Cell Senescence

Cell senescence is the stage in the cell reproduction process that is characterized by the gradual decline in the propagation of cells. Eventually, cells lose the capability to divide, albeit cells maintain metabolic activity. The decline and end of cell reproduction cause changes in the physiological functioning of cells explained as ageing. (Schulz et al. , 2006) Senescence in cells could also be perceived as the breakdown of regulatory processes at the intracellular and intercellular levels. Intracellular process occurs in response to environmental signals. Changes in the signals could influence the senescence or ageing of cells.

(Arking, 2006) Cell senescence has been observed in vitro or in artificial and laboratory environments. Since cells comprise the basic structure of living organisms, cell senescence has been attributed to the manifestations of ageing in vivo in animals and man. However, due to the limitations of in vivo studies, there remain differences in opinion over the existence of a link and if so, the extent that cell senescence contributes to the ageing of animals and humans. The affective or causal link between cell senescence and the ageing of the whole animal or human has become a matter of evidence.

The discussion critically considers the bulk of evidence on the ways that cell senescence contributes to the ageing of the whole animal or human. Research Evidence The widely studied direction of research on cell senescence is on the role of telomeres in cell ageing (Hamerman, 2005). Telomeres are the repetitive DNA at the end of chromosomes to serve a stabilizing purpose. There is sufficient evidence that telomeres give way to cell senescence. This is because the genetic mechanisms of cell ageing, particularly the capacity of cells to divide and replicate rests on telomeres.

During the ageing process of cells, the length of telomeres shortens with every cell division due to the inability to renew the telomere and insufficient telomerase, which is an enzyme responsible for the renewal of telomeres. When telomeres reach a certain shortened length, it signals a change in cell mechanism and limits cell division. The cessation of cell division then puts the cell in a senescent state. (Fossel, 2004) The link between the shortening of telomeres and its role as a trigger for cells to reach a senescent state provides strong support for the process of cell ageing.

While cell ageing may be linked to the ageing of whole animals or humans, composed of cells as basic units, by analogy or association, there is need to evaluate evidence explaining how cell senescence cause the ageing of tissues, organs and the whole organism. Nevertheless, the operation of telomeres represents the framework for studies attempting to link telomere mechanisms with cell ageing and to the ageing of whole animals or humans. The link between telomeres, cell senescence, and ageing of whole animals or humans has found evidence through age-related conditions and diseases.

A number of studies found that the mechanisms of telomeres affect the onset of age-related diseases. A limited number of studies provide direct link between cell senescence and aging of certain tissues, especially the skin. Most of the other studies provide indirect and correlative link between cell senescence and aging of other tissues and organs as well as whole animals and humans. One study showed direct link between cell senescence and skin ageing. This study compared cell senescence in the skin samples from different age groups.

This earlier study on biomarkers of cell senescence and skin aging in vivo showed that there is a relationship between the increase in cell senescence and aging of the human skin. The results came from the testing of skin samples from human donors of different ages. There was significant difference in skin senescence across different age groups, with increase in this biomarker for the older age group. Increased cell senescence was found in the dermal fibroblasts and epidermal keratinocytes of the older skin sample donors. (Dimri et al. , 1995) The results of the study shows evidence directly linking cell senescence and skin ageing.

Skin ageing is a determinant and manifestation of the ageing of whole animals and humans. However, the evidence provides a correlative link between cell senescence and aging of whole humans through the ageing effect of cell senescence on the human skin. Similar results have been found in the case of aging primates. The study of the extent of telomere dysfunction and cell senescence in aging primates showed that there is increased telomere dysfunction in the skin taken from primates in their old age. This was observed through the exponential increase in the number of senescent fibroblasts in the skin of the aging baboons tested.

The increase was to the extent of reaching the level of greater than 15 percent of all cells for the oldest donors. Moreover, the presence of activated ataxia-telaniectasia mutated kinase and heterochromatinized nuclei in the senescent fibroblasts provide confirmation of the senescent state of the skin cells. (Herbig et al. , 2006) The results of the study also show direct evidence linking cell senescence and ageing in the skin of old baboons. This corroborates the results found in human skin. However, similar to the results for humans, the direct link is only between cell senescence and the ageing of skin tissues.

There is no evidence to support generalization for the other tissues and organs. Another study sought further evidence and considered telomeres in different tissues of the same donor. The study looked at the telomere loss in the leukocyte, skin and synovial tissues of nine elderly patients by using telomere restriction fragment (TRF) as the biomarker. The results showed that there are differences in the length of telomeres in leukocyte tissues when compared to the skin and synovial tissues. The correlation between age and telomere length showed an inverse relationship between age and telomere length, which is significant in leukocyte tissues.

This means that older donors have shorter telomere length in their leukocyte tissues. However, the correlation between the telomere lengths for the three types of tissues shows that this is tissue-dependent. This means that the shortening of telomere lengths depends on the type of tissue even for older humans. (Friedrich et al. , 2000) The study confirms the shortening of telomere length and concurrently cell senescence in the three types of tissues of the elderly donors but the length differs depending on the type of cell.

This means that while cell senescence is highest in the leukocyte tissues of the elderly, the level of cell senescence in other tissues is not as high. By comparing the effect of cell senescence on three types of cells through an experiment, the impact on the ageing of the leukocyte tissues was the most significant. However, the study was not able to disprove that there was no impact on the other types of tissues, but that the effect was less than on leukocyte cells. The direct evidence linking cell senescence and aging is strong only in so far as the skin and some tissues such as leukocytes.

The same conclusion cannot be made for the whole of animals and the human body. The ageing of tissues differ, which could mean that cell senescence only causes the ageing of some parts of animals and the human body but not necessarily its entirety, pending the existence of evidence showing otherwise. The studies showing indirect link between cell senescence and ageing of the whole animal or human considered the relationship through age-related conditions. These studies, which applied the experimental approach, mostly focused on the condition of atherosclerosis, as an accepted manifestation of ageing.

One study focused on human atherosclerosis, which is a health condition involving the blocking of the arteries by hardened plaque in the blood. This restricts the flow of blood that could result to heart attack, stroke or death. This health condition is age-related because there is greater risk of developing this condition with age. The study considered whether cell senescence is present in the vasculature of older humans to support conclusions on its contribution to the development of atherosclerosis in the older population.

Investigation of the coronary and mammary arteries obtained from the bodies autopsied following death due to ischemic heart diseases using senescence-associated ? -galactosidase (? -gal) determined the existence of atherosclerotic lesions in the coronary arteries but not the in the mammary arteries. The lesions were caused by the dysfunction in vascular endothelial cells based on the results of the immunohistochemical analysis using anti-factor VIII antibody. Applying induced senescence in aortic endothelial cells of humans by inhibiting telomere function shows that endothelial senescence increased with inhibited telomere function.

On the contrary, the application of telomerase catalyst in the endothelial cells extended the life span and slowed down alterations linked to cell senescence. The study concluded that senescence in vascular endothelial cells is manifest in atherosclerotic lesions in humans. Atherogenesis may be caused by endothelial senescence due to telomere shortening. (Minamino et al. , 2002) The results of the study imply two things. One is the indirect relationship between cell senescence and aging of the vascular tissues and the higher risk of developing atherosclerosis by older individuals.

Cell senescence causes aging of the vascular tissues leading to the development of atherogenesis. The other is the differentiated results in comparing the vascular and mammary arteries, with the latter not experiencing a similar effect compared to vascular arteries. This means that the impact of cell senescence on the aging of other tissues and organs cannot be generalized for the entire animal or human body. The evidence based on various tests could not be extended beyond the ageing of the vascular arteries due to cell senescence.

An experimental study also considered the same direction of investigation by establishing the relationship between telomere attrition and its relationship to atherosclerosis, a disease strongly associated with old age. The study was of patients developing chronic kidney disease because they experience accelerated processes of atherogenesis caused by factors related to uraemia, primarily inflammation of tissues and oxidative stress. The study compared results for patients below and above the age of 65. Investigation of the length of telomeres shows that the patients with longer telomeres belonged to the younger age group.

Those with longer telomeres also experienced lesser inflammation as shown by lower counts of WBC, lower hs-CRP, lower IL-6 levels, lower 8-OH-dG, and higher fetuin-A. In addition, the study also found differences in telomere length between the genders, with younger and older males exhibiting shorter telomeres than younger and older females. Furthermore, the shorter telomere length caused higher rates of mortality in patients with chronic kidney disease dependent on the levels of fetuin-A but independent of age, gender or the degree of inflammation. (Carrero et al. , 2008)

The study was able to corroborate previous studies indicating the direct link between the length of telomere and cell senescence. In the case of patients with chronic kidney disease, the study was also able to show that younger patients have longer telomeres relative to the older patients with the same disease. Those with shorter telomere were prone to inflammation due to atherogenesis, an indicator of aging. However, there were differences in the length of telomeres between male and female patients that affect generalizations on the impact of cell senescence on the whole human body.

There may be differences in impact for males and females. The impact of the length of telomeres was also considered in terms of atherogenesis that affects the vascular tissues. The same results cannot be made for other tissues and organs. There are differences in cell senescence in the different tissues and organs as shown in other studies previously discussed. The correlative evidence linking cell senescence and the ageing of whole animals or humans considered co-occurrences between the processes of cell senescence and ageing. These are mostly from review studies.

A review of evidence of telomere and cell senescence studies shows the existence of in vivo evidence that the shortening of telomeres causes cell senescence. This suggested two possibilities relative to ageing. One possibility is the effect of the shortening of telomeres in causing the senescence of stem cells in certain types of tissues. This then leads to the reduction in the age-related functioning of the cells that could in turn influence systemic effects. The other possibility is the length of telomeres constitutes a biomarker for ageing.

Short telomeres could become indicators of intense damage and stress in the human body to support the higher risk of developing age-related diseases. (Von Zglinicki, Martin-Ruiz & Saretzki, 2005) There is mostly correlative evidence of these possibilities. Another review article also considered similarities in the molecules that explain aging and those that regulate cell senescence. On is the DNA-repair system. Defects in the DNA-repair system cause changes in tissues that are similar to the manifestations of ageing of tissues and organs. In senescent cells represent DNA damage accumulation in older age groups.

Another is insulin/Akt pathway. Intake of calories in excess could lead to diabetes and the dysregulation of the insulin pathway lead to cellular senescence. Restriction of caloric intake and reduction in insulin signals lengthens the life of different organisms and lowers the onset of cell senescence. (Minamino & Komuro, 2007) Again, the evidence presented is correlative. A different direction of study, away from the study of telomeres, considered the link between cell senescence and circadian rhythms to link cell senescence with ageing of whole animals or humans.

Circadian rhythms sets the biological clock of organisms through the clock genes that controls physical functions such as rest and activity and organ functions such as blood circulation and pressure, hormone secretion and metabolism. Impairment of the circadian rhythm is common in the elderly as shown in the propensity to sleep during the day and active functioning during the night together with other observable signs of impairment. A study showed that cell senescence affected circadian rhythms as shown in the weaker functioning of clock genes in senescent cells as compared to young cells.

This suggests that cell senescence could explain the disruption or impairment in the circadian rhythms of the elderly. (Kuneida et al. , 2006) Although, this is an experimental study, the evidence shown indirect and correlative evidence to support the impact of senescent cells on the ageing of whole animals and humans. Conclusion Based on the evidence drawn from various studies, cell senescence contributes to the whole animal or human ageing but only indirectly and correlatively.

Direct evidence only links cell senescence with the ageing of the skin, the development of the age related condition atherogenesis, and the disruption of circadian rhythms in the elderly. However, this direct links can only explain the impact on the whole ageing of animals and humans through indirect connections and correlative analogy. Furthermore, there is evidence showing differentiated impact of cell senescence on different types of tissues and organs. The evidence supports the impact of cell senescence on ageing manifested only in some tissues and organs.

Lastly, there is also evidence indicating that the impact of cell senescence could be more strongly based on the types of tissues affected instead of on age. Only evidence indicating impact of cell senescence on the ageing of different types of tissues and organs of the human body, manifested through proven and observable manifestations of ageing, could support the direct link, which remains lacking. References Arking, R. (2006). The biology of aging: Observations and principles. New York: Oxford University Press. Carrero, J. J. , Stenvinkel, P. , Fellstrom, B. , Qureshi, A. R. , Lamb, K.

, Heimburger, O. , et al. (2008). Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients. Journal of Internal Medicine, 263(3), 302-312. Dimri, G. P. , Leet, X. , Basile, G. , Acosta, M. , Scorrt, G. , Roskelley, C. et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Cell Biology, 92, 9363-9367. Fossel, M. (2004). Cells, aging, and human disease. New York: Oxford University Press. Friedrich, U. , Griese, E. , Schwab, M. , Fritz, P. , Thon, K. , & Klotz, U. (2000).

Telomere length in different tissues of elderly patients. Mechanisms of Ageing and Development, 15, 89-99. Hamerman, D. (2005). Focus on cell senescence as the basis for aging. Journal of the American Geriatrics Society, 53(5): 901-902 Herbig, U. , Ferreira, M. , Condel, L. , Carey, D. , & Sedivy, J. M. (2006). Cellular senescence in aging primates. Science, 311(5765), 1257. Kunieda, T. , Minamino, T. , Katsuno, T. , Tateno, K. , Nishi, J. , Miyauchi, H. , et al. (2006). Cellular senescence impairs circadian expression of clock genes in vitro and in vivo. Circulation Research, 98, 532-539.

Minamino, T. , Miyauchi, H. , Yoshida, T. , Ishida, Y. , Yoshida, H. , & Komuro, I. (2002). Endothelial cell senescence in human atherosclerosis: Role of telomere in endothelial dysfunction. Circulation, 105, 1541-1544. Minamino, T. , & Komuro, I. (2007). Vascular cell senescence contribution to atherosclerosis. Circulation Research, 100, 15-26. Schulz, R. , Noelker, L. S. , Rockwood, K. , & Sprott, R. L. (2006). The encyclopedia of aging. New York: Springer. Von Zglinicki, T. , Martin-Ruiz, C. M. , & Saretzki, G. (2005). Telomeres, cell senescence and human ageing. Signal Transduction, 5(3), 103-114.

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