Senescent Cells: What it Means for How Cells Age

It is fairly clear that we all age. As the years go by, we start to notice more aches and pains, wrinkles, and the onset of disease. The definition of aging is the functional decline of a biological system over time due to molecular, cellular, and, histological changes (1). Senescent cells are at the root of aging. Normal cells are capable of undergoing a limited number of divisions. Another concept which explains this is Hayflick limit (2). Typical phenotypic changes can occur in senescent cells. Enlargement in cellular morphology and elevated lysosomal β-galactosidase activity are common changes that occur in senescent cells (3).

Your Telomeres Change

Another feature of cellular senescence is telomere shortening. As cells divide, long strands of DNA at the end of chromosomes called telomeres begin to shorten. During DNA replication, identical copies of DNA are formed. A series of enzymes are responsible for this process including DNA polymerase which plays an important role. At the end of replication, DNA polymerase is unable to fully replicate the single-stranded 3’ ends of DNA which explains why our telomeres shorten after every replication. You can think of telomeres like the caps at the end of your shoelaces. They stop the DNA from ‘fraying’ as it replicates repeatedly. The effects of short telomeres can lead to illness, decreased lifespan, and cancer (4).

Free Radicals Increase

50 years ago, Harman proposed a theory of cell aging called the “Free Radical Theory of Aging”. It supports the idea that increases in intracellular oxidants and lower antioxidant levels can accelerate the rate of senescence. The main idea here is that the formation of free radicals, particles that are highly reactive, can cause aging. In addition, the mitochondrial theory suggests that energy formation can lead to the creation of molecules called reactive oxygen species (ROS) that are harmful to the cell. This molecule can cause oxidative stress which leads to DNA and lipid damage. Proteins inside the cell also are affected by oxidative stress and can become less effective at carrying out their functions overtime (5,6).

Epigenetic Changes

As cells age and they receive signals from the environment around them, changes can happen at the DNA level. For example, free radicals can cause unwanted mutations. Other changes can also occur inside the cells themselves. Epigenetic changes can also modify DNA. This can include acetylation and methylation of DNA. These changes affect the transcriptome which decides which functional proteins eventually become translated. Aged cells have different patterns of acetylation and methylation. Age-related degenerative disorders have been associated with some of these patterns (7).

Senescent Cells: Changes to the Cell Cycle

Cells also cycle in a series of events which enable them to divide properly into daughter cells. Cell cycle arrest is also another defining feature of cellular senescence. Two pathways which facilitate cell cycle exit, which allows cells to temporarily exit cell division, are the p53/p21 and p16/Rb tumour suppressor pathways. Cells that can eventually re-enter cell division are called quiescent cells, however, senescent cells cannot. These senescent cells are no longer able to properly respond to cellular signals from the environment such as mitogens or growth factors (8).

Senescence Associated Secretory Phenotype

Senescent cells also acquire a senescence associated secretory phenotype (SASP). Interleukins play a role in the immune response. Some interleukins such as IL-6, IL-7, IL-1, IL-13, and IL-15 become elevated in senescent cells. Chemokines attract cells to sites of infection and inflammation in the body. Some chemokines become upregulated in senescent cells, including IL-8, MCP-2, MCP-4, and MIP-1a. Insoluble factors are part of the non-cellular components of organs and tissues. More specifically, fibronectin, collagen, laminin become altered in senescent cells. Other factors also become effectively upregulated in the senescent phenotype. These include proteases, growth factors, and regulators of the cell (9).

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