In some instances, cellular senescence is thought to contribute to the development and/or progression of age-related disease, but in others, the presence of disease may accelerate the accumulation of senescent cells.
A recent study has provided strong evidence to suggest that intervertebral disc degeneration, a major cause of low back pain, is due to accelerated cellular senescence (Le Maitre et al, 2007). Cells isolated from normal and degenerate human tissue were assessed for mean telomere length, SA-β-Gal, and replicative potential. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. SA-β-Gal staining was not observed in non-degenerative patients unlike cells from degenerative discs which did exhibit 10-12% SA-β-Gal staining and decrease in replicative potential. However, the factors which may have led to accelerated senescence in this instance was not discussed. There are three possible reasons why cellular senescence was accelerated in this instance; (1) Unknown factors resulted in the damage and removal of cells, resulting in cell turnover for replacement, (2) ROS were involved causing stress induced premature senescence (SIPS) or (3) telomeres in these cells for some unknown reason started off shorter than normal, meaning less cell turnover is required for the appearance of senescent cells.
Other studies have shown a correlation between disease states and the presence of senescent cells in vivo. SA-β-Gal staining was used to detect senescent cells in normal liver, liver with chronic hepatitis C and hepatocellular carcinoma (HCC) (Paradis et al, 2001). They found senescent cells present in 3 of 15 (20%) normal livers tested, 16 of 32 (50%) in livers with chronic hepatitis C and in 6 of 10 (60%) livers with HCC. The presence of senescent cells in normal livers was found to be associated with old age. Interestingly, the presence of senescent cells in non-tumoural tissues was strongly correlated with the presence of HCC in the surrounding liver. This demonstrates not only that the ageing of one tissue can have a direct impact on another but also as suggested by Judith Campisi, senescent cells may contribute to carcinogenesis (Campisi, 1997).
Another study looked at cellular senescence in human benign prostatic hyperplasia (BPH) specimens (Choi et al, 2000). BPH is a disease associated with an abnormal growth of the adult prostate that begins mid to late life. Results from this study found that 40% of the analysed samples showed positive staining for SA-β-Gal and only in the epithelial cells. A high prostate weight (> 55g) was found to correlate strongly with the expression of SA-β-Gal. Prostates weighing less than 55g tended to lack senescent epithelial cells. It was suggested that the accumulation of senescent epithelial cells may play a role in the development of prostatic enlargement associated with BPH. However, the accumulation of senescent cells in this case is likely to be a consequence of the disease, which may lead further to its progression. The enlargement of the prostate may be the result of unregulated stimulated proliferation, increasing cell turnover and consequently the appearance of senescent cells. This may explain why a stronger expression of SA-β-Gal is detected in prostates weighing more than 55g since they may have undergone more cellular divisions.
During the pathogenesis of type 2 diabetes, insulin resistance causes compensatory proliferation of pancreatic beta cells. This compensatory proliferation might accelerate cellular senescence contributing further to the progression of diabetes. To investigate this, one group used nutrient-induced diabetic mice to analyse beta cells for SA-β-Gal and the proliferation marker Ki67 (Sone and Kagawa, 2005). At 4 months, the proliferation of beta cells was 2.2 fold higher than in the control group. At 12 months, the frequency of Ki67 decreased to one-third that of the control and SA-β-Gal positive cells increased to 4.7 fold that of the control group. This increase in the senescent beta cell fraction correlated with insufficient insulin release, suggesting cellular senescence may contribute to diet-induced diabetes. In this instance it is difficult to determine whether senescence is the cause or the consequence of insulin resistance. It later appears to be a contributor but whether it is also the initiating factor is unknown.
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An increase in the number of senescent primary lung fibroblasts has also been shown to increase in patients with emphysema compared with normal controls (Muller et al, 2006). An average of 4% of cells from control patients stained positive for SA-β-Gal compared to an average of 16% in patients with emphysema. It is possible that long-term exposure to tobacco smoke accelerates the formation of senescent cells, which subsequently may lead to loss of elasticity of the lung tissue, destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli observed with emphysema. One study has shown for example that cigarette smoke induces senescence in alveolar epithelial cells (Tsuji et al, 2004).
Another study used senescent associated p16 instead of SA-β-Gal to detect senescent cells in kidneys with glomerular disease (GD) (Sis et al, 2007). Glomerular diseases include many conditions which fall into two major categories; Glomerulonephritis describes the inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood. Glomerulosclerosis is the scarring or hardening of the tiny blood vessels within the kidney. This study found an increased expression of the nuclear p16 in samples with GD compared with normal. Independently, older age and interstitial inflammation was associated with increased expression of nuclear p16. Since senescent cells adopt a pro-inflammatory phenotype, their presence may be a contributing factor in inflammation observed in glomerulonephritis.
All these examples demonstrate the presence of senescent cells not only in vivo, but more specifically in disease states. This suggests that the accumulation of senescent cells in normal tissues is the result of injuries to those tissues or in some cases unregulated stimulation of proliferation. This suggests that if no injuries occurred as a consequence of disease, environmental factors or by normal biological/mechanical wear and tear, ageing of mitotic tissues would be greatly reduced.
Whether cellular senescence is the cause or the consequence of some diseases is yet to be answered.
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