CELLULAR SENESCENCE: AGING, CANCER, AND INJURY
Physiol Rev （生理学顶刊）
总之这篇综述很长，我连着看了两天才看完……并且涉猎的方位优点过于广了，但是优点是每个分门别类讲的都很细！
我个人觉得很有意义的是老化相关治疗，因为cell中讲的没有这个详细！治疗那部分可以一看！
别的尤其是组织修复那一块我根本就不懂！
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：这部分之前cell指南定义了检测方式）
虽然细胞周期停滞对于细胞老化的定义是至关重要的，但是不能作为老化细胞的一个独一无二的特征
然而即使在有丝分裂元的刺激下也无法进行有丝分裂是可以区分老化细胞和间歇期细胞的方式
SA--gal -流式细胞仪检查这个
Biomarker：细胞周期停滞+一些细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
端粒酶在端粒缩短的过程中并不能完全的修复缩短的端粒，因此会导致端丽损伤。
从而引起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-1is 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)
老化细胞表达IL-1可以使正常的老化细胞变成肿瘤细胞
分泌生长因子：insulin-like growth factor–binding proteins (IGFBPs) that can modulate the insulin-like growth factor (IGF) pathway ；IGF 可以作为一个潜在的诱导老化的成分
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的调节因子
大多数成分都被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
老化细胞可以通过旁分泌的方式影响周围的细胞
III. SENESCENT CELLS IN TISSUE REMODELING
在组织中，短期的老化细胞的积累有好处的，但是长期的老化细胞积累是有害的。
A. Embryogenesis
B. Tissue Repair
C. Fibrosis
肝脏细胞的纤维化
在肝脏中，老化的细胞可以通过分泌抗纤维化相关SASP，从而抑制肝脏纤维化
（senescent HSCs facilitate fibrotic resolution through decreased production of ECM components as well as increased expression ofantifibrotic SASP factors such asproteasesandMMPs.）
在肝细胞损伤的小鼠模型中，细胞老化的产生
induced by the matricellular protein CCN1
↓
activates the RAC1/NOX1 mechanism
↓
promote p16 and p53 activation
另外途径
IL-22
↓
STAT3 and SOCS3
↓
p53-dependent manner
/
IGF-1
p53-dependent manner
Idiopathic pulmonary fibrosis (IPF)
在IPF中老化的成纤维细胞得以诱导肌纤维话的分化，通过片旁分泌的途径，从而使老化细胞累积
↓
an increase in NOX4 and decrease in antioxidant response NFE2-related factor 2 (Nrf2) expression
↓
ROS levels increase
↓
leading to DNA damage and senescence
基因对于IPF的发病也有着很重要的影响，尤其是端粒相关基因：telo- mere maintenance, the telomerase reverse transcriptase(TERT) and the telomerase RNA component (TERC)
这些基因的突变会导致细胞的端粒变短
在IPF的患者中，老化细胞的清除和ROS的抑制相关
D. Tissue Reprogramming
IV. SENESCENT CELLS IN AGING
A. Senescence in Age-Related Disease
BubR1 低表达的小鼠出现了一个很多和老化有关的疾病，这个基因是正常有丝分裂中一个spindle checkpoint 基因
并且在这种基因持续表达的小鼠中可以导致选择性的凋亡，这些和老化相关的疾病可以延迟发生，并且小鼠的寿命也可能有所延长
B. Atherosclerosis
对于动脉粥样硬化的组织中老化相关因子出现升高。
但是老化对于动脉粥样硬化的产生具有保护作用，
CDKN2A, which result in decreasedp16 expression and potentially inability to enter senescence, are at increased risk for developing the disease
但是，对于粥样硬化的早起和晚期细胞老化起到了消极的作用，因为老化的细胞可以分泌炎症因子，这些炎症因子可以招募单核细胞从而加重泡沫样巨噬细胞形成的增加。
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 。
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在人类成纤维细胞中可以导致永久的细胞周期停滞。Ras基因在很多肿瘤中都存在突变，但是只有这一个基因的突变并不能导致肿瘤的发生，并且要需要很多其他的原癌基因和抑癌基因的突变，p19ARF, Pml, p53, retinoblastoma, and p16INK4a ，没有这些基因的突变ras基因缺失会是细胞回避老化；
原癌基因的抑制导致细胞老化
同样和一些原癌基因的抑制c-MYC, E1A, or DRIL1 也会导致细胞老化，通过改变SASP的方式。
原癌基因的突变所导致的细胞老化需要免疫体统参与。
抑癌基因的抑制导致的细胞老化
related to the tumor suppressor PTEN, whose loss induces a senescence response named PICS
In PICS：（这个过程的发生并没有DDR的存在）这个基因可以通过增加老化细胞的方式促进前列腺肿瘤前期的形成，并且再加上p53的突变的话，会使前列腺肿瘤的侵袭能力增强
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
大多是通过DNA damage 来进行老化诱导的
B. Noncell-Autonomous Regulation of Senescence in Cancer: Role of SASP
SASP对于肿瘤的形成来讲是一把双刃剑
senescent cells can induce paracrine senescence in neighboring cells, thus acting as a barrier against tumor growth.；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
对于肝脏肿瘤的生成来讲，早期的时候SASP发挥着肿瘤抑制的作用，但是到了晚期的时候SASP可以抑制免疫监视，从而导致肿瘤的发展。
C. Immune Clearance of Senescent Tumor Cells
在肝癌细胞中，p53重新表达的老化细胞可以增强巨噬细胞的计划，从而攻击抗肿瘤M1细胞。
但是巨噬细胞可以参与肿瘤前期细胞的清除
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
两种不同的老化治疗方式
一种通过SASP的交接来增加对于肿瘤的免疫反应
另外一种是通过抗衰老治疗来消灭老化的肿瘤细胞
A) TELOMERASE INHIBITION
因为很多肿瘤的发生都和端粒没得异常表达或者是过度激活有关，所以抑制端粒没的活性也可以作为抗肿瘤药物的一种
相关药物的种类
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
代表性的药物
3-Azido-2,3-dideoxythymidine (azi- dothymidine or zidovudine)
BIBR1532：端粒酶抑制剂
还可以用免疫治疗的方式
B) THERAPEUTIC MODULATION OF CELL CYCLE MACHINERY.
由于老化的开始是由于CDK抑制剂的聚集开始的，所以增加CDK抑制剂可以作为诱导肿瘤细胞老化的一种方式
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.
可以通过抑制MDM2/ p53 interaction 的方式来进行来增加p53的活性
target SIRT1, a deacetylase involved in the regulation of p53 activity 。这个分子可以通过使p53的去乙酰化来增加p53的降解，从而减少p53的活性
对于p53存在突变的肿瘤可以通增加p53的活性来增加细胞的老化情况，并且这种药物已经和抗肿瘤药物联合应用在了卵巢癌的治疗中
对于突变的p53肿瘤来讲，还可以通过逆转录载体来诱导老化
c-Myc
这个基因是个抗老化的癌基因，因此可以针对这个基因进行诱导老化。
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骨髓来源的抑制性细胞
在肿瘤生成中，不仅可以抑制肿瘤细胞的老化，还可以使免疫抑制
这种细胞可以在前列腺癌中街道老化的回避，通过在肿瘤微环境中释放IL-1 receptor antagonist (IL-1RA) ，从而IL1无法产生PICS，最后产生了老化回避。
对于高表达(IL-1RA)的肿瘤来讲，不仅会导致对化疗没有反应，还可以导致生存期的较短。
CXCR2 antagonist可以干扰MDSC的招募从而增强老化效应。
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
老化的肿瘤细胞可以作为一种抗肿瘤的疫苗来使用
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, 从而增强免疫抑制的作用吗。因此通过药物医治Jak2通路可以导致SASP的变成，从而使老化免疫监督重新的激活。
mTOR 也是一种调节SASP的因子，虽然说抑制mTOR 可以一种SASP的促进肿瘤效应，但是这种方式也可以影响旁分泌老化和老化监视，而这两种方式也是促进老化的两个重要的方式。
BRD4 这个分子的作用是SASP的激活和免疫清除，这个分子的抑制可以使这两种通路受到损伤
因此，SASP的编辑对于肿瘤的治疗来讲是一个潜在的方式，但是由于它有两面性，因此要明确SASP的成分并且针对性的对它进行编辑。
2. Selective elimination of senescent cells
在化疗药物治疗后的小鼠中， 老化细胞的清除可以减少肿瘤的复发和转移，并且减少药物的副反应。
因此对于化疗治疗后的肿瘤来讲，抗老化的治疗会起到一定的作用的。
A) BCL-2 PROTEIN FAMILY INHIBITORS.
这些自噬和凋亡相关的分子在老化的细胞中高比到达，因此这些因子的抑制剂可能对于抗衰老有一定的作用。
ABT-737
ABT-263 (navitoclax) 可以口服的药物
但是这些药物在肿瘤患者中又着很大的毒性，因此A1331852 and A1155463 被发明了出来
B) DASATINIB AND QUERCETIN
达沙替尼可以作为一种抗肿瘤药物了
槲皮素
这两个药物结合可以达到抗老化的作用
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：机体对于抗原的反应减弱，并伴随着长期的慢性炎症
适应性免疫老化：丢失T*B细胞受体的多样性，并且有记忆性免疫的形成缺陷
A. Innate Immune Response
1. Macrophages
有研究表明p16Ink4a and positivity to-galactosidase 在巨噬细胞中是一种对于免疫的生理反应，而不是一种老化的特异性表现，因此p16对于髓系细胞的成熟可能一起到一定的作用。
2. NK cells
和胚胎时期的老化可能相关
B. Adaptive Immune Response
1. T and B lymphocytes
对于这两种细胞来讲，复制性老化对于他们影响是最大的。
虽然老化的这两种细胞已经没有反应了，但是他们还是有活性的，并且可以产生很多炎症反应前期的细胞因子，和NK细胞的活性介质。
老化的T细胞会失去CD28的分子，从而无法进行调节反应。
在老化诱导的过程中，免疫反应也进行了参与，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
人类的调节性T细胞可能接到了功能变化并且诱导老化，通过by the regulation of STAT1/STAT3, ERK1/2, and p38 signaling and by metabolic competition during cross-talk
VII. MICROBIOTA AND SENESCENCE
Fusobacterium nucleatum 核算索性杆菌
enriched in human colorectal cancer (CRC), exacerbates intestinal tumorigenesis in vivo by inducing a proinflammatory signature inMDSC
并且微生物环境的情况，对于经典的化疗治疗、免疫治疗都有着重要的作用
可以改变肠内的微生物情况可以诱导SASP从而增加肿瘤的发生
（和老化没有什么关系？讲的都是免疫相关）
VIII. FUTURE DIRECTIONS
一直在寻找一个老化细胞上面特异性的marker
从而可以通过把这个marker作为target来特异性的消灭老化细胞
老化在肿瘤治疗中的应用主要还是抗老化药物清除老化的肿瘤细胞
