As a lipophilic tumour,ovarian cancer(OC)preferentially metastasizes to adipose-rich environments including the omentum and the peritoneum.Current research regarding the OC microenvironment has focused primarily on tu...As a lipophilic tumour,ovarian cancer(OC)preferentially metastasizes to adipose-rich environments including the omentum and the peritoneum.Current research regarding the OC microenvironment has focused primarily on tumour-associated immune cells,whereas little attention has been given to the adipose tissue and the adipose-derived stem cells(ADSCs)within it.Here,from the perspective of senescence,we hypothesized that the continuous presence and accumulation of tumour cells disrupts the homeostasis of adipose tissue by intercellular interactions.Through a series of in vitro and in vivo experiments,we found that OC cells induce adipose tissue ageing and ADSC senescence,leading to adipose tissue dysfunction,glucose intolerance,and insulin resistance.OC extracellular vesicle(OC-EV)and ADSC coculture revealed that OC-EVs trigger ADSC ageing and dysfunction.Moreover,coculture promoted the formation of inflammasomes in ADSCs and increased the levels of the inflammatory factors IL-1βand IL-18.RNA-sequencing and bioinformatics analysis revealed that the nuclear factor kappa B(NF-κB)signalling pathway is involved in ADSC senescence induced by OC cells.Immunofluorescence staining and Western blotting confirmed that increased expression of NF-κB signalling-related proteins is associated with senescent ADSCs.Further mechanistic studies revealed that OC-EVs deliver IL-1βto promote ADSC senescence and regulate the NF-κB signalling pathway in ADSCs.On the basis of these findings,we attempted to ameliorate the ovarian cancer microenvironment by eliminating senescent ADSCs,aiming to develop a therapeutic strategy against ovarian cancer.Both treatment with the senolytic cocktail dasatinib plus quercetin and treatment with the NF-κB inhibitor resveratrol(RSV)alleviated adipose tissue ageing,improved glucose tolerance and insulin sensitivity,and ultimately decreased OC progression and metastasis.Together,these results indicate an important role of ovarian cancer in adipose tissue ageing,and identify the elimination of senescent ADSCs in adipose tissue as a new potential strategy for the treatment of OC.展开更多
Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculo...Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.展开更多
Ovarian reserve is essential for fertility and influences healthy aging in women.Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes.The molecular mechanisms and vari...Ovarian reserve is essential for fertility and influences healthy aging in women.Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes.The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered.In this review,we highlight some of critical factors that impact oocyte quantity and quality during aging.Germ cell and follicle reserve at birth de-termines reproductive lifespan and timing the menopause in female mammals.Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency.Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes,telomere shortening,DNA damage and associated genetic mutations,oxidative stress,mitochondrial dysfunction and epigenetic alteration.We also discuss the intervention strategies to delay ovarian aging.Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed.Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells.We propose directions for future interventions.As couples increasingly begin delaying parenthood in life worldwide,understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.展开更多
基金supported by the National Natural Science Foundation of China(81972425,82103029)the Clinical Project of Shanghai Municipal Health Commission(202240217)+2 种基金the Clinical Project of International Peace Maternal and Child Health Hospital(IPMCH2022CR1-06)the Specialty Achievement Cultivation Project Plan Foundation of Shanghai Fourth People's Hospital(SY-XKZT-2023-1018)the Medical Scientific Research Project Plan Foundation of the Health Commission of Hongkou District(Hongwei2402-14)。
文摘As a lipophilic tumour,ovarian cancer(OC)preferentially metastasizes to adipose-rich environments including the omentum and the peritoneum.Current research regarding the OC microenvironment has focused primarily on tumour-associated immune cells,whereas little attention has been given to the adipose tissue and the adipose-derived stem cells(ADSCs)within it.Here,from the perspective of senescence,we hypothesized that the continuous presence and accumulation of tumour cells disrupts the homeostasis of adipose tissue by intercellular interactions.Through a series of in vitro and in vivo experiments,we found that OC cells induce adipose tissue ageing and ADSC senescence,leading to adipose tissue dysfunction,glucose intolerance,and insulin resistance.OC extracellular vesicle(OC-EV)and ADSC coculture revealed that OC-EVs trigger ADSC ageing and dysfunction.Moreover,coculture promoted the formation of inflammasomes in ADSCs and increased the levels of the inflammatory factors IL-1βand IL-18.RNA-sequencing and bioinformatics analysis revealed that the nuclear factor kappa B(NF-κB)signalling pathway is involved in ADSC senescence induced by OC cells.Immunofluorescence staining and Western blotting confirmed that increased expression of NF-κB signalling-related proteins is associated with senescent ADSCs.Further mechanistic studies revealed that OC-EVs deliver IL-1βto promote ADSC senescence and regulate the NF-κB signalling pathway in ADSCs.On the basis of these findings,we attempted to ameliorate the ovarian cancer microenvironment by eliminating senescent ADSCs,aiming to develop a therapeutic strategy against ovarian cancer.Both treatment with the senolytic cocktail dasatinib plus quercetin and treatment with the NF-κB inhibitor resveratrol(RSV)alleviated adipose tissue ageing,improved glucose tolerance and insulin sensitivity,and ultimately decreased OC progression and metastasis.Together,these results indicate an important role of ovarian cancer in adipose tissue ageing,and identify the elimination of senescent ADSCs in adipose tissue as a new potential strategy for the treatment of OC.
文摘Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.
基金by the National Natural Science Foundation of China(31970667,82230052,91749129,32030033)China National Key R&D Program(2018YFC1003004,2018YFA0107002)。
文摘Ovarian reserve is essential for fertility and influences healthy aging in women.Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes.The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered.In this review,we highlight some of critical factors that impact oocyte quantity and quality during aging.Germ cell and follicle reserve at birth de-termines reproductive lifespan and timing the menopause in female mammals.Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency.Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes,telomere shortening,DNA damage and associated genetic mutations,oxidative stress,mitochondrial dysfunction and epigenetic alteration.We also discuss the intervention strategies to delay ovarian aging.Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed.Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells.We propose directions for future interventions.As couples increasingly begin delaying parenthood in life worldwide,understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.
