All chronic diseases are due to chronic elevation of some (or many) stimulatory molecules in the blood.
For example, chronically elevated blood glucose levels, ongoing presence of pro-inflammatory factors, and chronic light exposure propagate cell senescence.
In this article, I will take you on a step by step outline to show why this is so.
Two ways that cells can respond
When you inject a molecule into the blood stream, a cell has a decision to make as that molecule reaches the plasma membrane: is that molecule activating or inhibiting? And what kind of activation is it?
Here are two (of many) ways that cells can respond to any given molecule.
Healthy activation of cells: Rhythmic oscillations
One way that cells can respond is for the molecule to wake up the plasma membrane and allow flow of calcium into the cell. This is a good thing, as it activates cells to secrete hormones and digestive enzymes, as well as mobilize immune cells to a site of injury.
- increasing the level of glucose in the blood stream allows the beta cells of the pancreas to secrete insulin.
- Waking up in the morning to daylight stimulates the suprachiasmic nucleus (SCN) neurons to produce vasoactive intestinal peptide (VIP). The VIP inhibits the release of melatonin from the pineal gland. The reverse happens at nighttime, allowing melatonin levels to rise.
- Activating muscle cells allows calcium entry which enables muscle contractions
- Stimulating neuron cell bodies at the synaptic junctions enables downstream transmission of the nerve impulse
When those stimuli follow a rhythm such that there is time for the cell to take breaks between periods of stimulation, the cell remains healthy. This is the basis for biological rhythms, our inbuilt rhythms that respond to natural cues.
Unhealthy activation of cells: rise in cytoplasmic calcium
Activating a cell and allowing the entry of calcium into the cytoplasm is a common and often a healthy response to a stimulus. Unfortunately, when you take that same stimulus and allow it to have a non-rhythmic and repetitive action on an organ, the cells don't like it. In fact, when cells are repeatedly stimulated with an activating molecule, they start showing signs of stress (1, 2, 3, 4).
Chronic elevation of stimulatory molecules creates stress
With chronic stimulation of cells, the cell's normal rhythms are disrupted. Calcium ions flood the cytoplasm, leading to elevation of intracellular calcium levels. Also cytoplasmic acid levels increase as the channels that allow calcium to come in also open the gates for H+ ions.
Cells can't take a breather or clear out the garbage
This leads to a number of abnormal downstream effects
- mitochondrial calcium levels also increase leading to increased production of reactive oxygen species
- cells start using up ATP (the cell's energy molecule) to pump the calcium out
- The endoplasmic reticulum (an extensive double-membraned envelope within the cytoplasm) loses its calcium reserves which results in misfolding of proteins within its lumen
- Increased cytoplasmic calcium levels promotes the production of pro-inflammatory proteins
Moreover, as cells rev up their machinery to kick the calcium and H+ ions out of the cell, they deplete their ATP reserves. Cells with deficient ATP reserves start pushing the mitochondria to work harder; this drives up the level of reactive oxygen species. And that in turn encourages the cell to produce more pro-inflammatory molecules.
Because of the repeated stimulation, the cell cannot take a breather to replenish their resources, clear out the garbage, or reset their intracellular systems.
Senescence begets senescence
What is the common theme ? Chronic elevation of certain proteins/factors can induce increased receptors on susceptible cells. The activating element attaches to those receptors and induces chronic stress-related changes in the cell.
Over time , the stressed out cell ages, and as it ages it produces its own set of stressed-out factors. Many of those factors that aging cells secrete are pro-inflammatory proteins.
This induces a vicious cycle where senescent cells promote senescence in neighboring cells as well as in distant organs. And the process continues as more senescent cells are added, like a pathological cult that continues to recruit new members to its group.
Examples of stimulatory molecules
Earlier I mentioned several stimulatory elements (glucose, light, neuron stimuli on muscle cells and each other). There are many others. Some of those molecules are large proteins that bind to membrane receptors on the plasma membrane of the cell.
For example, interleukin-6 and Interleukin-1 (and others listed in this table) are large peptides that are 184 and ~ 270 amino acids long. These molecules are pro-stimulatory. When they attach to the plasma membrane, they induce entry of calcium into the cell.
In healthy situations, the activated cell can then do what it is supposed to do, such as secrete other proteins, migrate to sites of injury, etc. However, with repetitive waking up of the plasma membrane, the cells get stressed out and demonstrate aging over time.
This is the basis for chronic disease.
- Arruda AP, Hotamisligil GS. Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes. Cell Metab. 2015 Sep 1;22(3):381-97. doi: 10.1016/j.cmet.2015.06.010. Epub 2015 Jul 16. PMID: 26190652; PMCID: PMC4558313.
- Gerasimenko JV, Gerasimenko OV. The role of Ca2+ signalling in the pathology of exocrine pancreas. Cell Calcium. 2023 Jun;112:102740. doi: 10.1016/j.ceca.2023.102740. Epub 2023 Apr 8. PMID: 37058923.
- Adasme T, Hidalgo C, Herrera-Molina R. Editorial: Emerging views and players in neuronal calcium signaling: synaptic plasticity, learning/memory, aging and neuroinflammation. Front Cell Neurosci. 2023 Apr 17;17:1197417. doi: 10.3389/fncel.2023.1197417. PMID: 37138767; PMCID: PMC10150380.
- Guerrero-Hernandez A, Verkhratsky A. Calcium signalling in diabetes. Cell Calcium. 2014 Nov;56(5):297-301. doi: 10.1016/j.ceca.2014.08.009. Epub 2014 Aug 27. PMID: 25217232.