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CELLULAR SENESCENE
ABSTRACT:-
The term cellular senescence was
introduced more than five decades ago to describe the state of
growth arrest observed in aging cells. Since this initial discovery,
the phenotypes associated with cellular senescence have
expanded beyond growth arrest to include alterations in cellular
metabolism, secreted cytokines, epigenetic regulation and
protein expression. Recently, senescence has been shown to
play an important role in vivo not only in relation to aging, but
also during embryonic development. Thus, cellular senescence
serves different purposes and comprises a wide range of distinct
phenotypes across multiple cell types. Whether all cell types,
including post-mitotic neurons, are capable of entering into a
senescent state remains unclear. In this review we examine
recent data that suggest that cellular senescence plays a role in
brain aging and, notably, may not be limited to glia but also
neurons. We suggest that there is a high level of similarity
between some of the pathological changes that occur in the
brain in Alzheimer’s and Parkinson’s diseases and those
phenotypes observed in cellular senescence, leading us to
propose that neurons and glia can exhibit hallmarks of
senescence previously documented in peripheral tissues.
1.WHAT IS SENESCENE ?
Cellular senescence was originally identified as a stable exit from the cell cycle caused by the finite
proliferative capacity of cultured human fibroblasts .
Currently, senescence is considered a stress response that can be induced by a wide range of intrinsic and
extrinsic insults, including oncogenic activation, oxidative and genotoxic stress, mitochondrial dysfunction,
irradiation, or chemotherapeutic agents .
While the defining characteristic of senescence is the estab_lishment of a stable growth arrest that limits
the replication of damaged and old cells, many other phenotypic alterations associ_ated with the senescent
program are relevant to understanding the pathophysiological functions of senescent cells .
For example, senescent cells undergo morphology changes, chromatin remod_eling, and metabolic
reprogramming, and secrete a complex mix of mostly proinflammatory factors termed the
senescence-associated secretory phenotype (SASP)
Here, we review the molecular mechanisms controlling cellular senescence with a special focus on their
translational relevance and suitability for identifying and characterizing senescent cells in vivo.
2. PHENOTYPIC CHARECTERISTICS OF
SENESCENE
Figure 1. Phenotypic characteristics of senescent cells. Diagram depicting some of the phenotypic
alterations associated with senescence initiation, early senescence, and late phases of senescence.
3. MORPHOLOGICAL CHANGES
In cell culture, senescence is normally accompanied by significant morphological changes.
Senescent cells become flat, enlarged, and vacuolized, and sometimes appear with multiple or enlarged
nuclei.
Changes in shape rely on the status of the scaffolding protein caveolin 1 and the Rho GTPases Rac1 and
CDC42 , and vacuolation has been associated with ER stress caused by the unfolded protein response .
Senescent cells also form cytoplasmic bridges that allow them to signal to neighboring cells via direct
intercellular protein transfer .
Beyond these examples, the functional significance of most morphological changes asso_ciated with
senescence is unclear.
In vivo, senescent cells appear to preserve the morphology dictated by the architecture of the tissue.
However, recent studies have discovered that SA β-gal+ cells in aged mice increase in size .
4. A SIMPLIFIED MODEL
Senescence has been traditionally considered as a defined, stat_ic cell fate. However, it is now recognized
that senescence is a dynamic multistep process.
suggests that although the initial senescence-inducing signals are sufficient to initiate cell cycle exit, this
merely constitutes an early step in the senescence process.
Senescent cells progressively remodel their chromatin and start to sequentially implement other aspects of
the senescence program, such as the SASP, to enter into a second step of “full senescence.”
If these senescent cells persist for extended periods of time, they continue evolving and can be categorized
as entering into a third step of “late senescence,” which can involve adaptation and diversification of the
senescent phenotype.
It is tempting to suggest that the concept of senescence progression may help account for the
heterogeneity of senescent cells and their associated phenotypes in vivo.
Indeed, the senescent responses occurring in vivo can be categorized into two types. Acute senescence
seems to be a programmed process that is triggered in response to discrete stressors, is established with
fast kinetics, and normally contributes to tissue homeostasis.
In contrast, chronic senescence may result from long-term unscheduled damage, and it is often associated
with detrimental processes such as aging.
4.1.Cell cycle arrest
One of the defining features of senescent cells is their stable cell cycle arrest.
This cell cycle exit is controlled by activation of the p53/p21CIP1 and p16INK4a/Rb tumor suppressor
pathways (Figure 2).
Unlike quiescent cells, senescent cells are nonresponsive to mito_genic or growth factor stimuli; thus, they
are unable to reenter the cell cycle even in advantageous growth conditions.
Figure 2. Molecular pathways controlling growth arrest during senescence. A variety of stressors induce
senescence-associated growth arrest. Cell cycle exit is regulated by induc_tion of the p16INK4a/Rb and
p53/p21CIP1 pathways. Figure reproduced with permission from McHugh and Gil (126).
4.2.DNA Damage response
The senescence growth arrest is often triggered by a persistent DNA damage response (DDR) caused by
either intrinsic (oxida_tive damage, telomere attrition, hyperproliferation) or external insults (ultraviolet,
γ-irradiation, chemotherapeutic drugs) .
4.3.Non–cell-autonomous effects of
senescence
Cellular senescence was initially considered to be a cell-intrinsic program.
Increasing evidence, however, has shown that senescent cells have the ability to signal and influence their
surrounding environment.
Senescent cells produce a complex mixture of soluble and insoluble factors that are collectively termed
senescence-associated secretory phenotype (SASP) or senescence-messaging secretome .
SASP is the general term given to the combination of cytokines, che_mokines, extracellular matrix
proteases, growth factors, and other signaling molecules secreted by senescent cells.
4.4. SA β-galactosidase activity
The most widely used senescence marker is senescence-associ_ated β-galactosidase (SA β-gal) activity. This
enzymatic activity, which is found in many normal cells under physiological conditions (pH 4.0–4.5), is
significantly amplified in senescent cells as a result of increased lysosomal content .
4.5.Chromatin reorganization
Senescence is associated with large-scale chromatin rearrangements .
Besides the already described DDR and the formation of PML bodies (a type of matrix-associated nuclear
domain) , the most striking chromatin change observed in senescent cells is the formation of
senescence-associated hetero_chromatic foci (SAHFs), which are more prominent in human cells
undergoing OIS .
These foci can be identified by DAPI staining and are characterized by enrichment of repressive marks such
trimethylated H3K9 and heterochromatic protein 1 (HP1), accumulation of high-mobility group HMGA
proteins, and loss of linker histone H1 .
4.6.Resistance to apoptosis
Senescence and apoptosis are alternative cell fates that often can be triggered by the same stressors.
While we do not have a full understanding of what makes the cell decide between one and another
program, mechanisms must be in place to lock those decisions.
In this regard, senescent cells are resistant to extrinsic and intrinsic apoptosis . Recent studies have
suggested that this is a result of the upregulation of BCL-2 family proteins such as BCL-W and BCL-XL .
This is of extraordinary practical rel_evance since inhibiting BCL-2 family proteins induces apoptosis on
senescent cells .
5. MARKERS OF CELLULAR SENESCENE
5.1.Telomere theory
Telomere theory depends on three specific principles, the three pillars the Telomere theory stands on:
first, that aging is programmed; the second being that irreversible cell cycle arrest happens in response to
the telomere shortening; and lastly, that the total number of cell divisions in the absence of telomerase
activity cannot exceed a particular limit termed the Hayflick limit .
5.2 Senescence-associated changes in cells
isolated from aged subjects
Cell factor Changes
Cell volume
Increased cell volume and surface area
in senescence
Cell adhesion
More focal adhesions present in
senescence (ILK activity is associated
with the expression of senescence
phenotype
Lysosome content
Dramatic increase in number in
senescence
SA-b-Gal activity
The most widely cited marker of
senescence
Glycogen granule content
High in cells undergoing replicative or
induced senescence
Mitochondria morphology
Increased mitochondria mass in
senescence
SAHF
One of the most prominent cellular traits
of senescence
TIF
A key factor responsible for irreversible
growth arrest in senescence
HGPS-like nucleus
Fraction of cells with the HGPS-like
nucleus increases with passage in vitro
and the slope is steeper during the
passage of fibroblasts from an old
individual
6.Future research areas
Our review of the literature has revealed that only indirect evidence exists to suggest the possibility of CS in
post-mitotic cells such as neurons.
We feel that experiments addressing four critical questions will shed light on the contribution of CS to CNS
aging and neurodegenerative disease: Does inhibiting cellular senescence in the brain in either neuronal or
glial populations attenuate age-related cognitive decline and progression of neurodegeneration?
Conversely, does artificially inducing senescence in either neuronal or glial populations produce enhanced
cognitive decline and accelerated neurodegeneration?
Are the common phenotypes observed in both classical CS and neurodegenerative disease representative
of a common mechanism of senescence or simply indicators of cellular stress and dysfunction?
What is the occurrence of neuronal senescence in vivo under normal cognitive aging and in neurological
disease?
Recent developments have now enabled researchers to answer these critical questions.
Progress in single cell analysis techniques now enables researchers to examine neuronal populations
expressing SA -gal using techniques like single-cell PCR to determine similarities between neuronal
senescence and senescence in mitotic populations.
A more thorough understanding of the mechanisms involved in CNS senescence will be critical to
understanding the contribution of CS to age-related neurodegenerative disease.
Such work will contribute to understanding of age-related cognitive decline and could help in the
development of novel therapeutic interventions in age-related neurodegenerative disease.
7.CONCLUSIONS
It has been accepted that cellular senescence is induced by a number of cellular stresses such as oncogene
activation, oxidative stress, and DNA damage in vitro and in vivo through elevated levels of ROS.
Unlike programmed differentiation, cellular senescence is likely to be a stochastic event that is induced by a
variety of genotoxic stresses.
Recently, we developed a real-time in vivo imaging system for visualizing the expression of
senescence_related genes, such as p21Waf1/Cip1 in mice .
Visualizing the dynamics of cellular senescence responses in vivo in the context of living animals is likely to
be a useful tool in the identification of the location and timing of gene expression and hence their likely
roles in cellular senescence in vivo.
Fig. 4. Real-time in vivo imaging of p21Waf1/Cip1 gene expression after doxorubicin (DXR) treatment. We
established a transgenic mouse line (p21-p-luc) expressing firefly luciferase under control of the
p21Waf1/Cip1 gene promoter. The 8-week-old p21-p-luc mouse was injected intraperitoneally with DXR (20
mg/kg) and was subjected to non-invasive bioluminescene imaging 24 h after DXR treatment under
anesthesia. DXR treatment (lower panels) and its control (untreated mice) (upper panels).The color bar
indicates photons with minimal and maximal threshold values.
8.REFERENCES
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Tan, F. C., Hutchison, E. R., Eitan, E., & Mattson, M. P. (2014). Are there roles for brain cell senescence in
aging and neurodegenerative disorders?. Biogerontology, 15, 643-660.
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Bernadotte, A., Mikhelson, V. M., & Spivak, I. M. (2016). Markers of cellular senescence. Telomere
shortening as a marker of cellular senescence. Aging (Albany NY), 8(1), 3.
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Herranz, N., & Gil, J. (2018). Mechanisms and functions of cellular senescence. The Journal of clinical
investigation, 128(4), 1238-1246.
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