It is not easy to admit that you are getting on in years and the dreaded three-letter word “old” is far worse to hear than some four-letter words! Rather use the fancy description that you have “senescence” and that your condition is caused by zombie cells in your body.
What is senescence?
As cells in your body also get on in years, they can become damaged by cellular stress or worn out by the continuous process of dividing into two new daughter cells. When the cell is no longer capable of dividing, it doesn’t necessarily die but becomes a “zombie” cell in the body. An accumulation of these cells is described as biological aging and makes the body more vulnerable to dysfunction and diseases.
The word “senescence” originates from the Latin word “senex”, which means “old” and it was also used in ancient Rome as the root of the word “senate” and where “Senatus” was used to referred to a “council of elders”, composed of the heads of noble families.
A senescent cell is no longer capable of dividing but it is still alive and metabolically active (with biochemical activity). Cellular senescence can lead to compromised tissue repair and regeneration and as such contribute toward aging. Senescence is an irreversible condition.
Senescent cells are usually resistant to normal programmed cell death, called apoptosis. Apoptosis is an orderly process in which cells are triggered to undergo programmed cell death and the cell’s contents are packaged in small packets of membrane, ready for “garbage collection and removal” by immune cells. While apoptosis refers to programmed cell death, the process when cells die due to injury is called necrosis.
The association between senescence and aging became clear when scientists found that senescent cells accumulate exponentially in multiple tissues as the individual ages. Scientists found that senescence itself can drive aging and is one of the hallmarks of aging. The normal growth (cell division) of cells is arrested in senescent cells. As they remain metabolically active and communicate to neighbouring cells via the secretion of chemicals and direct intercellular protein transfer, they may affect and alter the behaviour of nearby non-senescent cells. For example, scientists speculate that the secretion of dysfunctional mitochondria to healthy neighbouring cells may induce senescence in these cells.
However, there is currently no single reliable biomarker that allows accurate detection of senescent cells.
Causes of senescence:
Despite the link between the presence of senescent cells and aging, cells can also undergo senescence due to a variety of stimuli, of which a few examples are discussed below.
Senescence can result from DNA damage in the cell due to the erosion (shortening) of telomeres. The spirally chromosomes (“shoelaces”) in the nucleus of the cell are strands of DNA that house your genes and is the blueprint to make new, young cells. Each parent cell divides into two new cells, with the original genetic material duplicated. To ensure that the genetic material is passed on correctly to each new cell, the strands of chromosomes (“shoelaces”) have protective caps – called telomeres – at the ends of the strands (“tips of shoelaces”). Telomeres prevent chromosome “strands” from losing base pair sequences at their ends and stop chromosomes from fusing with each other. Every time a cell divides, some part of the telomere is lost because it fails to replicate completely, and it gets shorter. When the telomeres become too short, the chromosomes can no longer replicate. The cell becomes old and dies or becomes a senescent cell.
Senescence can be triggered by different kinds of cellular stress. Depending on the intensity and nature of the stress on the various cell types, cells may invoke repair, cell death, or senescence. Cellular stresses that may trigger senescence include oxidative stress (an imbalance between free radicals and antioxidants); telomere dysfunction (as seen above); DNA damage; or oncogenic activation (the development from a normal cell into a cancer cell).
Mitochondrial dysfunction has been linked to several conditions, with senescence amongst them.
Role of senescence in age-related diseases:
The accumulation of senescent cells in the aging body have been associated with the onset of several diseases, according to a 2019 article in the journal Aging.
- Cancer: Aging is viewed as the main cause of cancer and the presence of senescent cells in older people has a correlation with the incidence of cancer. Research on the removal of senescent cells is currently under the spotlight for its potential to delay tumor formation and reduce metastasis (spreading of cancerous cells).
- Neurodegenerative disorders: The presence of senescent cell accumulation at sites of brain pathology has been correlated with the onset of Parkinson’s and Alzheimer’s disease.
- Cardiovascular disease: Senescent cells were found to play a key role in atherosclerosis and seem to contribute to coronary heart disease and vascular stiffness in the aorta.
- Osteoarthritis: Accumulation of senescent cells correlates with the progression of this degenerative disease, which causes the joints in the body to become painful and stiff.
- Type 2 diabetes: As aging is the main cause of type 2 diabetes, there is an association between the detection of markers for senescent cells and the progression of type 2 diabetes.
- Kidney-related diseases: The incidence of kidney related diseases is associated with an increase in senescent cells.
- Idiopathic pulmonary fibrosis (IPF): The lung tissue of patients with this chronic lung disease shows the presence of senescent cells.
- Cataracts: The lens capsules from patients with cataracts indicate the presence of senescent cells.
- Liver diseases: The presence of senescent cells shows a correlation with the onset of liver fibrosis, cirrhosis, and non-alcoholic fatty live disease.
- Metabolic syndrome: The presence of senescent cells is associated with metabolic disorders such as increased blood pressure, high levels of blood sugar, excess body fat around the waist, and abnormal cholesterol levels.
- Erectile dysfunction: The presence of senescent cells has been directly linked to erectile dysfunction.
- Cachexia: Disruption caused by senescent cells contributes to this condition that causes extreme weight loss and muscle wasting. It predominantly affects people in the late stages of chronic renal failure, multiple sclerosis, cancer, HIV or AIDS, and congestive heart failure.
As we know, nothing lasts forever, and the cells in our body are no different.
Senescent cells are found in all tissues. Senescent cells are thought to mediate tissue development when they form in the embryo, and to promote tissue regeneration and wound repair later in life.
The total percentage of senescent sells in aged tissues is usually below 20%. Senescence is a process by which a cell ages and permanently stops dividing but does not die. Senescent cells have altered cell function. They remain metabolically active, but secrete pro-inflammatory cytokines, which can fuel chronic inflammation. These pro-inflammatory chemicals attract cells of the immune system, the macrophages and NK (natural killer) cells, which play a major role in clearing senescent cells. Senolytic drugs that induce apoptosis in senescent cells rely on the phagocytic macrophages (cells highly specialized in the removal of dead cells) of the immune system to then remove them. Aging of the immune system (immuno-senescence) as B cells, T cells and NK cells themselves become senescent, results in less removal and thus a general increase in senescent cells with time.
Senescence occurs in 3 different scenarios – senescence due to normal aging; senescence due to age-related diseases; and senescence induced by exposure to cell damaging agents used in therapy (such as chemotherapy).
Senescence can be triggered by a wide variety of stress factors, such as a DNA damage response due to the shortening of telomeres, increased oxidative stress (ROS), and activation of oncogenes, to name a few.
Senescent astrocytes (star shaped glial cells) and microglia (immune cells) in the brain contribute to neurodegeneration.
The association of senescent cells with various age-related diseases and conditions in the body highlights the importance of finding new therapies to target such “zombie cells”, to delay or cure these diseases. It has been shown that intermittent fasting, through a process called autophagy, helps to get rid of these “zombie cells”, and thus improve longevity. Intermittent fasting restricts when you eat rather than how much you eat. In general, by fixing your lifestyle through reducing stress, regular daily exercise, and healthy eating, one can in essence slow down the aging process.
The role of senescence cells in aging. 22 May 2014. Published in the journal Nature. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. (www.ncbi.nlm.nih.gov)
Scientists find mechanism that eliminates senescent cells. Published 10 May 2021. University of California. San Francisco. (www.ucsf.edu)
Mechanisms of cellular senescence: Cell cycle arrest and senescence secretory phenotype. Published 29 March 2021. Frontiers in Cell Division Biology. (www.frontiersin.org)
Targeting senescent cells: approaches, opportunities, challenges. Published 31 December 2019 in the journal Aging. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. (www.ncbi.nlm.nih.gov)
On the evolution of cellular senescence. Published December 2020 in the journal Aging Cell. Volume 19. Issue 12. 12 December 2020. (www.onlinelibrary.wiley.com)
Senescent cells talk frankly to their neighbors. Published 1 June 2015 in the journal Cell Cycle. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. (www.ncbi.nlm.nih.gov)
Telomeres. Published online as a Health Insight blog. (www.healthinsight.co.za)