Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

Ogrodnik, Mikołaj; Zhu, Yi; Langhi, Larissa G.P.; Tchkonia, Tamar; Krüger, Patrick; Fielder, Edward; Victorelli, Stella; Ruswhandi, Rifqha A.; Giorgadze, Nino; Pirtskhalava, Tamar; Podgorni, Oleg; Enikolopov, Grigori; Johnson, Kurt O.; Xu, Ming; Inman, Christine; Palmer, Allyson K.; Schafer, Marissa J.; Weigl, Moritz; Ikeno, Yuji; Burns, Terry C.; Passos, João F.; Zglinicki, Thomas von; Kirkland, James L.; Jurk, Diana

doi:10.1016/j.cmet.2019.01.013

Cited by 126 publications

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“…Because our interventions target senescent cells not only in adipose, but also in other tissues, their potential effects could exceed those limited to alleviating adipose tissue dysfunction. Senolytics may affect senescence‐related comorbidities associated with obesity (e.g., hepatic steatosis, osteoarthritis, and neuropsychiatric dysfunction), accelerated aging‐like states associated with obesity (e.g., sarcopenia and frailty), and the consequences of chronological aging itself by acting on nonadipose senescent cells (Kirkland et al, ; Ogrodnik et al, ; Palmer et al, ). They may also decrease the complications of diabetes and obesity related to persistent inflammation caused by senescent cell accumulation, including cardiovascular and renal dysfunction.…”

Section: Resultsmentioning

confidence: 99%

“…(b) On the other hand, Q, unlike D, is effective against senescent endothelial cells (Zhu et al, ), a cell type implicated in vascular complications of diabetes (Caballero, ). (c) D + Q is effective in alleviating multiple age‐ and senescence‐associated disorders, including many that are frequent complications or comorbidities of diabetes in preclinical animal models; these comorbidities include arteriosclerosis, vascular hyporeactivity, osteoporosis, hepatic steatosis, physical dysfunction, neurodegeneration, and neuropsychiatric dysfunction (Farr et al, ; Kirkland & Tchkonia, ; Kirkland et al, ; Musi et al, ; Ogrodnik et al, ,; Roos et al, ; Xu et al, ). (d) Navitoclax and other BCL‐2 family member inhibitors can be toxic, for example, causing severe thrombocytopenia, which can occur even with intermittent dosing (Wilson et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

et al. 2019

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Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

et al. 2019

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“…These findings are consistent with the hypothesis that clearing senescent cells can beneficially alter stem and progenitor cell function across multiple tissues. D + Q enhances function of osteoblastic progenitors, leading to new bone formation in mice with age‐related osteoporosis, impedes function of the osteoclast progenitors that lead to bone resorption in these same mice (Farr et al, ), and enhances neurogenesis in mice with metabolically induced impairment of nerve cell generation (Ogrodnik et al, ).…”

Section: Discussionmentioning

confidence: 99%

Aged‐senescent cells contribute to impaired heart regeneration

et al. 2019

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Aging leads to increased cellular senescence and is associated with decreased potency of tissue‐specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32–86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A, SA‐β‐gal, DNA damage γH2AX, telomere length, senescence‐associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK‐ATTAC or wild‐type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67‐, EdU‐positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.

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“…To determine the impact that BTK inhibition may have on brain functions during aging, we performed a series of tests on the ibrutinib‐treated Zmpste24 −/− mice. We first used the elevated plus maze (EPM) to measure anxiety‐like behaviour in mice (Figure a), since anxiety has been shown to be strongly associated with aging (Perna, Iannone, Alciati, & Caldirola, ) and the presence of senescent cells (Ogrodnik et al, ). In the EPM test, we measured the willingness of mice to explore the open arm of the maze, which is inversely proportional to the anxiety experienced (Loxton & Canales, ; Walf & Frye, ), by counting the number of times a mouse entered into, and the time spent in, the open arms.…”

Section: Resultsmentioning

confidence: 99%

Amelioration of age‐related brain function decline by Bruton's tyrosine kinase inhibition

et al. 2019

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One of the hallmarks of aging is the progressive accumulation of senescent cells in organisms, which has been proposed to be a contributing factor to age‐dependent organ dysfunction. We recently reported that Bruton's tyrosine kinase (BTK) is an upstream component of the p53 responses to DNA damage. BTK binds to and phosphorylates p53 and MDM2, which results in increased p53 activity. Consistent with this, blocking BTK impairs p53‐induced senescence. This suggests that sustained BTK inhibition could have an effect on organismal aging by reducing the presence of senescent cells in tissues. Here, we show that ibrutinib, a clinically approved covalent inhibitor of BTK, prolonged the maximum lifespan of a Zmpste24−/− progeroid mice, which also showed a reduction in general age‐related fitness loss. Importantly, we found that certain brain functions were preserved, as seen by reduced anxiety‐like behaviour and better long‐term spatial memory. This was concomitant to a decrease in the expression of specific markers of senescence in the brain, which confirms a lower accumulation of senescent cells after BTK inhibition. Our data show that blocking BTK has a modest increase in lifespan in Zmpste24−/− mice and protects them from a decline in brain performance. This suggests that specific inhibitors could be used in humans to treat progeroid syndromes and prevent the age‐related degeneration of organs such as the brain.

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Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

Cited by 126 publications

References 0 publications

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

Aged‐senescent cells contribute to impaired heart regeneration

Amelioration of age‐related brain function decline by Bruton's tyrosine kinase inhibition

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