Cellular senescence is a phenomenon characterized by the cessation of

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ...

. In their experiments during the early 1960s,

Leonard Hayflick Leonard Hayflick (born 20 May 1928) is a Professor of Anatomy at the UCSF School of Medicine, and was Professor of Medical Microbiology at Stanford University School of Medicine. He is a past president of the Gerontological Society of America and ...

and Paul Moorhead found that normal human fetal

fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

s in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things. The physiological importance for cell senescence has been attributed to prevention of

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

, and more recently, aging, development, and tissue repair. Senescent cells contribute to the aging

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

, including frailty syndrome, sarcopenia, and aging-associated diseases. Senescent astrocytes and microglia contribute to neurodegeneration.

Cellular mechanisms

Stress response and DNA damage

Mechanistically, replicative senescence can be triggered by a

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

response due to the shortening of telomeres. Cells can also be induced to senesce by DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes, and cell-

cell fusion Cell fusion is an important cellular process in which several uninucleate cells (cells with a single nucleus) combine to form a multinucleate cell, known as a syncytium. Cell fusion occurs during differentiation of myoblasts, osteoclasts and tropho ...

. Normally, cell senescence is reached through a combination of a variety of factors (i.e., both telomere shortening and oxidative stress). The

response (DDR) arrests cell cycle progression until DNA damage, such as double-strand breaks (DSBs), are repaired. Senescent cells display persistent DDR that appears to be resistant to endogenous

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...

activities. The prolonged DDR activates both ATM and ATR DNA damage kinases. The phosphorylation cascade initiated by these two kinases causes the eventual arrest of the cell cycle. Depending on the severity of the DNA damage, the cells may no longer be able to undergo repair and either go through

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

or cell senescence. Such senescent cells in mammalian culture and tissues retain DSBs and DDR markers. It has been proposed that retained DSBs are major drivers of the

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

process. Mutations in genes relating to genome maintenance has been linked with premature aging diseases, supporting the role of cell senescence in aging (see DNA damage theory of aging). Depletion of NAD+ can lead to DNA damage and cellular senescence in vascular smooth muscle cells. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt an immunogenic

consisting of a pro-inflammatory secretome, the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE), and stain positive for senescence-associated β-galactosidase activity. Two proteins, senescence-associated beta-galactosidase and p16^Ink4A, are regarded as biomarkers of cellular senescence. However, this results in a false positive for cells that naturally have these two proteins such as maturing tissue macrophages with senescence-associated beta-galactosidase and T-cells with p16^Ink4A. Senescent cells can undergo conversion to an immunogenic phenotype that enables them to be eliminated by the immune system. This

consists of a pro-inflammatory

secretome The secretome is the set of proteins expressed by an organism and secreted into the extracellular space. In humans, this subset of the proteome encompasses 13-20% of all proteins, including cytokines, growth factors, extracellular matrix proteins a ...

, the up-regulation of immune

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s, a pro-survival response, promiscuous gene expression (pGE) and stain positive for senescence-associated β-galactosidase activity. The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases.

Role of telomeres

Telomeres are DNA tandem repeats at the end of chromosomes that shorten during each cycle of cell division. Recently, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the

chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

telomeres with each

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...

is also believed to limit the number of divisions of the cell, contributing to aging. After sufficient shortening, proteins responsible for maintaining telomere structure, such as TRF2, are displaced, resulting in the telomere being recognized as a site of a double-strand break. This induces replicative senescence. Theoretically, it is possible upon the discovery of the exact mechanism of biological immortality to genetically engineer cells with the same capability. The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as progerin, which degrades tissue and makes it more prone to failure.

Role of oncogenes

BRAF^V600E and Ras are two oncogenes implicated in cellular senescence. BRAF^V600E induces senescence through synthesis and secretion of IGFBP7. Ras activates the MAPK cascade which results in increased p53 activation and p16^INK4a upregulation. The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS). Interestingly, even after oncogenic activation of a tissue, several researchers have identified a senescent phenotype. Researchers have identified a senescent phenotype in benign lesions of the skin carrying oncogenic mutations in neurofibroma patients with a defect that specifically causes an increase in Ras. This finding has been highly reproducible in benign prostate lesions, in melanocytic lesions of UV-irradiated HGF/SF-transgenic mice, in lymphocytes and in the mammary gland from N-Ras transgenic mice, and in hyperplasias of the pituitary gland of mice with deregulated E2F activity. The key to these findings is that genetic manipulations that abrogated the senescence response led to full-blown malignancy in those carcinomas. As such, the evidence suggests senescent cells can be associated with pre-malignant stages of the tumor. Further, it has been speculated that a senescent phenotype might serve as a promising marker for staging. There are two types of senescence ''in vitro''. The irreversible senescence which is mediated by INK4a/Rb and p53 pathways and the reversible senescent phenotype which is mediated by p53. This suggests that p53 pathway could be effectively harnessed as a therapeutic intervention to trigger senescence and ultimately mitigate tumorigenesis. p53 has been shown to have promising therapeutic relevance in an oncological context. In the 2007 ''Nature'' paper by Xue et al., RNAi was used to regulate endogenous p53 in a liver carcinoma model. Xue et al. utilized a chimaeric liver cancer mouse model and transduced this model with the ras oncogene. They took embryonic progenitor cells, transduced those cells with oncogenic ras, along with the tetracycline transactivator (tta) protein to control p53 expression using doxycycline, a tetracycline analog and tetracycline responsive short hairpin RNA (shRNA). In the absence of Dox, p53 was actively suppressed as the microRNA levels increased, so as Dox was administered, p53 microRNA was turned off to facilitate the expression of p53. The liver cancers that expressed Ras showed signs of senescence following p53 reactivation including an increase in senescence associated B-galactosidase protein. Even if the expression of p53 was transiently activated or deactivated, senescence via SA B-gal was observed. Xue et al. show that by briefly reactivating p53 in tumors without functional p53 activity, tumor regression is observed. The induction of cellular senescence was associated with an increase in inflammatory cytokines as is expected based on the SASP. The presence of both senescence and an increase in immune activity is able to regress and limit liver carcinoma growth in this mouse model.

Signaling pathways

There are several reported signaling pathways that lead to cellular senescence including the p53 and p16^Ink4a pathways. Both of these pathways are activated in response to cellular stressors and lead to cell cycle inhibition. p53 activates p21 which deactivates cyclin-dependent kinase 2(Cdk 2). Without Cdk 2, retinoblastoma protein (pRB) remains in its active, hypophosphorylated form and binds to the transcription factor

E2F1 Transcription factor E2F1 is a protein that in humans is encoded by the ''E2F1'' gene. Function The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of c ...

, an important

regulator. This represses the transcriptional targets of E2F1, leading to cell cycle arrest after the

G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps ...

. p16^Ink4a also activates pRB, but through inactivation of

cyclin-dependent kinase 4 Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the ''CDK4'' gene. CDK4 is a member of the cyclin-dependent kinase family. Function The protein encoded by this gene is a member o ...

(Cdk 4) and cyclin-dependent kinase 6 (Cdk 6). p16^Ink4a is responsible for the induction of premature, stress-induced senescence. This is not irreversible; silencing of p16^Ink4a through promotor methylation or deletion of the p16^Ink4a locus allows the cell to resume the cell cycle if senescence was initiated by p16^Ink4a activation. Senescence-associated secretory phenotype (SASP) gene expression is induced by a number of

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s, including C/EBPβ, of which the most important is NF-κB. Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.

Characteristics of senescent cells

Senescent cells are especially common in

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

and adipose tissue. Senescent cells are usually larger than non-senescent cells. Transformation of a dividing cell into a non-dividing senescent cell is a slow process that can take up to six weeks. Senescent cells affect tumor suppression, wound healing and possibly embryonic/placental development, and play a pathological role in age-related diseases. There are two primary tumor suppressor pathways known to mediate senescence: p14arf/ p53 and INK4A/RB. More specifically p16INK4a-pRb tumor suppressor and p53 are known effectors of senescence. Most cancer cells have a mutated p53 and p16INK4a-pRb, which allows the cancer cells to escape a senescent fate. The p16 protein is a cyclin dependent kinase inhibitor (CDK) inhibitor and it activates Rb tumor suppressor. p16 binds to CDK 4/6 to inhibit the kinase activity and inhibit Rb tumor suppressor via phosphorylation. The Rb tumor suppressor has been shown to associate with E2F1 (a protein necessary for transcription) in its monophosphorylated form, which inhibits transcription of downstream target genes involved in the G1/S transition. As part of a feedback loop, increased phosphorylation of Rb increases p16 expression that inhibits Cdk4/6. Reduced Cdk4/6 kinase activity results in higher levels of the hypo-phosphorylated (monophosphorylated) form of Rb, which subsequently leads to reduced levels of p16 expression. The removal of aggregated p16 INK 4A positive senescent cells can delay tissue dysfunction and ultimately extend life. In the 2011 ''Nature'' paper by Baker et al. a novel transgene, INK-ATTAC, was used to inducibly eliminate p16 INK4A-positive senescent cells by action of a small molecule-induced activation of caspase 8, resulting in apoptosis. A BubR1 H/H mouse model known to experience the clinicopathological characteristics of aging-infertility, abnormal curvature to the spine, sarcopenia, cataracts, fat loss, dermal thinning, arrhythmias, etc. was used to test the consequences of p16INK4a removal. In these mice p16 INK4a aggregates in aging tissues including the skeletal and eye muscle, and adipose tissues. Baker et al. found that if the senescent cells are removed, it is possible to delay age-associated disorders. Not only does p16 play an important role in aging, but also in auto-immune diseases like rheumatoid arthritis that progressively lead to mobility impairment in advanced disease. In the nervous system, senescence has been described in astrocytes and microglia, but is less understood in neurons. Because senescence arrests cell division, studies of senescence in the brain were focused mainly on glial cells and less studies were focused on nondividing neurons. Analyzing single nucleus RNA-Seq data from human brains suggested p19 as a marker for senescent neurons, which are strongly associated with neurons containing neurofibrillary tangle.

SASP

The

of senescent

cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

is very complex. The products are mainly associated with

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

, proliferation, and changes in the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

. A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

s, growth factors, and

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s is another characteristic feature of senescent cells. There are many SASP effector mechanisms that utilize

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...

paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...

signalling. SASP induces an unfolded protein response in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...

because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function. Autophagy is upregulated to promote survival. Considering cytokines, SASP molecules IL-6 and IL-8 are likely to cause senescence without affecting healthy neighbor cells. IL-1beta, unlike IL-6 or IL-8, is able to induce senescence in normal cells with paracrine signaling. IL-1beta is also dependent on cleavage of IL-1 by

caspase-1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosi ...

, causing a pro-inflammatory response. Growth factors, GM-CSF and VEGF also serve as SASP molecules. From the cellular perspective, cooperation of transcriptional factors NF-κB and

C/EBP CCAAT-enhancer-binding proteins (or C/EBPs) is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C ...

β increase the level of SASP expression. Regulation of the SASP is managed through a transcription level autocrine feedback loop, but most importantly by a continuous DDR. Proteins p53, p21, p16ink4a, and Bmi-1 have been termed as major senescence signalling factors, allowing them to serve as markers. Other markers register morphology changes, reorganization of

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

resistance, altered metabolism, enlarged cytoplasm or abnormal shape of the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

. SASPs have distinct effects depending on the cellular context, including inflammatory or anti-inflammatory and tumor or anti-tumor effects. While considered a pro-tumorogenic effect, they likely support already tumor-primed cells instead of shifting healthy cells into transformation. Likewise, they operate as anti-tumor protectors by facilitating the elimination of damaged cells by phagocytes. The SASP is associated with many age-related diseases, including type 2 diabetes and atherosclerosis. This has motivated researchers to develop senolytic drugs to kill and eliminate senescent cells to improve health in the elderly. The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).

Clearance of senescent cells by the immune system

Due to the heterogeneous nature of senescent cells, different immune system cells eliminate different senescent cells. Specific components of the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells attract and activate different components of both the innate and

adaptive immune system The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...

Natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repre ...

s (NK cells) and macrophages play a major role in clearance of senescent cells. Natural killer cells directly kill senescent cells, and produce

s which activate macrophages which remove senescent cells. Senescent cells can be phagocytized by

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

s as well as by macrophages. Senolytic drugs which induce

in senescent cells rely on phagocytic immune system cells to remove the apoptosed cells. Natural killer cells can use

NKG2D NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by ''KLRK1'' (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated ...

killer activation receptor Killer Activation Receptors (KARs) are receptors expressed on the plasmatic membrane of Natural Killer cells ( NK cells). KARs work together with inhibitory receptors (abbreviated as KIRs in the text), which inactivate them in order to regulate ...

s to detect the

MICA Micas ( ) are a group of silicate minerals whose outstanding physical characteristic is that individual mica crystals can easily be split into extremely thin elastic plates. This characteristic is described as perfect basal cleavage. Mica is ...

and ULBP2

s which become upregulated on senescent cells. The senescent cells are killed using perforin pore-forming

cytolytic Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to diffuse into the cell. Water can enter the cell by diffusion through the cell membrane or through selective membrane channels ...

protein. CD8+ cytotoxic T-lymphocytes also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells. Aging of the immune system ( immunosenescence) results in a diminished capacity of the immune system to remove senescent cells, thereby leading to an increase in senescent cells. Chronic inflammation due to SASP from senescent cells can also reduce the capacity of the immune system to remove senescent cells. T cells, B cells, and NK cells have all been reported to become senescent themselves. Senescent-like aging CD8+ cytotoxic T-lymphocytes become more innate in structure and function, resembling NK cells. Immune system cells can be recruited by SASP to senescent cells, after which the SASP from the senescent cells can induce the immune system cells to become senescent.

Chimeric antigen receptor T cell In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specif ...

s have been proposed as an alternative means to senolytic drugs for the elimination of senescent cells. Urokinase receptors have been found to be highly expressed on senescent cells, leading researchers to use

chimeric antigen receptor T cell In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specif ...

s to eliminate senescent cells in mice. Chimeric antigen receptor natural killer cells have been proposed as an allogeneic means of eliminating senescent cells.

Transient senescence

It is important to recognize that cellular senescence is not inherently a negative phenomenon. During mammalian embryogenesis, programmed cellular senescence plays a role in tissue remodeling via macrophage infiltration and subsequent clearance of senescent cells. A study on the mesonephros and endolymphatic sac in mice highlighted the importance of cellular senescence for eventual morphogenesis of the embryonic kidney and the inner ear, respectively. They serve to direct tissue repair and regeneration. Cellular senescence limits fibrosis during wound closure by inducing cell cycle arrest in myofibroblasts once they have fulfilled their function. When these cells have accomplished these tasks, the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

clears them away. This phenomenon is termed acute senescence. Senescence of hepatic stellate cells could prevent progression of liver fibrosis, although this has not been implemented as a therapy, and would carry the risk of hepatic dysfunction. The negative implications of cellular senescence present themselves in the transition from acute to chronic senescence. When the immune system cannot clear senescent cells at the rate at which senescent cells are being produced, possibly as a result of the decline in immune function with age, accumulation of these cells leads to a disruption in tissue homeostasis.

Cellular senescence in mammalian disease

Transplantation of only a few (1 per 10,000) senescent cells into lean middle-aged mice was shown to be sufficient to induce frailty, early onset of aging-associated diseases, and premature death. Biomarkers of cellular senescence have been shown to accumulate in tissues of older individuals. The accumulation of senescent cells in tissues of vertebrates with age is thought to contribute to the development of ageing-related diseases, including Alzheimer's disease, Amyotrophic lateral sclerosis, type 2 diabetes, and various

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

s. Progeria is another example of a disease that may be related to cell senescence. The disease is thought to be caused by mutations in the DNA damage response, telomere shortening, or a combination of the two. Progeroid syndromes are all examples of aging diseases where cell senescence appears to be implicated.

List of progeroid syndromes

Hutchinson–Gilford progeria syndrome Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...

* Rothmund–Thomson syndrome * Werner syndrome * Bloom syndrome * Cockayne syndrome *

Xeroderma pigmentosum Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in ...

* Trichothiodystrophy *

- Cockayne syndrome * Restrictive dermopathy * Mandibuloacral dysplasia * Fanconi anaemia * Seckel syndrome *

Ataxia telangiectasia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

* Dyskeratosis congenita * Hoyeraal-Hreidarsson syndrome * Néstor-Guillermo progeria syndrome

Senolytic drugs

Targeting senescent cells is a promising strategy to overcome age-related disease, simultaneous alleviate multiple comorbidities, and mitigate the effects of frailty. Removing the senescent cells by inducing apoptosis is the most straightforward option, and there are several agents that have been shown to accomplish this. Some of these senolytic drugs take advantage of the senescent-cell anti-apoptotic pathways (SCAPs); knocking out expression of the proteins involved in these pathways can lead to the death of senescent cells, leaving healthy cells.

Organisms lacking senescence

Cellular senescence is not observed in some organisms, including

perennial A perennial plant or simply perennial is a plant that lives more than two years. The term ('' per-'' + '' -ennial'', "through the years") is often used to differentiate a plant from shorter-lived annuals and biennials. The term is also widel ...

plants, sponges,

coral Corals are marine invertebrates within the class Anthozoa of the phylum Cnidaria. They typically form compact colonies of many identical individual polyps. Coral species include the important reef builders that inhabit tropical oceans and se ...

s, and lobsters. In other organisms, where cellular senescence is observed, cells eventually become post- mitotic: they can no longer replicate themselves through the process of cellular mitosis (i.e., cells experience replicative senescence). How and why cells become post-mitotic in some species has been the subject of much research and speculation, but it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of

. Somatic cells that have divided many times will have accumulated DNA

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s and would be more susceptible to becoming

ous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.

Research

A paper published on 29 March 2022 by a group of scientists at

Insilico Medicine Insilico Medicine is a biotechnology company based in Pak Shek Kok, Hong Kong in Hong Kong Science Park near the Chinese University of Hong Kong and in New York, at The Cure by Deerfield. The company combines genomics, big data analysis, and de ...

University of Chicago The University of Chicago (UChicago, Chicago, U of C, or UChi) is a private research university in Chicago, Illinois. Its main campus is located in Chicago's Hyde Park neighborhood. The University of Chicago is consistently ranked among the b ...

, George Mason University, and

University of Liverpool , mottoeng = These days of peace foster learning , established = 1881 – University College Liverpool1884 – affiliated to the federal Victoria Universityhttp://www.legislation.gov.uk/ukla/2004/4 University of Manchester Act 200 ...

demonstrated that there might be several alternative senolytic targets and pathways that can be targeted with small molecules drugs. A list of dual-purpose targets implicated in aging and age-associated diseases is yielded by using

artificial intelligence Artificial intelligence (AI) is intelligence—perceiving, synthesizing, and inferring information—demonstrated by machines, as opposed to intelligence displayed by animals and humans. Example tasks in which this is done include speech ...

models. It may impact multiple age-associated diseases and retard aging, including cellular senescence for extending healthspan. A study suggests that in some cases, some apparently senescent cells are required for regeneration and raises the question whether all p16^Ink4A-expressing cells are senescent. * University press release:

References

External links

*{{Commons category-inline Ageing processes Cell biology Cells Cellular processes Senescence