James P. Bennett, Jr. M.D., Ph.D.
If we are alive, we age each day. What is happening during that process? Why, as we age, do we become more vulnerable to Corona virus complications?
Right now the last thing most of us want to read is another Corona virus article. Yet, I would like to propose a hypothesis that, if correct, means that we should work even harder to avoid Corona virus infections beyond the immediate questions of personal infection and transmission to others (these are very important issues, and I don’t mean to minimize these concerns). And that hypothesis is: Corona virus can accelerate our aging.
One way to look at aging is that we are composed of two basic types of tissues- those that replicate (create new cells by cell division, a.k.a. mitosis), and those that do not replicate or replicate very little (so-called “non-mitotic” tissues). We all began as single cells (fertilized egg cells), so in one sense, we all developed from cells that replicate. At some point in our developments, we created cells that were destined to become muscle (this includes heart muscle) or nerve cells. These formed the “non-mitotic” cells that we, as adults, have in our skeletal muscles, heart muscles and nervous systems.
Normally these muscle and nerve cells (neurons) divide very little if at all, so if you lose one of these cells, normally it is not replaced. While we possess stem cells for these non-mitotic tissues, normally these muscle or neuron stem cells (which can replicate) are not that prevalent, and one aspect of aging is that over our lives the stem cells become less prominent and active.
Contrast this situation in non-mitotic tissues with our many types of cells that do replicate (are mitotic). These include cells in our skin, bone marrow and gastrointestinal and urinary tracts. Every time one of these cells replicates, its genome (DNA inherited from mother and father) is copied and corrected, usually perfectly, and distributed equally to the “daughter” cells. If the DNA genome is not perfectly copied and corrected, the daughter cell getting the defective genome may either die or become cancerous.
Successful DNA genome copying in replicating cells depends on the use of telomeres, the special ends of our chromosomes that are copied using a specific biochemistry. Telomeres shorten a little bit each time they are used, and aging is characterized by short telomeres in replicating cells. Eventually telomeres become so shortened that cells cannot replicate and are “senescent”. Senescent cells may help us understand what occurs in some types of aging.
What is not commonly appreciated is that we have two independent genomes in our cells, in both the non-mitotic and the mitotic populations. Whereas our usual DNA genome inherited from mother and father at the time of egg fertilization is very large, protected by a separate structure (nucleus), error-corrected during copying and repaired using several mechanisms, there is a separate DNA genome inherited exclusively from mothers that lives inside mitochondria as multiple copies and has limited amounts of these nuclear genome properties. This is called “mitochondrial DNA”, and I will abbreviate it as mtDNA.
Mitochondria are small “organelles” found in all of our cells and are responsible for making energy chemicals, initiating many forms of cell death, buffering calcium levels in our cells, and potentially more cell processes we have yet to discover. Mitochondria likely arose several billions of years ago in simple single-cell organisms as bacterial invaders that could manage oxygen safely and use oxygen to make an energy chemical. Over evolutionary time, these bacteria became mitochondria and transferred much of the genetic control of their functions to the host cell genome but retained genetic control of 13 proteins in the energy system. mtDNA is also circular (like DNA in bacteria), is present in multiple copies within each mitochondria and replicates independently of the host cell genome DNA. Mitochondria fuse into larger organelles and divide into smaller pieces. We know a little about the control of these fusion and fission processes. In many ways mitochondria “do their own thing” within host cells, and much of their control mechanisms remains unknown.
Here’s the strange thing. In non-mitotic cells, the host cell rarely if ever divides (thus is “non-mitotic”), but its mitochondria lead their own lives and fuse, fission (break into smaller fragments), replicate their mtDNA, etc under their own control. As we age, all of our mitochondria are damaged by oxygen free radicals (compounds with unpaired electrons), but the mitochondria of non-mitotic cells are more energetic (thus use more oxygen) and suffer greater free radical damage. These phenomena have yielded the “oxygen free radical theory of aging”, which has some experimental support but remains controversial. This hypothesis arose from the finding that older organisms have more free radical mitochondrial damage and impairment than younger organisms.
So what about Corona virus? Turns out that Corona virus messenger RNA (mRNA; used to make viral proteins) and some Corona virus proteins themselves target mitochondria of host cells (viruses have no mitochondria) and, among other problems, appear to cause release of mtDNA into the cell. mtDNA release is one of several factors known to activate inflammasomes, cell components that lead to synthesis and secretion of cytokines. These are powerful chemicals used in the inflammatory response that may underlie the “cytokine storm” believed to cause multiple organ failure and death in some persons infected with Corona virus.
Even if the person with Corona virus infection has only mild-moderate symptoms, the mitochondrial damage resulting from Corona virus infection may set the stage for earlier appearance of aging deficits, which can include muscle atrophy and weakness (“sarcopenia”), or heart failure, or degeneration of neurons (Alzheimer’s disease, Parkinson’s disease and others).
Thus, it may not be a good idea to acquire ANY Corona virus infection, even if the symptoms over the first few weeks are mild. According to the hypothesis stated earlier, Corona virus infections, even mild ones, may damage mitochondria enough so that aging deficits appear prematurely. So far, even with only a few months of observation, some persons who have recovered from Corona virus infections remain weak in their muscles, or in heart failure, or cognitively impaired. Are these persons the “tip of the iceberg” of Corona virus-induced mitochondrial damage?
We are presently engaged in a world-wide experiment to define the long-term consequences of Corona virus infection. It may take several decades before we know whether infections with Corona virus cause the survivors to age prematurely. But based on what we already know, it seems prudent to work harder to eliminate any Corona virus infection, especially in young people.