Anti-aging is an eternal topic of human beings, but do you understand cellular aging?

Anti-aging is an eternal topic of human beings, but do you understand cellular aging?

Before introducing cellular senescence, let's look at the definition of senescence: we define it broadly as the time-dependent functional decline that affects most organisms

Cellular senescence is a permanent state of cell cycle termination

Major changes after cellular senescence

1.

In the new proposed third edition of Cancer Markers in 2022, the cellular senescence of tumors can be assessed based on these markers

The following is a brief introduction to a senescent cell-based tumor therapy approach

Antitumor therapy that induces cellular senescence

1.

Since then, in 2005, the concept of OIS was extended to multiple oncogenic models, including lymphoma, prostate cancer, lung adenoma, hyperplastic pituitary, and melanocytic nevi

Likewise, deletion of tumor suppressor genes, such as Pten, also causes senescence in primary prostate epithelial cells, termed Pten deletion-induced cellular senescence (PICS)

2.

Mechanistically, many chemotherapy induces DNA damage in cancer cells, thereby triggering senescence through activation of the P53-Rb pathway mediated by ATM-CHK2 and ATR-CHK1 kinases

Inhibitors of topoisomerase I and II, such as doxorubicin, isofolic acid, and camptothecin, are widely used to treat various types of cancer and have been shown to disrupt DNA strands after DNA supercoils are unwound

This results in massive DNA damage and increased expression of p53 and its downstream targets CDKN1A and PAI1 (also known as SERPINE1), which leads to senescence

Platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin, also cause extensive DNA damage through DNA cross-linking, leading to aging

Although a considerable number of existing chemotherapeutic agents have the ability to induce senescence, apoptotic responses predominate in most cancers

Radiation therapy is widely used in the treatment of many types of cancer

Unlike chemotherapy, this treatment can be applied topically, so there is less collateral damage to normal tissue, so it can also reduce secondary cancers

3.
Inhibit cell cycle and induce cell senescence

A hallmark of senescent cells is the upregulation of cyclin-dependent kinase (CDK) inhibitory proteins, such as Ink4a and p21, to induce cell cycle arrest
.

In contrast, cancer cells typically upregulate CDK levels in order to progress throughout the cell cycle
.

Therefore, drugs that inhibit CDKs or increase the levels of CDK inhibitory proteins are currently being investigated for use in cancer therapy to induce senescence
.

In particular, CDK4 and CDK6 (hereinafter referred to as CDK4/6) play an important role in the development process from G1 phase to S phase, and are overexpressed in many human cancers
.

CDK4/6 inhibitors mimic the function of INK4A and induce senescence in a variety of cancer cells
.
Finally, XL413 or TAK931 induced senescence in hepatoma cells by inhibiting DNA replication by inhibiting CDC7 kinase
.

4.
Inhibition of telomerase to induce cellular senescence

As mentioned above, replicative senescence is a response to telomere attrition
.
Cancer cells usually avoid this by reactivating the activity of telomerase
.

So far, many compounds that inhibit the telomerase complex have been identified as candidates for anticancer therapy
.

Among them, BIBR15 and GRN163L are potent telomerase inhibitors that induce senescence and inhibit cancer cell proliferation
.

However, the use of GRN163L for anti-aging therapy requires further investigation, as this compound can also induce apoptosis in human pancreatic cancer cells
.

5.
Modulation of the epigenome to induce cellular senescence

Another way to induce senescence is by modulating the epigenome of cancer cells
.

Inhibition of DNA methyltransferases by decitabine results in demethylation of the cpg-rich region of the CDKN2A promoter, induction of Ink4a and ARF expression and senescence
.

Vorinostat, a histone deacetylase inhibitor, can also upregulate the expression of various tumor suppressor genes such as CDKN2A and TP53, and induce senescence in different cancer cell lines through these two main pathways
.

6.
Targeting tumor suppressor genes or oncogenes

The initiation and maintenance of cellular senescence is dependent on p53, which is frequently damaged in cancer cells
.
In mouse models, Tp53 gene repair leads to regression of sarcomas and liver cancers by inducing senescence responses, whereas apoptotic responses are observed in lymphoma treatment
.

Furthermore, senescence induction was accompanied by the upregulation of SASP and the recruitment of tumor immune cells, indicating that senescent cancer cells were efficiently cleared
.
Currently, several compounds that activate p53 are under development
.

For example, the MDM2 inhibitors Nutlin 3 and RG7112 can interfere with the p53-MDM2 interaction to induce senescence in a human cancer cell model (wild-type TP53)
.
Notably, disruption of the p53-MDM2 complex also induced apoptosis, but not senescence
.

In addition, cells with mutations in the PTEN gene experience premature aging, while cancer cells expressing the PTEN gene undergo apoptosis
.

Furthermore, inactivation of PTEN leads to p53-mediated senescence and inhibits tumor formation in mice
.

Considering the frequent mutations of the TP53 and RB1 pathways in human cancers and the involvement of these pathways in the senescence response, scientists speculate that cancer cells are mostly resistant to senescence induction
.

However, this is not the case: almost all cancer cells can senesce in vitro using DNA disruptors or AURK inhibitors, regardless of the mutational status of RB1 and TP53
.
Obviously, these genes only play a regulatory role in the process of tumor cell senescence, and are not necessary factors for inducing tumor cell senescence
.

Depletion of senescent tumor cells

Interestingly, the factors secreted by senescent cells, in addition to the "please kill me" message, also have an effect on surrounding cells
.

This effect may promote tumor migration and metastasis by promoting epithelial-mesenchymal transition (EMT)
.

To make matters worse, senescent tumor cells can promote tumor growth and metastasis by recruiting specialized macrophages to promote the formation of blood vessels and lymphatic vessels that provide other tumor cells with the oxygen and nutrients they need to survive
.

The good news is that while senescent tumor cells can "strengthen" surrounding tumor cells, senescent cells themselves cannot divide and proliferate, so senescent cell scavengers come in handy
.

One of the hallmarks of senescent cells is changes in chromatin structure that lead to changes in gene expression
.

These changes can affect fundamental cellular processes, such as the regulation of apoptosis
.

These processes may lead to the acquisition of new vulnerabilities unique to senescent cells that can be targeted by drugs that act as "scavengers.

" The table below summarizes the current applications, mechanisms, preclinical evidence, and clinical studies of “clearers” in cancer
.

Summarize

In the process of anti-aging, clearing senescent cells has received extensive attention as a potential strategy
.

Senescent cells are also "credited" during tumor development and progression
.
Using senescent cells to fight tumors is an effective treatment
.

However, in the special microenvironment of tumors, senescent cells can also become "complicit" unexpectedly.
Therefore, how to detect, utilize and remove senescent cells is the main direction for future researchers to explore
.