senolytics

Chaib, Selim; Tchkonia, Tamara; Kirkland, James L.

doi:10.1007/164_2021_555

Cited by 15 publications

(9 citation statements)

References 131 publications

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“…If successful, larger randomized studies with optimized dosing schedules will be needed to establish senolytics as preventive or early interventional treatments for patients with severe COVID-19 (ref. 149 ).…”

Section: Senolytic Strategiesmentioning

confidence: 99%

COVID-19 and cellular senescence

et al. 2022

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The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.

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Section: Senolytic Strategiesmentioning

confidence: 99%

COVID-19 and cellular senescence

et al. 2022

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“…The onset of obesity is related to increased senescent cells within adipose tissue and other organs in response to various stressful stimuli ( Chaib et al, 2021 ). Thus, the SASP is increasingly recognized as a critical driver of age-related pathologies, such as chronic inflammation.…”

Section: Discussionmentioning

confidence: 99%

Chronic consumption of a hypercaloric diet increases neuroinflammation and brain senescence, promoting cognitive decline in middle-aged female Wistar rats

Salas-Venegas

Santín-Márquez

Ramírez-Carreto

et al. 2023

Front. Aging Neurosci.

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Being overweight and obesity are world health problems, with a higher prevalence in women, defined as abnormal or excessive fat accumulation that increases the risk of chronic diseases. Excess energy leads to adipose expansion, generating hypertrophic adipocytes that produce various pro-inflammatory molecules. These molecules cause chronic low-intensity inflammation, affecting the organism’s functioning and the central nervous system (CNS), inducing neuroinflammation. The neuroinflammatory response during obesity occurs in different structures of the CNS involved in memory and learning, such as the cortex and the hippocampus. Here we analyzed how obesity-related peripheral inflammation can affect CNS physiology, generating neuroinflammation and promoting cellular senescence establishment. Since some studies have shown an increase in senescent cells during aging, obesity, and neurodegenerative diseases, we proposed that cellular senescence participation may contribute to the cognitive decline in an obesity model of middle-aged female Wistar rats. The inflammatory state of 6 and 13 months-old female Wistar rats fed with a hypercaloric diet was measured in serum and CNS (cortex and hippocampus). Memory was evaluated using the novel object recognition (NOR) test; the presence of senescent markers was also determined. Our data suggest that the systemic inflammation generated by obesity induces a neuroinflammatory state in regions involved in learning and memory, with an increase in senescent markers, thus proposing senescence as a potential participant in the negative consequences of obesity in cognition.

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“…Senescent cells, which are in a state of essentially irreversible cell cycle arrest but remain viable, can accumulate with aging, especially in more frail individuals, and at pathogenic sites of multiple disorders and diseases in experimental animals and humans across the lifespan. The senescent cell fate can be triggered by a number of stressors including DNA damage, cancerous mutations or oncogene activation, mitochondrial dysfunction, reactive metabolites, hyperoxia or hypoxia, proteotoxic stress, extracellular signals, infections, mechanical or shear stresses that deform cells, resistance exercise and factors secreted by other senescent cells 18,[38][39][40][41][42][43][44][45][46][47] . Many such stressors activate DNA damage response signaling and activation of the p53/p21 CIP1/WAF1 , p16 INK4a /retinoblastoma protein or other pathways, resulting in cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP) 24,40,[48][49][50][51][52][53] (Fig.…”

Section: Cellular Senescence: Mechanisms and Pathwaysmentioning

confidence: 99%

“…Diabetes/obesity/age-related lipodystrophy 23,25,42,48,[144][145][146][147][148][149][150][151][152] PLD 145 INK-ATTAC 23,25,150 p16-3MR 25 D + Q 25 N 150 Improved metabolic and adipose tissue function 23,25,145,150 , reduced inflammation 25 , improved adipogenesis 25 , improved beta cell function 150 Cardiac dysfunction 14,26,[153][154][155][156][157][158][159] INK-ATTAC 26,[157][158][159] p16-3MR 159 Q 153 N [155][156][157]159 D + Q 14,26,158 Activation of resident cardiac progenitor cells and cardiomyocyte formation 26 , alleviated myocardial hypertrophy and fibrosis…”

Section: Table 2 | Disorders and Diseases Linked To Senescent Cell Ac...mentioning

confidence: 99%

Cellular senescence and senolytics: the path to the clinic

Chaib

Tchkonia

Kirkland

2022

Nat Med

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519

332

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he aging population is steadily increasing. The World Health Organization (WHO) estimates that 1 in 6 people, or 2.1 billion, are expected to be over age 60 by 2030 (ref. 1 ). Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle-and high-income countries [2][3][4][5][6][7] .Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children 6,[8][9][10][11][12] . Indeed, fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome 12,13 . A fundamental aging mechanism that has gained increasing attention is cellular senescence. Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases. After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14 ), promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics, some of which have now been published (Table 1).Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence 3,15 . The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction (including the geriatric syndromes such as frailty, immobility, sarcopenia/ muscle wasting, mild cognitive impairment and incontinence) and loss of resilience (for example, decreased ability to recover from stresses such as injury, surgery, chemotherapy or infections or to mount an antibody response to immunizations) 3,[15][16][17][18] . The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others 6 . For example, interventions that target cellular senescence tend to attenuate other

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Obesity, Senescence, and Senolytics

Cited by 15 publications

References 131 publications

COVID-19 and cellular senescence

COVID-19 and cellular senescence

Chronic consumption of a hypercaloric diet increases neuroinflammation and brain senescence, promoting cognitive decline in middle-aged female Wistar rats

Cellular senescence and senolytics: the path to the clinic

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