Sublethal whole-body irradiation causes progressive premature frailty in mice

Fielder, Edward; Weigand, Melanie; Agneessens, Julien; Griffin, Brigid; Parker, Craig; Miwa, Soichi; Zglinicki, Thomas von

doi:10.1016/j.mad.2019.03.006

Cited by 30 publications

(41 citation statements)

References 32 publications

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“…Animal models of aging could play an essential role in the research of aging mechanisms, as well as in clinical studies of anti-aging therapy. Current widely used aging animal models include the spontaneous aging model (natural aging model and senescence accelerated mouse [44]) and the induced aging model (irradiation-induced aging model [45], β-amyloid-induced aging model [46], transgenic aging model [47], and Dgalactose-induced accelerated aging model [48]). In our study, the whole-body irradiation of 2 Gy γ-rays was used as a stressor to successfully induce cellular senescence and bone loss.…”

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Osteocyte Senescence Alters Bone Marrow Mesenchymal Stem Cell Differentiation Potential via Paracrine Signaling

Wang

et al. 2021

IJMS

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Cellular senescence and its senescence-associated secretory phenotype (SASP) are widely regarded as promising therapeutic targets for aging-related diseases, such as osteoporosis. However, the expression pattern of cellular senescence and multiple SASP secretion remains unclear, thus leaving a large gap in the knowledge for a desirable intervention targeting cellular senescence. Therefore, there is a critical need to understand the molecular mechanism of SASP secretion in the bone microenvironment that can ameliorate aging-related degenerative pathologies including osteoporosis. In this study, osteocyte-like cells (MLO-Y4) were induced to cellular senescence by 2 Gy γ-rays; then, senescence phenotype changes and adverse effects of SASP on bone marrow mesenchymal stem cell (BMSC) differentiation potential were investigated. The results revealed that 2 Gy irradiation could hinder cell viability, shorten cell dendrites, and induce cellular senescence, as evidenced by the higher expression of senescence markers p16 and p21 and the elevated formation of senescence-associated heterochromatin foci (SAHF), which was accompanied by the enhanced secretion of SASP markers such as IL-1α, IL-6, MMP-3, IGFBP-6, resistin, and adiponectin. When 0.8 μM JAK1 inhibitors were added to block SASP secretion, the higher expression of SASP was blunted, but the inhibition in osteogenic and adipogenic differentiation potential of BMSCs co-cultured with irradiated MLO-Y4 cell conditioned medium (CM- 2 Gy) was alleviated. These results suggest that senescent osteocytes can perturb BMSCs’ differential potential via the paracrine signaling of SASP, which was also demonstrated by in vivo experiments. In conclusion, we identified the SASP factor partially responsible for the degenerative differentiation of BMSCs, which allowed us to hypothesize that senescent osteocytes and their SASPs may contribute to radiation-induced bone loss.

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Section: Discussionmentioning

confidence: 99%

Radiation-Induced Osteocyte Senescence Alters Bone Marrow Mesenchymal Stem Cell Differentiation Potential via Paracrine Signaling

Wang

et al. 2021

IJMS

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“…The impact of radiation on frailty index scores was investigated in male C57BL/6 mice, starting at 20-24 weeks of age [94]. This work shows that mice treated with sublethal irradiation exhibit premature frailty, premature mortality, a decline in cognitive function and early tumour development [94]. This demonstrates that the frailty index may useful to test and validate novel interventions to prevent premature ageing in cancer survivors.…”

Section: Drug Interventions That Exacerbate Frailty In Animal Modelsmentioning

confidence: 99%

“…The rationale is that radiation therapy induces fatigue [91,92] and reduces physical activity [93], which would be expected to worsen frailty. The impact of radiation on frailty index scores was investigated in male C57BL/6 mice, starting at 20-24 weeks of age [94]. This work shows that mice treated with sublethal irradiation exhibit premature frailty, premature mortality, a decline in cognitive function and early tumour development [94].…”

Section: Drug Interventions That Exacerbate Frailty In Animal Modelsmentioning

confidence: 99%

Preclinical models of frailty: Focus on interventions and their translational impact: A review

Mishra

Howlett

2020

Nutrition and Healthy Aging

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The concept of frailty refers to heterogeneity in the risk of adverse outcomes for people of the same age. It is traditionally thought of as the inability of the body to maintain homeostasis. It can help explain differences between chronological and biological age and can quantify healthspan in experimental studies. Although clinical studies have developed tools to quantify frailty over the past two decades, preclinical models of frailty have only recently been introduced. This review describes the notion of frailty and outlines two commonly used clinical approaches to quantify frailty: the frailty phenotype and the frailty index. Translation of these methodologies for use in animals is introduced and studies that use these models to evaluate interventions designed to attenuate or exacerbate frailty are discussed. These include studies involving manipulation of diet, implementation of exercise regimens and tests of pharmaceutical agents to exacerbate or attenuate frailty. Together, this body of work suggests that preclinical frailty assessment tools are a valuable new resource to quantify the impact of interventions on overall health. Future studies could deploy these models to evaluate new frailty therapies, test combinations of interventions and assess interventions to enhance the ability to resist stressors in the setting of ageing.

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“…IR-treated cells show numerous markers of senescence including SA-β-galactosidase, p16, p21, and SASP induction [30,[42][43][44][45][46][47][48]. Cancer-free mice irradiated with sublethal doses of γ-radiation also show several signs of senescence in various tissues, including p16 upregulation [49][50][51] (Table 1).…”

Section: Radiotherapymentioning

confidence: 99%

“…Total-body γ-irradiation of mice also induces senescence and an upregulated SASP in various tissues [49,51]. Irradiated mice also developed early onset of symptoms associated with frailty including decreased cognition, weight loss, and reduced grip strength [50].…”

Section: Roles Of Senescent Cells In Side Effects Of Cancer Therapiesmentioning

confidence: 99%

Senescent Cells in Cancer Therapy: Friends or Foes?

2020

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Cellular senescence is a common outcome of various anticancer interventions.Senescence-associated secretory phenotypes (SASPs) have pro-tumorigenic functions.Evidence exists of increased cellular senescence in patients treated for various types of cancer.Therapy-induced senescence can cause cancer metastasis and relapse and several adverse reactions to cancer treatments.Pharmacological interference with detrimental senescence might be considered to improve the efficacy of cancer treatments and improve the life quality of treated patients.

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Sublethal whole-body irradiation causes progressive premature frailty in mice

Cited by 30 publications

References 32 publications

Radiation-Induced Osteocyte Senescence Alters Bone Marrow Mesenchymal Stem Cell Differentiation Potential via Paracrine Signaling

Radiation-Induced Osteocyte Senescence Alters Bone Marrow Mesenchymal Stem Cell Differentiation Potential via Paracrine Signaling

Preclinical models of frailty: Focus on interventions and their translational impact: A review

Senescent Cells in Cancer Therapy: Friends or Foes?

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