Cellular Senescence and Aging; An Overview

Cellular senescence refers to the essentially irreversible arrest of cell proliferation or cell growth. It is the phenomenon by which normal diploid cells cease to divide as they age. This was first introduced by Dr. Leonard Hayflick along with his colleague, Dr. Paul Moorhead. The process demonstrated limited capacity of cellular divisions by most of the cells (approximately maximum of 50 cell divisions before it cease to divide). This phenomenon was latter on recognized as “replicative senescence”, or the Hayflick limit.

In addition to arrested growth, senescent cells show widespread changes in chromatin organization and gene expression.  Although there is no further replication in senescent cells, they stay metabolically active and normally show an immunogenic phenotype comprising of a pro-inflammatory secretome, a pro-survival response, the up-regulation of immune ligands, promiscuous gene expression and also stain positive for β-galactosidase activity associated with senescence. Senescent cells impact tumour suppression, healing of wounds, development of placenta in embryo and depict pathological role in age-related diseases.

Characteristics of Cellular Senescence

In addition to the essentially perpetual growth arrest, several other features called molecular markers identify senescent cells. However, like ceasing of cellular growth, no other characteristic is limit to the senescent state of cell. Likewise, not all cells in a senescent state exhibit all the senescence markers identified so far. Thus, a constellation of physiognomies identifies senescent cells.

Because the most prominent feature of a senescent cell is ceasing of growth, an essential but insufficient indicator of senescent cells is lack of proliferation markers. In addition, senescent cells are mostly larger in size, having doubled volume than normal cells and sometimes also depict a flattened appearance in comparison with normal cells.

In some senescent cells senescence-associated heterochromatin foci (SAHF) are present. These are heterochromatin domains that are cytologically detectable and also hold certain proliferative genes (probably silenced ones). These foci are link to some senescent human cells but not present in all. Senescent mouse cells, on the other hand, have similar foci in the form of pericentric chromatin rather than SAHF.

Some other markers that are helpful in characterising cellular senescence comprises of; 
•      Amplified expression of tumour suppressor protein, p16INK4a  
•      Increased expression of the tumour suppressor proteins DEC1 (Deleted in Esophageal Cancer) and DcR2 (Decoy Receptor 2), 
•      Existence of telomere dysfunction–induced foci (TIF) or DNA damage foci.

Factors Influencing Senescence

Nucleic acids (DNA or RNA) codes most of the information. Despite of this stored information, many chemical processes are triggere by environmental component throughout lifetime of human being. Following are some of the factors that affect largely on process of cellular senescence or cellular aging.

•      High levels of UV radiation (as present in sun rays) can cause damage to DNA molecule and initiate cellular senescence in normal cells.
•      Magnetic or electromagnetic field produce by solar energy or electrical appliances such as microwaves increase the production of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). These may trigger cellular senescence.

Some other factors include smoking which causes wear and tear. Also some stress conditions such as organ transplant can give rise to cellular senescence.

Benefits of Cellular Senescence

Due to growth arrest of senescent cells, most of the pathways act as tumour suppressors. Therefore, cellular senescence prevents tumourigenesis by halting proliferation of malignant cells. Senescence has also a major role in prevention of fibrosis. In case of injury or tissue damage, cells proliferate and the damage is repair by production of extracellular matrices. But after repair, they instantly undergo senescence. If this do not happen then cells continue to divide and excessive ECM is produced eventually leading to tissue fibrosis.

In case of tissue injury, there is another important role played by senescence which is of wound healing. Cutaneous wounds are responded by myofibroblasts differentiation by growth factor secretion. This is how senescence accelerates wound enclosure. If p16INK4a is removed from cells, they show delaying in closing of wounds. Another beneficial role of senescent cells is that they involve natural killer cells, immune cells to eliminate tumour cells. In this way senescence also plays its role in tumourigenesis suppression by immune surveillance. Moreover, senescence also helps during development of embryo and in morphogenesis. It also plays an important role in tissue repair. 

Drawbacks of senescence and SASP

SASP plays a role in creating microenvironment for pro-tumourigenesis in many ways.
•      Destruction of tissue structures caused by SASP supports invasion of tumour cells and their metastasis.
•      Large amount of proteases secreted by senescent cells cause relaxing of structures of tissues which facilitates cancer cell invasion.
•      Some interleukins that are portion of SASP contribute to inflammation and senescence.
•      Senescent cells can also cause proliferation due to angeogenic factors and enhance tumour vascularization.
•      SASP can also cause immunosuppression as senescent cells secretes cytokines.

Moreover, aging is also promoted by senescence as tissue regeneration is impaired due to cease in proliferation activity of senescent cells. 

Conclusion

Cellular senescence can be caused in mitotic cells like epithelial cells, endothelial cells or fibroblasts due to DNA damage caused by extrinsic or intrinsic stresses. These damage trigger DNA damage response which converts normal cells to senescent cells. Senescence can be natural or induced, beneficial or deleterious depending upon its causes and effects respectively. There is still bi room for research in cellular senescence and its importance.

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