Why We Age and Die— Senescence: Part 2
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Introduction
In the last article, I defined senescence as the progressive breakdown of the body's functions. It begins before birth and has a relationship with aging. It is a self-preservation mechanism that tries to stop cancerous cells' proliferation and growth but eventually turns awry in our lives. Our chromosomes' protective ends, called telomeres, diminish due to ceased cell division and DNA damage. This is called telomere attrition.
The last article highlights the possible links between bladder cancer, telomere attrition, and smoking. DNA injuries linked to oxidative stress (imbalance between uncharged highly reactive molecules and the defenders against them) and obesity could be linked to telomeres' shortening. There is concern that telomere attrition is linked to pollution and the volatile hydrocarbons from coal tar and petroleum. Telomere attrition is linked to glucocorticoid steroid hormones released from the adrenal gland during stress.
To understand senescent cells' strong effect on tissues and organs, I should elaborate on a class of cells called senescence-associated secretory phenotypes (SASP) that are quite important to inflammation, immunity, and cell signaling [1].
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What is Important to Inflammation
Our bodies have cytokines that are responsible for inflammation. "Cyto" is the Greek word for cell, and "kinos" is the Greek word for movement. Cytokines facilitate communication between cells and invigorate cellular movement toward damaged areas [2]. They are prompted by macrophages that guard against pathogens and release a reactive oxygen species, such as nitric oxide, to squash dead cells [3].
Interleukin (IL)-1 and tumor necrosis factor (TNF) are two types of cytokines that trigger a fever, inflammation, tissue destruction, and occasional shock and death. The IL-1 and TNF cytokines bring about the event of sticking your white blood cells to endothelial surfaces lining the interior of your blood vessels. This involves a kind of inflammation with a torrent of gene products not typically accompanying healthy individuals [4].
Chemokines are another type of cytokines that are small proteins responsible for influencing the immune system, migrating the cell through small blood veins and tissue, and inducing the cell to respond to a chemical gradient. They regulate the development of your organs that execute immune functions. They regulate the white blood cell functions integral to adaptive immunity [5]. Lastly, they dispatch your white blood cell defenders to the microenvironment of your tumors [6].
Our bodies' SASP cells employ growth factors that promote cells' production of daughter cells (cell proliferation). Growth factors help to restore injured tissue (wound healing). They also help cells transform into other types of cells, a process of differentiation happening multiple times throughout a multicellular organism's development. Growth factors' take on the role of signaling molecules between the cells [7].
Our SASP cells have proteases, which are the enzymes (agents of change) that crush proteins into smaller polypeptides or single amino acids (chains of organic compounds). Proteases facilitate cell-signaling, the digestion of proteins, and the transformation of proteins into amino acids for passage through the plasma membrane [8].
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Our SASP cells are like a double-edged sword. Firstly, we perhaps can blame them for the pain we feel from inflammation and the senescence that spreads to nearby cells. But they also set up the ramparts of our fortress against foreign enemies. It seems that senescent cells could be the cause of their own death if they help make the "pro-inflammatory environment" that takes them down the road of getting eaten by phagocytes [1].
SASP cells emerge onto the scene initially because of the nuclear factor kappa B (NF-kB) signaling pathway that is a major gene regulator during innate and adaptive defenses. The NF-kB is activated by an evolved mechanism that identifies DNA lesions and relays the need for restoration [1].
The Mammalian Target of Rapamycin (mTOR) governs the manufacturing of SASP cells. The mTOR is a special protein without which our cells cannot grow, proliferate, and survive. The mTOR protein will hinder the breakdown of many SASP pieces by hindering specific ancient RNA-binding proteins that can degrade the transcripts of many SASP cells [1].
Evidence is building to show that senescent cells are mediated by exosomes (vesicles the size of nanometers) that are transporting proteins, nucleic acids, and lipids that all play a part in enabling and continuing the internal steady state of cells by expelling DNA waste materials [1] [9].
A profile is shared between the stress-induced premature senescence (SIPS), which is unintended by your body but hastened by stress, and the replicative senescence (RS) that happens inescapably through time. However, different compounds come from the senescence arising from the blockage of proteasomes that destroy unnecessary proteins [10].
I wonder if that profile is implied in a 2016 comparative analysis from BMC Genomics. Specific enzymes and fibrous structural proteins that are key orchestrators of irreversible growth arrest were found among both SIPS and RS in human fibroblasts (fiber producers in connective tissue) [11].
We cannot live forever, as evidenced by replicative senescence. No one can exactly quantify how many times your cells can multiply and divide before they reach their limit. But we at least know that replicative senescence tells us there is a limit. The communications between your somatic cells are changed, and your telomeres are shortened by ataxia telangiectasia mutated (ATM) kinase activation, an unfortunate event that involves severing both strands in the double helix of your DNA and generating the cell cycle arrest. Following close behind is the aging phenotype that chemically deteriorates your tissues and cells throughout time. Your telomeres are slightly reduced with every cell division because the enzymes that read and create your DNA strands can only polymerize in one direction. They will never be able to become bidirectional. Telomere attrition could be undone, and senescence could be prevented by telomerase, but most cells do not have telomerase [10].
Studies on human dermal fibroblasts that play a significant part in wound healing have revealed that aneuploidy (odd number of chromosomes) becomes greater as we age because of impairment in the machinery that divides our cells. This is said to be associated with early senescence [12].
When mitochondria fail to provide adequate energy for the cell to replicate, senescence follows close behind. Reaction oxygen species (oxygen-containing, unstable molecules) result from mitochondrial failure that provokes telomere attrition and senescence [10].
Though replicative senescence is inescapable, (SIPS) can be delayed if you avoid things that introduce DNA damage and oncogenes (potential cancer-causing genes) [10].
Your telomeres gradually wear away because your DNA polymerases (which read and form new copies of your DNA strands) cannot copy new chromosomal ends after every cell division. Our cells are eukaryotic, causing our chromosomes to be linear and thus only able to polymerize in one direction. However, germ cells and cancer cells have telomerase to prevent their telomere attrition. The telomerase can add new nucleotides to germ cells and cancer cells after their DNA replication, implying that these cells can defeat the whole problem of aging. They can live forever, while we cannot live forever because our fibroblasts cannot express telomerase. Our somatic cells have low amounts of telomerase [13] [14].
As long as cancer cells have telomerase to enable their self-replication, cancer will inevitably overtake us. It is only a matter of time. However, if our stem cells have some life-prolonging telomerase, it is unfortunate that stem cells must be embroiled in ethical controversies that will hold us back from getting the prolonged lifespans that we want.
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All information in this article is intended for educational/entertainment purposes only. This information should not be used as medical/therapeutic advice. Please seek a doctor/therapist for health advice.
Works cited:
[2] What are Cytokines? (news-medical.net)
[3] Macrophages | British Society for Immunology
[4] pro-inflammatory cytokines (sinobiological.com)
[5] Chemokines: Introduction | British Society for Immunology
[6] Chemokines in Cancer (nih.gov)
[10] https://www.labome.com/method/Cellular-Senescence.html
[11] https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-016-3352-4
[12] https://pubmed.ncbi.nlm.nih.gov/30026603/