FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice

Zhang, Chi; Xie, Yizhen; Chen, Haicheng; Lv, Linyan; Yao, Jiahui; Zhang, Min; Xia, Kai; Feng, Xin; Li, Yanqing; Liang, Xiaoyan; Sun, Xiangzhou; Deng, Chao; Liu, Guihua

doi:10.18632/aging.102682

Cited by 47 publications

(39 citation statements)

References 35 publications

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“…Recently, it has been shown that FOXO4-DRI selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency (Zhang et al, 2020 ).…”

Section: Senolytics In Brain Rejuvenationmentioning

confidence: 99%

Cellular Senescence in Brain Aging

Sikora

Bielak-Żmijewska

Dudkowska

et al. 2021

Front. Aging Neurosci.

133

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Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

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Section: Senolytics In Brain Rejuvenationmentioning

confidence: 99%

Cellular Senescence in Brain Aging

Sikora

Bielak-Żmijewska

Dudkowska

et al. 2021

Front. Aging Neurosci.

133

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show abstract

“…Again, in the first study using FOXO4-DRI to induce apoptosis in senescent cells, the senescent cells were generated by irradiation or doxorubicin ( Baar et al, 2017 ). In a recent study, FOXO4-DRI decreased levels of p53, p21, and p16 in the testes of aged mice, when compared to young mice ( Zhang et al, 2020 ). Therefore, our study and published work collectively showed that FOXO4-DRI was able to remove senescent cells created by different methods.…”

Section: Discussionmentioning

confidence: 86%

Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes

Huang

Makarcyzk

et al. 2021

Front. Bioeng. Biotechnol.

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Autologous chondrocyte implantation (ACI) is a procedure used to treat articular cartilage injuries and prevent the onset of post-traumatic osteoarthritis. In vitro expansion of chondrocytes, a necessary step in ACI, results in the generation of senescent cells that adversely affect the quality and quantity of newly formed cartilage. Recently, a senolytic peptide, fork head box O transcription factor 4-D-Retro-Inverso (FOXO4-DRI), was reported to selectively kill the senescent fibroblasts. In this study, we hypothesized that FOXO4-DRI treatment could remove the senescent cells in the expanded chondrocytes, thus enhancing their potential in generating high-quality cartilage. To simulate the in vitro expansion for ACI, chondrocytes isolated from healthy donors were expanded to population doubling level (PDL) 9, representing chondrocytes ready for implantation. Cells at PDL3 were also used to serve as the minimally expanded control. Results showed that the treatment of FOXO4-DRI removed more than half of the cells in PDL9 but did not significantly affect the cell number of PDL3 chondrocytes. Compared to the untreated control, the senescence level in FOXO4-DRI treated PDL9 chondrocytes was significantly reduced. Based on the result from standard pellet culture, FOXO4-DRI pre-treatment did not enhance the chondrogenic potential of PDL9 chondrocytes. However, the cartilage tissue generated from FOXO4-DRI pretreated PDL9 cells displayed lower expression of senescence-relevant secretory factors than that from the untreated control group. Taken together, FOXO4-DRI is able to remove the senescent cells in PDL9 chondrocytes, but its utility in promoting cartilage formation from the in vitro expanded chondrocytes needs further investigation.

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“…A relevant factor associated with late-onset hypogonadism 48 , as well as with an irreversible failure to reinstate testosterone production after critical situations that may compromise the LH-androstenedione axis is old age 49 , which has been linked to senescent dysfunction of Leydig cells 50 . The fact that a majority of non-survivor patients in our study who failed to reinstate testosterone levels are older than 60 years of age would be consistent with the senescence hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients

Paciucci¹

2021

Preprint

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Infection with SARS-CoV-2 portends a broad range of outcomes, from a majority of asymptomatic cases or mild clinical courses to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty and co-morbidities such as obesity, diabetes or cardiovascular disease. A precise knowledge is still lacking of the molecular and biological mechanisms that may explain the association of severe disease with male sex. Here, we show that testosterone trajectories are highly accurate individual predictors (AUC of ROC = 0.928, p < 0.0001) of survival in male COVID-19 patients. Longitudinal determinations of blood levels of luteinizing hormone (LH) and androstenedione suggest an early modest inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by either full recovery in survivors or a peripheral failure in lethal cases. Moreover, failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and decrease of non-classical monocytes. The strong association of recovery or failure to reinstate testosterone levels with survival or death from COVID-19 in male patients is suggestive of a significant role of testosterone status in the immune responses to COVID-19.

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FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice

Cited by 47 publications

References 35 publications

Cellular Senescence in Brain Aging

Cellular Senescence in Brain Aging

Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes

Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients

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