CELLULAR SENESCENCE: AGING, CANCER, AND INJURY?

Physiol Rev （生理學(xué)頂刊）

總之這篇綜述很長(zhǎng)敌完，我連著看了兩天才看完……并且涉獵的方位優(yōu)點(diǎn)過(guò)于廣了懂讯，但是優(yōu)點(diǎn)是每個(gè)分門(mén)別類(lèi)講的都很細(xì)华蜒！

我個(gè)人覺(jué)得很有意義的是老化相關(guān)治療股缸，因?yàn)閏ell中講的沒(méi)有這個(gè)詳細(xì)！治療那部分可以一看颊咬！

別的尤其是組織修復(fù)那一塊我根本就不懂肪笋！

I. INTRODUCTION?

replicative senescence.?

premature senescence ：independent from the telomere shortening?

? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? This senescence response occurs immediately after certain insults, such as genotoxic stress ormetabolic shock, triggered in cells by culture conditions.?

? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Oncogenic stress triggered by theoverexpression of certain oncogenesor loss of tumor suppressor genes (TSGs) in primary and tumor cells also induces senescence?

II. CELLULAR SENESCENCE?

A. Hallmarks of Cellular Senescence （ps：這部分之前cell指南定義了檢測(cè)方式）

雖然細(xì)胞周期停滯對(duì)于細(xì)胞老化的定義是至關(guān)重要的，但是不能作為老化細(xì)胞的一個(gè)獨(dú)一無(wú)二的特征

然而即使在有絲分裂元的刺激下也無(wú)法進(jìn)行有絲分裂是可以區(qū)分老化細(xì)胞和間歇期細(xì)胞的方式

SA-??-gal -流式細(xì)胞儀檢查這個(gè)

Biomarker：細(xì)胞周期停滯+一些細(xì)胞周期抑制分子的升高（p16INK4a, p21CIP1, and p27 ）+elevated expression of p19ARF, p53, and PAI-1?

senescent cells are commonly character：

?altered cell size with a more smoothed shape compared with proliferating cells

exhibit senescence-associated heterochromatin foci formation

accumulation of lipofuscin

DNA dam- age foci?

loss of lamin B1?

senescence-associated distension of satellites

expression of embryonic chon- drocyte–expressed 1 (DEC1) and decoy death receptor 2 (DCR2)?

upregulation of some microRNAs (miRNAs)

SASP：including growth factors, cytokines, chemokines, and proteases,

senescence-messaging secretome?

B. Role of Senescence in Evolution and Different Organisms?

（……）

C. Causes and Effector Pathways of Senescence?

telomere shortening最重要的原因

端粒酶在端廖卦縮短的過(guò)程中并不能完全的修復(fù)縮短的端粒敌买，因此會(huì)導(dǎo)致端麗損傷。

從而引起DDR

↓

(ATM) or ATM- and Rad3-related (ATR) kinases?

↓

stabilization of the p53 protein /transcriptional activation of the cyclin-dependent kinase (Cdk) inhibitor p21?

↓

block cell-cycle progression

physiological stresses imposed to healthy and cancer cells?

Abnormal O2 levels induce shortening of telomeres?

“culture shock” culturing condition of both human and mouse cells?

Oxidative stress,

endoplasmic reticulum stress?

interferon (IFN)-related responses?

“therapy-induced senescence” (TIS) :Treatment with DNA damage agents such as UV,??-irradiation , tertbutyl hydroperoxide or anticancer chemo- therapy agents?

activation of oncogenes[oncogene-induced senescence (OIS)] and loss of TSGs?

inflammaging?

D. Autocrine and Paracrine Senescence and Its Impact on the Tissue Microenvironment?

Key elements of the SASP are the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1??(IL-1??)「 IL-1??is considered one of the master regulators of the SASP 」

in OIS: chemokines binding to the IL-8 receptor C-X-C motif chemokine receptor 2 (CXCR2), such as CXCL-2, CXCL-3, and CXCL-5?

OIS and replicative senescence :CCL-2 (MCP-1), CCL-20 (MIP-3??), CCL-7 (MCP-3), CXCL-4 (PF-4), CXCL1 (Gro-??), and CXCL-12 (SDF-1)?

?老化細(xì)胞表達(dá)IL-1可以使正常的老化細(xì)胞變成腫瘤細(xì)胞??

分泌生長(zhǎng)因子：insulin-like growth factor–binding proteins (IGFBPs) that can modulate the insulin-like growth factor (IGF) pathway 阶界；IGF 可以作為一個(gè)潛在的誘導(dǎo)老化的成分

matrix metalloproteinases (MMPs) ：MMP-1 and -3, that can also act as regulatory elements of senescence, as they can cleave IL-8, IL-1, VEGF, and other CXCL/CCL family chemokines?

serine proteases like urokinase- or tissue-type plasminogen activators, the re- spective uPA receptor, and inhibitors of these serine pro- teases (PAI-1 and -2).?

nonmacromolecular elements such as nitric oxide (NO) and reactive oxygen species (ROS) that can affect the phenotype of neighboring cells?

SASP的調(diào)節(jié)因子

大多數(shù)成分都被NF-????B, CCAAT/enhancer-binding protein beta (CEBP/??) and by mTOR 控制

transcription factor GATA4, acting upstream of NF-??B, is also required for senescence establishment and SASP induction?

bromodomain and extraterminal domain (BET) family member bromodomain-containing protein 4 (BRD4) that positively regulates the senescence secretome and promotes senescence immune clearance?

signal transducer and activator of transcription 3 (STAT3) in certain tissues?

cGAS/STING pathway?

老化細(xì)胞可以通過(guò)旁分泌的方式影響周?chē)募?xì)胞

III. SENESCENT CELLS IN TISSUE REMODELING?

在組織中虹钮，短期的老化細(xì)胞的積累有好處的，但是長(zhǎng)期的老化細(xì)胞積累是有害的荐操。

A. Embryogenesis?

B. Tissue Repair?

C. Fibrosis?

肝臟細(xì)胞的纖維化

在肝臟中芜抒，老化的細(xì)胞可以通過(guò)分泌抗纖維化相關(guān)SASP珍策，從而抑制肝臟纖維化

（senescent HSCs facilitate fibrotic resolution through decreased production of ECM components as well as increased expression ofantifibrotic SASP factors such asproteasesandMMPs.）

在肝細(xì)胞損傷的小鼠模型中托启，細(xì)胞老化的產(chǎn)生

induced by the matricellular protein CCN1?

↓

activates the RAC1/NOX1 mechanism

↓

promote p16 and p53 activation?

另外途徑

IL-22

↓

STAT3 and SOCS3?

↓

p53-dependent manner?

/

IGF-1?

p53-dependent manner?

Idiopathic pulmonary fibrosis (IPF)?

在IPF中老化的成纖維細(xì)胞得以誘導(dǎo)肌纖維話(huà)的分化，通過(guò)片旁分泌的途徑攘宙，從而使老化細(xì)胞累積

↓

an increase in NOX4 and decrease in antioxidant response NFE2-related factor 2 (Nrf2) expression?

↓

ROS levels increase

↓

leading to DNA damage and senescence?

基因?qū)τ贗PF的發(fā)病也有著很重要的影響屯耸，尤其是端粒相關(guān)基因：telo- mere maintenance, the telomerase reverse transcriptase(TERT) and the telomerase RNA component (TERC)?

這些基因的突變會(huì)導(dǎo)致細(xì)胞的端粒變短

在IPF的患者中，老化細(xì)胞的清除和ROS的抑制相關(guān)

D. Tissue Reprogramming?

IV. SENESCENT CELLS IN AGING?

A. Senescence in Age-Related Disease?

BubR1 低表達(dá)的小鼠出現(xiàn)了一個(gè)很多和老化有關(guān)的疾病蹭劈，這個(gè)基因是正常有絲分裂中一個(gè)spindle checkpoint 基因

并且在這種基因持續(xù)表達(dá)的小鼠中可以導(dǎo)致選擇性的凋亡疗绣，這些和老化相關(guān)的疾病可以延遲發(fā)生，并且小鼠的壽命也可能有所延長(zhǎng)

B. Atherosclerosis?

對(duì)于動(dòng)脈粥樣硬化的組織中老化相關(guān)因子出現(xiàn)升高铺韧。

但是老化對(duì)于動(dòng)脈粥樣硬化的產(chǎn)生具有保護(hù)作用多矮，

CDKN2A, which result in decreasedp16 expression and potentially inability to enter senescence, are at increased risk for developing the disease?

但是，對(duì)于粥樣硬化的早起和晚期細(xì)胞老化起到了消極的作用，因?yàn)槔匣募?xì)胞可以分泌炎癥因子塔逃，這些炎癥因子可以招募單核細(xì)胞從而加重泡沫樣巨噬細(xì)胞形成的增加讯壶。

因此，clearingp16-positive senescent cells inLdlr??/??mice led to reduce fatty streaks in early stage and reduced plaque burden in late stages of the disease 湾盗。

V. SENESCENT CELLS IN CANCER?

A. Cell-Autonomous Regulation of Senescence in Cancer?

1. Oncogene-induced senescence?

The induction of senes- cence by oncogene activation is termedOIS?

oncogenic HRASG12V在人類(lèi)成纖維細(xì)胞中可以導(dǎo)致永久的細(xì)胞周期停滯伏蚊。Ras基因在很多腫瘤中都存在突變，但是只有這一個(gè)基因的突變并不能導(dǎo)致腫瘤的發(fā)生格粪，并且要需要很多其他的原癌基因和抑癌基因的突變躏吊，p19ARF, Pml, p53, retinoblastoma, and p16INK4a ，沒(méi)有這些基因的突變r(jià)as基因缺失會(huì)是細(xì)胞回避老化帐萎；

原癌基因的抑制導(dǎo)致細(xì)胞老化

同樣和一些原癌基因的抑制c-MYC, E1A, or DRIL1 也會(huì)導(dǎo)致細(xì)胞老化比伏，通過(guò)改變SASP的方式。

原癌基因的突變所導(dǎo)致的細(xì)胞老化需要免疫體統(tǒng)參與疆导。

抑癌基因的抑制導(dǎo)致的細(xì)胞老化

related to the tumor suppressor PTEN, whose loss induces a senescence response named PICS?

In PICS：（這個(gè)過(guò)程的發(fā)生并沒(méi)有DDR的存在）這個(gè)基因可以通過(guò)增加老化細(xì)胞的方式促進(jìn)前列腺腫瘤前期的形成凳怨，并且再加上p53的突變的話(huà)，會(huì)使前列腺腫瘤的侵襲能力增強(qiáng)

PTEN loss?

↓

through activation of mTOR and ARF-mediated inhibition of MDM2

↓

drives p53 activation.

/

PTEN loss?

↓

upregulation of the transcription factor Ets2? and involves APC/CDH1?

↓

induce p16INK4At

2. Therapy-induced senescence?

大多是通過(guò)DNA damage 來(lái)進(jìn)行老化誘導(dǎo)的

B. Noncell-Autonomous Regulation of Senescence in Cancer: Role of SASP?

SASP對(duì)于腫瘤的形成來(lái)講是一把雙刃劍

senescent cells can induce paracrine senescence in neighboring cells, thus acting as a barrier against tumor growth.是鬼；SASP can activate immune surveillance and bring innate and adaptive immune responses to clear senescent and proliferating tumor cells?

senescent tumor cells through the SASP can promote tumor progression, boosting cell proliferation and driving tumor vascularization (73), a phenomenon named as maladaptive senescence? eg TIS

對(duì)于肝臟腫瘤的生成來(lái)講肤舞，早期的時(shí)候SASP發(fā)揮著腫瘤抑制的作用，但是到了晚期的時(shí)候SASP可以抑制免疫監(jiān)視均蜜，從而導(dǎo)致腫瘤的發(fā)展李剖。

C. Immune Clearance of Senescent Tumor Cells?

在肝癌細(xì)胞中，p53重新表達(dá)的老化細(xì)胞可以增強(qiáng)巨噬細(xì)胞的計(jì)劃囤耳，從而攻擊抗腫瘤M1細(xì)胞篙顺。

但是巨噬細(xì)胞可以參與腫瘤前期細(xì)胞的清除

D. Therapies Targeting Senescent Cells?

1. Prosenescence therapy for cancer?

prosenescence therapy for cancer and differs from chemotherapy-induced senescence that affects both normal and cancer cells in that it specifically aims at senescence induction in cancer cells?

兩種不同的老化治療方式

一種通過(guò)SASP的交接來(lái)增加對(duì)于腫瘤的免疫反應(yīng)

另外一種是通過(guò)抗衰老治療來(lái)消滅老化的腫瘤細(xì)胞

A) TELOMERASE INHIBITION?

因?yàn)楹芏嗄[瘤的發(fā)生都和端粒沒(méi)得異常表達(dá)或者是過(guò)度激活有關(guān)，所以抑制端粒沒(méi)的活性也可以作為抗腫瘤藥物的一種

相關(guān)藥物的種類(lèi)

antisense oligonucleotides,

?targeting RNA component of telomerase

chemical inhibitors of telomerase?

oligonucleotides and nucleoside?

small molecule pharmaceuticals that target human (h) TERT?

gene therapy constructs

molecules that target telomere and telomerase-associated proteins,

inhibitors from microbial sources?

代表性的藥物

3-Azido-2,3-dideoxythymidine (azi- dothymidine or zidovudine)?

BIBR1532：端粒酶抑制劑

還可以用免疫治療的方式

B) THERAPEUTIC MODULATION OF CELL CYCLE MACHINERY.?

由于老化的開(kāi)始是由于CDK抑制劑的聚集開(kāi)始的充择，所以增加CDK抑制劑可以作為誘導(dǎo)腫瘤細(xì)胞老化的一種方式

eg：SKP2 inhibitors?

Skp2 is a F-box protein constituting one of the four subunits of the Skp1/ Cullin-1/F-Box (SCF) ubiquitin E3 ligase complex that regulates apoptosis, cell cycle progression, and prolifer- ation by promoting the ubiquitination and degradation of p27?

CDK inhibitors：

prevent the phosphorylation of retinoblastoma, thus arresting the cell cycle?

CDK4/6 inhibitors, such as pal- bociclib, ribociclib, and amebaciclib, are able to induce se- nescence.?

inhibition of Cdk2?

A recent study has indeed demonstrated that the pharmacological inhibition of Cdk2 induces Myc- dependent senescence in various cell type?

C) P53 AND MYC TARGETING.?

可以通過(guò)抑制MDM2/ p53 interaction 的方式來(lái)進(jìn)行來(lái)增加p53的活性

target SIRT1, a deacetylase involved in the regulation of p53 activity 德玫。這個(gè)分子可以通過(guò)使p53的去乙酰化來(lái)增加p53的降解椎麦，從而減少p53的活性

對(duì)于p53存在突變的腫瘤可以通增加p53的活性來(lái)增加細(xì)胞的老化情況宰僧，并且這種藥物已經(jīng)和抗腫瘤藥物聯(lián)合應(yīng)用在了卵巢癌的治療中

對(duì)于突變的p53腫瘤來(lái)講，還可以通過(guò)逆轉(zhuǎn)錄載體來(lái)誘導(dǎo)老化

c-Myc?

這個(gè)基因是個(gè)抗老化的癌基因观挎，因此可以針對(duì)這個(gè)基因進(jìn)行誘導(dǎo)老化琴儿。

抑制基因

Myc is viewed as an antisenescence oncogene, and different strategies targeting Myc have been shown to induce a senescence response?

D) IMMUNOTHERAPY?

MDSCs骨髓來(lái)源的抑制性細(xì)胞

在腫瘤生成中，不僅可以抑制腫瘤細(xì)胞的老化嘁捷，還可以使免疫抑制

這種細(xì)胞可以在前列腺癌中街道老化的回避造成，通過(guò)在腫瘤微環(huán)境中釋放IL-1 receptor antagonist (IL-1RA) ，從而IL1無(wú)法產(chǎn)生PICS雄嚣，最后產(chǎn)生了老化回避晒屎。

對(duì)于高表達(dá)(IL-1RA)的腫瘤來(lái)講，不僅會(huì)導(dǎo)致對(duì)化療沒(méi)有反應(yīng)，還可以導(dǎo)致生存期的較短鼓鲁。

CXCR2 antagonist可以干擾MDSC的招募從而增強(qiáng)老化效應(yīng)履肃。

Many cancer immunotherapies based on vaccination or T cells reactivation in cancer do not cause cytotoxic cancer elimination but arrest cancer growth or induce slow cancer regression.?

在胰腺癌中，autologous infusion of tumor antigen–specific CD4 Th1 cell that produces IFN-??, and TNF-??induces senescence in RIP1/tumor anti- gen 2?

老化的腫瘤細(xì)胞可以作為一種抗腫瘤的疫苗來(lái)使用?

E) SASP REPROGRAMMING?

therapies reprogramming the SASP can enhance the tumor suppressive role of senes- cence in cancer and restrain the negative effects of the SASP?

Eg：

Stat3 regulates the SASP of PICS, 從而增強(qiáng)免疫抑制的作用嗎坐桩。因此通過(guò)藥物醫(yī)治Jak2通路可以導(dǎo)致SASP的變成尺棋，從而使老化免疫監(jiān)督重新的激活。

mTOR 也是一種調(diào)節(jié)SASP的因子绵跷，雖然說(shuō)抑制mTOR 可以一種SASP的促進(jìn)腫瘤效應(yīng)膘螟，但是這種方式也可以影響旁分泌老化和老化監(jiān)視，而這兩種方式也是促進(jìn)老化的兩個(gè)重要的方式碾局。

BRD4 這個(gè)分子的作用是SASP的激活和免疫清除荆残，這個(gè)分子的抑制可以使這兩種通路受到損傷

因此，SASP的編輯對(duì)于腫瘤的治療來(lái)講是一個(gè)潛在的方式净当，但是由于它有兩面性内斯，因此要明確SASP的成分并且針對(duì)性的對(duì)它進(jìn)行編輯。

2. Selective elimination of senescent cells?

在化療藥物治療后的小鼠中像啼， 老化細(xì)胞的清除可以減少腫瘤的復(fù)發(fā)和轉(zhuǎn)移俘闯，并且減少藥物的副反應(yīng)。

因此對(duì)于化療治療后的腫瘤來(lái)講忽冻，抗老化的治療會(huì)起到一定的作用的真朗。

A) BCL-2 PROTEIN FAMILY INHIBITORS.?

這些自噬和凋亡相關(guān)的分子在老化的細(xì)胞中高比到達(dá)，因此這些因子的抑制劑可能對(duì)于抗衰老有一定的作用僧诚。

ABT-737?

ABT-263 (navitoclax) 可以口服的藥物

但是這些藥物在腫瘤患者中又著很大的毒性遮婶，因此A1331852 and A1155463 被發(fā)明了出來(lái)

B) DASATINIB AND QUERCETIN?

達(dá)沙替尼可以作為一種抗腫瘤藥物了

槲皮素

這兩個(gè)藥物結(jié)合可以達(dá)到抗老化的作用

C) FOXO4 INHIBITORS?

D) OTHER SENOLYTIC COMPOUNDS?

VI. SENESCENCE OF THE IMMUNE SYSTEM?

innate immune senescence are a reduction in the antigen processing and presentation capacity associated with a decreased response to stimuli but keeping a chronic activation state.?

Adaptive immune senescenceis associated with loss of T or B cell receptor repertoire diversity and impaired immunological memory formation. This phenomenon is the cause of an inefficient control of infec- tions and tissue damage with age, as well as of an impaired tumor immunosurveillance that leads to an increased risk of tumorigenesis in old individuals.?

固有免疫老化：機(jī)體對(duì)于抗原的反應(yīng)減弱，并伴隨著長(zhǎng)期的慢性炎癥

適應(yīng)性免疫老化：丟失T*B細(xì)胞受體的多樣性湖笨，并且有記憶性免疫的形成缺陷

A. Innate Immune Response?

1. Macrophages?

有研究表明p16Ink4a and positivity to??-galactosidase 在巨噬細(xì)胞中是一種對(duì)于免疫的生理反應(yīng)旗扑，而不是一種老化的特異性表現(xiàn)，因此p16對(duì)于髓系細(xì)胞的成熟可能一起到一定的作用慈省。

2. NK cells?

和胚胎時(shí)期的老化可能相關(guān)

B. Adaptive Immune Response?

1. T and B lymphocytes?

對(duì)于這兩種細(xì)胞來(lái)講臀防，復(fù)制性老化對(duì)于他們影響是最大的。

雖然老化的這兩種細(xì)胞已經(jīng)沒(méi)有反應(yīng)了辫呻，但是他們還是有活性的清钥，并且可以產(chǎn)生很多炎癥反應(yīng)前期的細(xì)胞因子，和NK細(xì)胞的活性介質(zhì)放闺。

老化的T細(xì)胞會(huì)失去CD28的分子，從而無(wú)法進(jìn)行調(diào)節(jié)反應(yīng)缕坎。

在老化誘導(dǎo)的過(guò)程中怖侦，免疫反應(yīng)也進(jìn)行了參與，eg Tregs, known to be crucial for the maintenance of the immune self-tolerance and homeostasis (for review, see Ref. 171), induce senescence in effector T cells, limiting their proliferation by the activation of the p38MAPK and p53 signaling pathways that control both the cell cycle inhibitors p16INK4a and p21WAF1?

人類(lèi)的調(diào)節(jié)性T細(xì)胞可能接到了功能變化并且誘導(dǎo)老化，通過(guò)by the regulation of STAT1/STAT3, ERK1/2, and p38 signaling and by metabolic competition during cross-talk?

VII. MICROBIOTA AND SENESCENCE?

Fusobacterium nucleatum 核算索性桿菌

enriched in human colorectal cancer (CRC), exacerbates intestinal tumorigenesis in vivo by inducing a proinflammatory signature inMDSC?

并且微生物環(huán)境的情況匾寝，對(duì)于經(jīng)典的化療治療搬葬、免疫治療都有著重要的作用

可以改變腸內(nèi)的微生物情況可以誘導(dǎo)SASP從而增加腫瘤的發(fā)生

（和老化沒(méi)有什么關(guān)系？講的都是免疫相關(guān)）

VIII. FUTURE DIRECTIONS?

一直在尋找一個(gè)老化細(xì)胞上面特異性的marker

從而可以通過(guò)把這個(gè)marker作為target來(lái)特異性的消滅老化細(xì)胞

老化在腫瘤治療中的應(yīng)用主要還是抗老化藥物清除老化的腫瘤細(xì)胞