Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary

Hense, Jéssica D; Garcia, Driele Neske; Isola, José Victor Vieira; Rincón, Joao Alveiro Alvarado; Zanini, Bianka M; Prosczek, Juliane B.; Stout, Michael B.; Mason, Jeffrey B.; Walsh, Patrick; Brieño‐Enríquez, Miguel A.; Schadock, Ines; Barros, Carlos Castilho; Masternak, Michał M.; Schneider, Augusto

doi:10.1007/s11357-022-00573-9

Cited by 24 publications

(16 citation statements)

References 68 publications

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“…In addition to infertility, the aging ovary is associated with several age-related diseases, including cardiovascular disease, osteoporosis, hypertension, and ovarian cancer. It is thus crucial to understand the mechanisms that promote its deterioration [ 35 ]. Lipofuscin is evident in the ovaries of mice of advanced age.…”

Section: Discussionmentioning

confidence: 99%

“…Lipofuscin is considered a marker of senescent cells in various tissues [ 4 ]. Moreover, hypercaloric diets may exacerbate senescent cell-type aging [ 35 , 37 ]. Recently, Hense and colleagues reported that obese mice showed a more significant presence of senescent cells, characterized by lipofuscin accumulation and elevated p21 and p16 expression (cell cycle inhibitors) [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, hypercaloric diets may exacerbate senescent cell-type aging [ 35 , 37 ]. Recently, Hense and colleagues reported that obese mice showed a more significant presence of senescent cells, characterized by lipofuscin accumulation and elevated p21 and p16 expression (cell cycle inhibitors) [ 35 ]. However, the authors failed to determine the type of ovarian cells that become senescent.…”

Section: Discussionmentioning

confidence: 99%

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A High-Fat and High-Carbohydrate Diet Promotes Reminiscent Hallmarks of an Aging Ovary in the Rabbit Model

et al. 2022

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The primary definition of ovarian aging refers to the loss of follicles. Moreover, the aging of the microenvironment in ovaries, specifically affecting the follicles, may reveal deterioration with advancing age. Besides aging, metabolic disorders associated with hypercaloric diets may affect ovarian health and manifest characteristics associated with premature aging. In this study, we used 10-week-old chinchilla rabbits fed with a high-fat and high-carbohydrate diet (HFCD) until 25 weeks of age to explore hallmarks of reminiscent ovarian aging. The HFCD diet appeared to affect the ovarian reserve, reflected in a significant decrease in primordial follicles. Likewise, Sudan black stain detection revealed substantial differences in the deposits of lipofuscin in the interstitial glands of HFCD-fed rabbits compared to controls, constituting a “hallmark” of aging. The HFCD showed no induced changes in the expression of SOD 2 in the interstitial gland; however, surface epithelium cells were greater expressed. Besides this, the HFCD induced nuclear translocation of NF-ΚΒ p65 factor transcription in surface epithelium cells. We conclude that an HFCD induces a greater accumulation of senescence cells in the interstitial gland, promoting characteristics reminiscent of ovarian aging. However, the activation mechanism of NF-KB caused by an HFCD, which may be stress-responsive and generated by the interstitial gland, requires further study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A High-Fat and High-Carbohydrate Diet Promotes Reminiscent Hallmarks of an Aging Ovary in the Rabbit Model

et al. 2022

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“…The authors who reported the induction of cellular senescence in the ovaries of mice during aging 28 also characterized the cellular senescence of aged (12-month-old) genetically obese leptin-deficient ob/ob mice. 46 The identified cellular senescence in the ovaries of aged ob/ob mice, but not in agematched lean mice, was evidenced by higher expression of p16 and p21, lipofuscin accumulation in lysosomes, and infiltration with macrophages. Six-month-old ob/ob mice that had been treated with the senolytic DQ for 4 months from 2 months of age had significantly fewer senescent cells in their ovaries than untreated ob/ob mice, although there was no difference in number of ovarian follicles present in the two groups.…”

Section: Obesitymentioning

confidence: 96%

“…Six-month-old ob/ob mice that had been treated with the senolytic DQ for 4 months from 2 months of age had significantly fewer senescent cells in their ovaries than untreated ob/ob mice, although there was no difference in number of ovarian follicles present in the two groups. 46 It remains to be determined whether obesity induces cellular senescence in the ovary, regardless of chronological age. Moreover, further studies are needed to determine whether the elimination of senescent cells from the ovary improves the fertility of individuals with obesity, because ob/ob mice are anovulatory and their ovarian function differs from that of diet-induced obese mice.…”

Section: Obesitymentioning

confidence: 99%

Cellular senescence in the pathogenesis of ovarian dysfunction

Harada

2024

J of Obstet and Gynaecol

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The follicular microenvironment is crucial for normal ovarian function, and intra‐ovarian factors, in coordination with gonadotropins, contribute to its regulation. Recent research has revealed that the accumulation of senescent cells worsens the adverse environment of various tissues and plays critical roles in chronological aging and various pathological conditions. Cellular senescence involves cell‐cycle arrest, a senescence‐associated secretory phenotype (SASP), macromolecular damage, and dysmetabolism. In this review, I summarize the latest knowledge regarding the role of cellular senescence in pathological conditions in the ovary, in the context of reproduction. Specifically, cellular senescence is known to impair follicular and oocyte health in cisplatin‐ and cyclophosphamide‐induced primary ovarian insufficiency and to contribute to the pathogenesis of polycystic ovary syndrome (PCOS). In addition, cellular senescence is induced during the decline in ovarian reserve that is associated with chronological aging, endometriosis, psychological stress, and obesity, but it remains unclear whether it plays a causative role in these conditions. Finally, I discuss the potential for use of cellular senescence as a novel therapeutic target. The modification of SASP using a senomorphic and/or the elimination of senescent cells using a senolytic represent promising therapeutic strategies. Further elucidation of the role of cellular senescence in the effects of various insults on ovarian reserve, including chronological aging, as well as in pathogenesis of ovarian pathologies, including PCOS, may facilitate a new era of reproductive medicine.

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Ovarian aging in humans: potential strategies for extending reproductive lifespan

et al. 2023

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Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary

Cited by 24 publications

References 68 publications

A High-Fat and High-Carbohydrate Diet Promotes Reminiscent Hallmarks of an Aging Ovary in the Rabbit Model

A High-Fat and High-Carbohydrate Diet Promotes Reminiscent Hallmarks of an Aging Ovary in the Rabbit Model

Cellular senescence in the pathogenesis of ovarian dysfunction

Ovarian aging in humans: potential strategies for extending reproductive lifespan

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