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LIVER DISEASES AND PATHOLOGIES
Baqoev Shukur Muzafarovich
Buxoro davlat tibbiyot instituti
Telefon: +998934529493
baqoyevshukur93@gmail.com
https://doi.org/10.5281/zenodo.13907035
Abstract.
He proportion of elderly people in the world population is constantly
increasing. With age, the risk of numerous chronic diseases and their complications also rises.
Research on the subject of cellular senescence date back to the middle of the last century, and
today we know that senescent cells have different morphology, metabolism, phenotypes and
many other characteristics. Their main feature is the development of senescence-associated
secretory phenotype (SASP), whose pro-inflammatory components affect tissues and organs,
and increases the possibility of age-related diseases. The liver is the main metabolic organ of
our div, and the results of previous research indicate that its regenerative capacity is greater
and that it ages more slowly compared to other organs. With age, liver cells change under the
influence of various stressors and the risk of developing chronic liver diseases such as non-
alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic
steatohepatitis (ASH) and hepatocellular carcinoma (HCC) increases. It has been proven that
these diseases progress faster in the elderly population and in some cases lead to end-stage
liver disease that requires transplantation. The treatment of elderly people with chronic liver
diseases is a challenge and requires an individual approach as well as new research that will
reveal other safe and effective therapeutic modalities.
Key words
: cell, senescence, SASP, DDR, inflammaging, liver, elderly.
Introduction.
The most important stimulus for the initiation and maintenance of
senescence is DDR [8,]. Activation of the p53 tumor-suppressor gene causes the permanent
activation of this mechanism [3]. Double-strand breaks are the most important form of DNA
damage [41]. These damages by complex mechanisms lead to cell cycle arrest and apoptosis.
During the aging process, the number of such damages increases but this increase is not linear
[4]. Cells reach their maximum while they still have the possibility of replication, that is, until
they became senescent [1]. In research conducted on cell cultures, it has been proven that the
factors that lead to the formation of double-strand breaks are stressors that affect cell
replication and are important for the induction of reproductive senescence [10].
DDR has been shown to be important for the activation of oncogene-induced senescence.
In that case, certain oncogenes are activated, for example, Serrano et al. showed that rat
sarcoma (Ras) or rapidly accelerated fibrosarcoma (Raf) are often involved, and the initial
response to this is cell proliferation. During intense proliferation and DNA replication that is
why errors are more frequent. For this reason, DDR activation was also more expressed in
order to try to fix these errors. It is interesting that some studies have shown that inhibition of
DDR, in this case, leads to inhibition of oncogene-induced senescence.
Another way to initiate DDR is the occurrence and registration of telomere damage and
shortening. Salama et al. in their review report on the importance of telomeres and their
shortening for the initiation of DDR. According to research known so far, there are three
functional states in which telomeres can be found: closed state, intermediate state and
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uncapped state. In each of these three conditions, the ends of chromosomes are exposed to
different influences, and in response to the damage, DDR is initiated. The most important for
the emergence of persistent DDR, which is important for the induction of senescence, is the
intermediate state. In this state, regardless of the damage, the chromosomes retain the TRF2
protein, which, in addition to protecting against further damage, also prevents the repair of the
one that has occurred up to that point, thus, starting a persistent DDR. As we said before,
senescent cells change at the metabolic, morphological, epigenetic and transcriptional levels,
and they are also characterized by increased secretory activity [8]. The secretome represents
all proteins secreted by a cell, tissue or organ. Therefore, senescent cells have a specific
secretome that differs from the secretome of young cells in which senescence has not yet been
induced [8]. The secretome of senescent cells includes mostly pro-inflammatory cytokines,
chemokines, proteases and growth factors.
The action of these molecules enables changes in the pathophysiology of cells and tissues,
which are characteristic of senescence and play a role in the development of age-related
diseases. Secretome proteins of senescent cells were mostly discovered by research on human
diploid fibroblasts, but also by research conducted on other cells in vitro and in vivo. They can
be considered the markers of senescence, and they need to be interpreted in several different
contexts [6,]. Considering that they are also found in other cellular processes and are not
specific only to senescence, it is important to interpret the combination of several markers [9].
The secretome of senescence cells is called by another name senescence-associated secretory
phenotype or SASP. The composition of SASP depends on the cell type and the way it entered
in senescence [2]. SASP is regulated on several different levels: through persistent DDR,
transcriptional regulation and autocrine regulation [4]. The inflammasome, which will be
described later, also proved to be a factor in the induction of SASP. Persistent DDR, which was
discussed earlier, has proven to be the most important factor in SASP regulation for now. For
example, the loss of ataxia telangiectasia-mutated factor (ATM), Nijmegen breakage syndrome
1 mutated gene (NBS1) or checkpoint kinase 2 (CHK2), which participate in DDR, leads to a
decrease in the release of certain SASP products such as IL-6 and IL-8. These two interleukins
are not only important for DDR but are also mentioned as important components of oncogene-
induced senescence (OIS), which means that they are involved in the process of tumor genesis.
Another example is that the expression of p16 or p21 leads to the initiation of senescence
without the initiation of DDR and changes in SASP in terms of reduced release of pro-
inflammatory cytokines. The loss of the p53 tumor-suppressor gene in human diploid
fibroblasts promotes the secretion of IL-6 and the formation of DDR, which has a role in the
genesis of tumors. Lujambio et al. demonstrated that p53-mediated SASP in hepatic stellate
cells suppresses the formation of HCC by activating special M1 macrophages. This study was
conducted on a mice model in which the formation of HCC was induced by chemotherapeutic
agents. Some transcription factors, such as nuclear factor kappa B (NF-κβ) and
CCAAT/enhancer-binding proteins β (C/EBPβ), also participate in the regulation of the release
of proinflammatory components of SASP. C/EBPβ has as a target the synthesis of IL-6 and its
inactivation leads to a reduction in the inflammatory effect of SASP. NF-κβ and C/EBPβ also
regulate the release of IL-1 and IL-8. These two transcription factors have been shown to play
an important role in the OIS process.
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