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Ageing can be seen a progressive deterioration in the structure and function of the cells, tissues, organs and organ system in the body with advancing age. Aging damage occurs to molecules such as DNA, proteins, lipids and to cells and organs. Ageing is accompanied by impairment of physiological functions; this is known as senescence and is characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased incidence of pathology. This series of irreversible changes inevitably ends in death. The term ageing is somewhat ambiguous. Ageing can be defined in different ways:
Free radical theory is one of the most advanced theories of aging and it was proposed by Dr Harman in 1956. (Anisimove, 2003). This theory postulated that different oxidative reactions occurring in the organism especially in mitochondria produce free radicals as byproducts which cause multiple lesions in macromolecules such as nucleic acids, proteins and lipids, resulting in their damage and aging. This theory did not only explain the mechanism of aging per second but it also explained the age related diseases including cancer. Recent evidence suggested that stress induced DNA damage caused by reactive oxygen species is the mechanisms for both cancer and aging. (Anisimove, 2003).
Cellular senescence is the phenomenon by which the cells will lose the ability to divide. This senescence is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit as Dr hayflick was the first who discovered this information in1965. In response to DNA damage (including shortened telomeres) cells either senescence or self-destruct (apoptosis) if the damage cannot be repaired. (Barron, 2005). This process is accompanied by a series of changes, including enlargement of cells, increased acidic Î²-galactosida se activity (senescence-associated Î²-galactosidase [SA-Î²-gal]), and changes in the structure of chromatin. Replicative senescence is proposed to represent certain aspects of organismal aging (Campisi, 2005).
Cellular senescence is not universal and it is not been observed in signal celled organisms that reproduce through the process of cellular mitosis. Cellular senescence is found to be in sponges, corals and lobsters. In these it had came to notice that cells becomes post-mitotic when they can no longer replicate or double through cellular mitosis for example cells experience replicative senescence. (Answers Corporation, 2010). It is widely accepted that cellular senescence evolved as far as to prevent the invasion and spread of cancer. Somatic cells that have divided many times often have accumulated DNA mutations and in danger of becoming cancerous if cell division continues. Cell senescence is the final step before cell death. However, these cells are still alive and metabolically active, but are not capable of dividing any more. (Barron, 2005).
Cellular senescence is clearly important in suppressing the development of cancer in young organisms, but it may facilitate tumorigenesis in old organisms. Because a variety of stimuli, many of which are potentially oncogenic, induce a senescent phenotype, cellular senescence, or the senescence response, is very likely a reliable mechanism to prevent the proliferation of cells that are at risk for tumorigenic transformation. In this view, cellular senescence is similar to apoptosis; however, it is different from apoptosis in many respects. Apoptosis, causes damaged or potentially oncogenic cells to die, thus eliminating them from tissues, whereas cellular senescence, on the other hand, arrests the proliferation of such cells, but does not eliminate them from tissues (Campisi, 2000). Although there are dissimilarities in both cellular senescence and apoptosis but both are important in suppressing the development of cancer in mammals and both processes are regulated at critical step by p53. (Beitzinger et al., 2006). P53 clearly plays an essential role in controlling the senescence response to diverse stimuli. This is constant with the idea that cellular senescence is a tumour suppressive mechanism and the known role of p53 as a tumour suppressor (Itahana, 2001).
Telomeres and telomerase:
The role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. Shortening of telomeres within each cell cycle is believed to be accompanied to limit the number of cell division, thus contributing to aging. There have been reports on the other hand showing that cloning could alter the shortening of telomeres. (Answers Corporation, 2010).
Telomeres are DNA sequences found at the end of eukaryotic chromosomes in somatic cells and it is involved in the replication and stability of the chromosome. It is made up of a recurring motif of 6 nucleotides bases (TTAGGG) along with various associated proteins. During cell replication; telomeres are preserved by the enzyme telomerase, a ribonucleoprotein enzyme that adds the telomere sequences TTAGGG to chromosome ends. (Anisimove, 2003).In the absence of telomerase, telomere is shortened with each cell division. The Loss of the distal region of telomeres correlates with the decline of the proliferative life-span of cells both in vitro and in vivo. There is substantial evidence supporting the hypothesis that telomere shortening and reactivation of telomerase are important aspects of aging and carcinogenesis respectively. It was stated that the main function of wild-type p53 may be to signal growth arrest in response to telomere loss in senescent cells .This hypothesis is reliable with the actions of most tumors that reveal p53 mutation and also explain the reality and characteristics of rarer tumor types in which p53 function appears to be reserved. (Anisimove, 2003)
Telomerase has an essential role in the formation, maintenance and renovation of telomeres. It acts as a telomerase- reverse transcriptase enzymes (TERT) meaning that it uses RNA as a template to make DNA and thus to create new telomeres. Telomerase has two unique features: 1- Its ability to recognize a single-stranded (G-rich) telomere primer. 2- Its ability to add multiple telomeric repeats to its end by using an RNA template. (Medicine Net, 1998).
The inability of DNA polymerase to complete replication of the 3'end of a DNA duplex due to the obligate requirement for an upstream RNA primer, which means in every round or replication the newly synthesized lagging strand is missing the extreme 5'-terminues, which sets up a progressive erosion of telomere sequence, giving 50-200bp per generation in mammalian cells. (Smeal et al., 2007). Germ cells, stem cells and immortalized cancer cells contain telomerase thus preventing them from experiencing the Hayflick limit. In contrast, somatic cells have limited proliferative life span in vitro. (Anisimove, 2003)
When the primary human cells in culture invariably stop dividing, they enter a state of growth arrest known as replicative senescence and this is induced by programmed shortening of telomeres but the mechanisms underlying this is not yet clear. Studies have reported that over expression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without causing senescence. TRF2 reduced the senescence setpoint which is known as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by an altered state of telomere rather than by a complete loss of telomeric DNA. (Karlseder et al., 2002)
The senescent phenotype:
There are other mechanisms apart from telomeres shortening inducing phenotype of cellular senescence. These include oncogenic, mitogenic signals as well as DNA damage. Replicative senescence due to telomere shortening can, for example, be caused by a dominant negative version of telomerase, premature senescence by the over expression of oncogenic ras, or p16.(Nakagawa and Opitz, 2007)
Researches have developed techniques in order to test for senescent cells as these cells exhibit changes in form and function such as the differences between the supple skin of the child and the wrinkled skin of old people. Blue stain is one of the tests developed by LBL researchers to detect the presence of senescent cells. Old tissue cells containing blue stain reveals the presence of senescent cells. Two major types of human skin cells fibroblasts and keratinocytes produce beta-galactosidase which in turn is converted to galactose and the blue precipitate. Cells that express beta-galactosidase turn blue. Another stain used is the (Acridine orange) which is taken up by lysosomes. Lysosomal mass increases in senescent cells. (Campisi, 2000). Lipofusion is another marker that depends on autoflourescence pigment. The senescent phenotype also involves cell type-specific changes. For example, senescent fibroblasts develop a constitutive matrix-degrading phenotype, secreting huge amounts of matrix metalloproteinases such as interstitial collagenase and stromelysin. These cells also secrete inflammatory cytokines such as interleukin-1 and growth factors such as heregulin (Shelton, 1999).
Reactive oxygen species (ROS) and aging:
(ROS) has been investigated over the past 50 years as putative mediators of the process of aging. (Laura et al., 2005). ROS can be produced from exogenous sources such as ultraviolet light, ionizing radiation and pollutants or from different intracellular sources. These free radicals or ROS can causes lipid oxidation, protein oxidation, DNA strands break, base modification and modulation of gene expression. A suggestion came up by Harman (2000) saying that the main reactive oxygen species causing the oxidation of cells and tissues are superoxide anion and hydrogen peroxide (H2O2). Mitochondria are considered to be one the main reactive oxygen species and free radicals as approximately 1% to 5% of the oxygen taken up by mitochondria is reduced and converted to ROS. (Lee et al., 2004). Lipoxygenase is a form of prooxidative enzymes that generate free radicals. The antioxidant systems in the body which are enzymatic and non-enzymatic such as lipid-soluble vitamin E, water-soluble vitamin C, catalase, etc, are known to regulate the balance of ROS/ antioxidants in the body and therefore help to minimize the oxidative stress in the body and reduces the risk of cancer and cardiovascular diseases. The efficiency of antioxidant defence system lowers as aging proceed and decreases the ability to remove ROS or free radicals. ROS are also known to induce apoptosis of cells. The imbalance between ROS and antioxidants leads to oxidative stress. Furthermore, increase production of ROS and failure of anti-oxidant defence system also causes oxidative stress. (Lee et al., 2004)
Tumor suppressor genes and cellular senescence:
The senescence response is critically dependent on the activity of several tumor suppressor genes, most notably those genes that participate in p53 and pRb tumor suppressor pathways. The p53 tumour suppressor is important to act to reduce proliferation in response to DNA damage or deregulation of mitogenic oncogenes resulting in the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies.
Human cells that have deficient p53 and pRb functions are generally refractory to multiple-senescence inducing stimuli. (Serrano et al., 1997; Dimri et al., 2000). Both p53 and pRB are also important for maintaining the senescence growth arrest which is thought to be irreversible in human cells. The human senescent cells arrest growth with a G1 DNA content and cannot be induced to divide by physiological mitogens. Although the potent viral onco protein SV-40 T antigen stimulates DNA replication in senescent human fibroblasts, it does not stimulate the proliferation of cells. T-antigen binds and inactivates both p53 and pRB and mutants faulty in either p53 or pRB binding fail to stimulate DNA synthesis in senescent cells (Sakamoto et al., 1993; Hara et al., 1996b). From these findings it was concluded that p53 and pRB together prevent senescent cells from initiating S phase, but another activity prevents completion of the cell cycle.(Beausejour et al., 2003).
p53 elicits the senescence response by increasing the expression of p21 cyclin-dependent kinase inhibitor (CDKI) which in turn prevents the phosphorylation and inactivation of pRB. (Sherr and Roberts, 1999).
P21 is triggered by p53 dependent and p53-independent mechanisms and it is essential for the onset of cell cycle arrest in damage response and cell senescence. The effects of p21 knockout in mice and ways of its expression in human cancer are consistent with its role as a tumour suppressor and as an oncogene. Several functions of p21 are likely to promote cancer development and progression. These include endoreduplication and abnormal mitosis that develop in tumour cells after release from p21-induced growth arrest, the ability of p21 to inhibit apoptosis through several different mechanisms, and its ability to stimulate transcription of secreted factors with mitogenic and anti-apoptotic activities. The latter effects of p21 show close similarity to paracrine activities of senescent cells and to tumour-promoting functions of stromal fibroblasts. (Roninson, 2002).
P16INK4a is another type of CDK inhibitor that is encoded by the INK4a gene. P16INK4a binds to and inactivates D-type CDKs, CDk4 and CDK6. This binding also induces the redistribution of CIP/KIP family of CDK inhibitors, p21Cip1/Waf1/Sdi1 and p27Kip1 resulting in the inactivation of CDK-2 Kinases. The induction of P16INK4a collaborates with p21Cip1/Waf1/Sdi1 in order to prevent the phosphorylation of pRb and this leads to a stable G1 arrest in senescent cells. Therefore, the P16INK4a gene is recognized as a tumor suppressor gene as it is frequently found inactivated in human cancers. (Takahashi et al., 2007)
Cellular senescence and stress-induced premature senescence (SIPS):
The shortening of telomeres is the most well known cause of cellular senescence and can be induced by many other intrinsic and extrinsic factors. The exhaustion of human diploid fibroblasts (HDFs) or melanocytes proliferative potential is the cause of replicative senescence. (SIPS) occurs after many different sublethal stresses including H(2)O(2), hyperoxia, or tert-butylhydroperoxide. Common features are shared between cells in replicative senescence and SIPS including, morphology, senescence-associated beta-galactosidase activity, regulation of cell cycle, gene expression and telomere shortening. Telomere shortening is attributed to the accumulation of DNA single-strand breaks induced by oxidative damage. SIPS could be a mechanism of accumulation of senescent-like cells in vivo. Replicative senescence and SIPS are relied on two main pathways. The first pathway is triggered by a damage to DNA, or shortening and /or damage to telomere and involves the activation of the p53 and p21 (waf-1) proteins. The second pathway leads to the accumulation of p16 (Ink-4a) with the MAP kinase signalling pathway as possible intermediate. These data agree with the thermodynamical theory of ageing, as exposure of cells to sublethal stresses of different natures may simulate SIPS, with possible modulations of this process by bioenergetics. (Toussaint et al., 2000)
Aging and age -related diseases:
Aging associated diseases is a disease that is seen with increasing frequency with increasing senescence. Age -associated disease are to be distinguished from the aging process itself because all adult animals age, but not all adult animals experience all age-associated diseases. Here are examples of age-associated diseases, cardiovascular disease, cancer, arthritis, cataract, osteoporosis, typeÂ 2 diabetes, hypertension and Alzheimer's disease. The incidence of all of these diseases increases rapidly with aging (increases exponentially with age, in the case of cancer). one of the characteristics of cancer cells isÂ that they have unlimited replicative potential asÂ they lose the ability to undergo senescence by acquring mutations in the genes regulating theÂ cellular senescenceÂ process and from this point of view senecence gained a lot of interest as inducing senescence in cancer cells might have a curative potential. Senescence contributes largely into the normal physiological homeostatsis of the cells and tissues and so the body in whole but when dysregualted the homeostasis balance is disturbed allowing diseases such as cancer to arise.
Aging is a multifactorial process in which free radicals oxidative damage plays a very important role in the mechanism of aging. Anti-oxidant defence mechanisms in human are known to regulate and balance the oxidative damage caused by reactive oxygen species. Dietary foods containing high amounts of antioxidative nutraceuticals such as fruits and vegetables are beneficial in the reduction of the deleterious ROS and free radicals in human as well as balancing the oxidative stress in order to slow down the aging process.
Recent reports suggested that cellular senescence may be one of the mechanisms in which treatment of cancer by chemotherapy drugs works in vivo.
P53 clearly plays a pivotal role in controlling the senescence response to diverse stimuli. On the other hand, loss of p53 can be required for the maintenance of aggressive carcinomas and illustrates how the program of cellular senescence along with the innate immune system acts together to potentially limit tumor growth.
Therapeutic strategies that target oncogenic consequences of the expression of p21 provide a new approach to chemoprevention and cancer treatment. (Roninson, 2002)
Understanding of the irreversibility of cell aging strict new insights into the development of cancer and may open a new way of its control.