Strategies for late phase preclinical and early clinical trials of senolytics

Gerdes, Erin O. Wissler; Misra, Avanish; Netto, Jair Machado Espindola; Tchkonia, Tamar; Kirkland, James L.

doi:10.1016/j.mad.2021.111591

Cited by 58 publications

(44 citation statements)

References 53 publications

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“…Furthermore, SARS‐CoV‐2 can cause non‐senescent cells to become senescent (Camell et al, 2021 ; Lee et al, 2021 ; Tripathi et al, 2021 ). The hallmarks of aging, inflammation, and multiple chronic diseases are highly interrelated (Tchkonia et al, 2021 ; Wissler Gerdes et al, 2021 ) and directly correlate with pathological outcomes of severe COVID‐19. It may be the case that underlying chronic inflammation and senescent cell burden in the elderly or chronically ill can fuel cytokine storm and so cause severe, serious consequences of SARS‐CoV‐2 infection (Camell et al, 2021 ; Tripathi et al, 2021 ; Wissler Gerdes et al, 2021 ).…”

Section: Introdutionmentioning

confidence: 99%

TNF‐α/IFN‐γ synergy amplifies senescence‐associated inflammation and SARS‐CoV‐2 receptor expression via hyper‐activated JAK/STAT1

et al. 2022

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Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID‐19 infection. The pathogenesis of COVID‐19‐related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS‐CoV‐2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF‐α + IFN‐γ or a cocktail of TNF‐α + IFN‐γ + IL‐6, increased expression of ACE2/DPP4, accentuated the pro‐inflammatory senescence‐associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence‐like state. IL‐6 by itself failed to induce substantial effects on viral entry receptors or SASP‐related genes, while synergy between TNF‐α and IFN‐γ initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper‐inflammation, normalized SARS‐CoV‐2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine‐mediated viral entry receptor activation and links with senescence and hyper‐inflammation.

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Section: Introdutionmentioning

confidence: 99%

TNF‐α/IFN‐γ synergy amplifies senescence‐associated inflammation and SARS‐CoV‐2 receptor expression via hyper‐activated JAK/STAT1

et al. 2022

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“…Accumulation of senescent cells is considered as one of the key processes responsible for the functional deterioration in aging. A growing body of literature suggests that senolytic treatment may alleviate multiple geriatric syndromes and diseases occurring in advanced age [20]. Only recently the improvement of memory and learning skills upon clearance of senescent cells with the combination of D+Q in aged mice has been reported [25].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is postulated that those compounds may also exert senostatic activity, by inhibiting SASP, which otherwise leads to spreading of senescence due to the paracrine effect of senescence progression [18]. Till now several published animal studies have shown that the eradication of senescent cells alleviates many aging-related pathologies [19][20][21]. The natural senolytic fisetin and a combination of dasatinib and quercetin (D+Q) treatment improve cognitive ability in mouse models of Alzheimer's disease and dementia [22,23].…”

Section: Introductionmentioning

confidence: 99%

“…The natural senolytic fisetin and a combination of dasatinib and quercetin (D+Q) treatment improve cognitive ability in mouse models of Alzheimer's disease and dementia [22,23]. Fisetin or D+Q appear to be the most effective senolytics tested in many preclinical studies and growing body of clinical trials [20,24]. In a recent study Ogrodnik et al provided the first evidence for beneficial effects of D+Q in alleviating age-associated cognitive decline in mice, tested in water -escape version of the Stone T-maze [25].…”

Section: Introductionmentioning

confidence: 99%

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Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile

Krzystyniak

Wesierska

Petrazzo

et al. 2022

Aging

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Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice. To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats. Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration. Our results expand and provide new insights to the existing knowledge associated with effects of senolytics on alleviating age-related associated cognitive dysfunctions.

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“…Moreover, quercetin plus dasatinib has been proven to enhance health span and lifespan in old mice [6] and improve age-related diseases such as cardiovascular disease and temporomandibular joint degeneration [76]. Furthermore, in an open-label clinical trial, within three weeks, oral quercetin and dasatinib improved the 6-min walking distance, walking speed, and ability to stand up from a chair and shortened the body function battery five days after the last dose [5,77].…”

Section: Senolytic Flavonoidsmentioning

confidence: 99%

Flavonoids—Natural Gifts to Promote Health and Longevity

Fan

Yang

et al. 2022

IJMS

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The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.

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Strategies for late phase preclinical and early clinical trials of senolytics

Cited by 58 publications

References 53 publications

TNF‐α/IFN‐γ synergy amplifies senescence‐associated inflammation and SARS‐CoV‐2 receptor expression via hyper‐activated JAK/STAT1

TNF‐α/IFN‐γ synergy amplifies senescence‐associated inflammation and SARS‐CoV‐2 receptor expression via hyper‐activated JAK/STAT1

Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile

Flavonoids—Natural Gifts to Promote Health and Longevity

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