In a couple of my previous entries, I’ve talked about how inflammation damages tissues and how chronic inflammation becomes more common with age. I would have liked to go into more details then, but that would have involved discussing the mechanisms of aging. So today, let’s talk about just that. In theory, aging in humans happens for the same reason aging happens in everything else; for any complex system (including our bodies), there are only a few arrangements of the pieces that produce a working mechanism and a near infinite number that produce a non-working mechanism. Given enough time and the ability to change, any system will see its pieces changed in such a way as to render the mechanism inoperable. But living organisms are “designed” to repair damage to their systems and to maintain themselves in a particular arrangement, so the answer has to be more complicated than just “it’s easier to break things than to fix them.” So at the risk of being insensitive, please allow someone in their mid-twenties to lecture you about getting older.
The Theories
As a reminder, the word ‘theories’ in this context does not mean that what I discuss here is unproven. A scientific theory is an explanation of how something works that can be either proven or unproven. While the theories I discuss today are hotly studied in order to determine which mechanisms of aging are most important and which aging-related illnesses are most affected by which mechanisms, all of these theories are understood to be proven causes of aging.
Telomeres and Cellular Senescence
An organism’s genetic material is divided into chromosomes, long strands of DNA writing out genetic information all wrapped around proteins to provide structure. The number of chromosomes an organism has varies depending on species, but humans have 23 pairs of chromosomes (one from each parent). Every time a cell divides, each chromosome has to be copied. But due to the structure of eukaryotic chromosomes and how DNA replication works, a few nucleotides at the end of the chromosome don’t get copied, meaning that both daughter cells have slightly shorter chromosomes than its parent cell. To prevent each replication stripping away your chromosomes until daughter cells are produced missing important genetic information, eukaryotic chromosomes have telomeres, a stretch of nucleotides on the end of each chromosome which don’t code for anything but instead are a burnable buffer for the cell. When the cell divides, the telomere gets shortened instead of something important.
The downside to this is that each cell has a limited number of times it can replicate before its telomeres are too worn down. For humans, this means that once a cell has exited its fetal stage, it can only divide 40 to 60 times before their telomeres are too worn down to continue. Once all the cells in one’s body have worn down their telomeres, cells can’t replicate or be replaced, injuries can’t be repaired, and small tissue damages lead to certain degenerative diseases.
Not all cells in the body are limited like this. Certain cells, such as those of the bone marrow, digestive tract, skin, and hair follicles, express a protein called telomerase that adds more nucleotides to the telomeres. These cells can functionally reproduce indefinitely, which is why these tissues grow so quickly. So why don’t all of our cells express telomerase? Well, these tissues that express telomerase are also the tissues most prone to becoming cancerous. Telomeres act as a curb for continuous cell replication, meaning that any precancerous cells must mutate to continuously express telomerase in order to become cancerous. Cells that already produce telomerase have one less obstacle to becoming cancerous.
Once a cell’s telomeres have been worn down and the cell can no longer replicate, it enters a state called cellular senescence. The cell stops replicating, shuts down several other systems, and begins secreting cytokines which promote inflammation and attract immune cells. Cellular senescence occurs in cells that experience DNA damage or high stress environments, not just those with worn down telomeres, because it gives these cell time to repair DNA damage, attracts immune cells to the site of injuries, and flags these cells for destruction by immune cells if the damage can’t be repaired. Senescent cells serve a few purposes, specifically cancer prevention and wound healing, but only when there are few senescent cells that are promptly removed. Since all cells wear down their telomeres as one gets older, the number of senescent cells in their body builds up over time. As one ages, cells become senescent faster than the immune system can clear them out. These cells don’t perform necessary functions as well and the cytokines they produce lead to chronic inflammation which damages tissue with mechanical strain. Diseases linked to a buildup of senescent cells include osteoporosis, cardiovascular disease, Alzheimer’s disease, arthritis, and declines in eyesight and mobility. Ironically, the stresses caused by this chronic inflammation makes DNA damage far more common, which makes cancer more common.
Oxidative Stress
I used the word ‘stress’ a couple of times in that last paragraph, so let’s define it a bit more succinctly. This might come as a surprise, but oxygen is actually a really toxic substance. It is one of the most reactive elements on the periodic table, meaning oxygen atoms are very good at strongly attaching themselves to other atoms, which releases energy and rips apart whatever molecules those atoms had been attached to first. Oxygen is the reason we have rust and fire; oxygen atoms are ripping apart metal (rust) or hydrocarbons (fire) so they can bind to what they ripped off. This reactivity makes oxygen really useful at breaking apart large molecules like sugar to produce energy, which is why we breathe the stuff. But organisms that use oxygen or live around it require defenses against oxygen poisoning.
Fun fact; the largest extinction event in Earth’s history in terms of the total amount of Earth’s biosphere killed was the Great Oxygen Catastrophe roughly 2.4 billion years ago. This was very early in Earth’s history. Earth itself is about 4.5 billion years old while the first macroscopic organisms (ones you could see with the naked eye) emerged 600 million years ago, so the only life on Earth at the time were prokaryotes like bacteria. The leading theory is that some of these bacteria evolved to photosynthesize, using sunlight to generate energy but producing oxygen as a waste product. This was the beginning of oxygen on our planet which would make multicellular life possible, but first it would kill approximately 80% of all life because it wasn’t adapted to deal with oxygen.
The defense the survivors evolved was antioxidants. When oxygen reacts with molecules that it shouldn’t, these molecules turn into free radicals, highly reactive molecules that can damage other molecules. To defend against this, cells produce antioxidant chemicals that prevent the formation of free radicals, antioxidants such as NAD+ and FAD+. But these antioxidants aren’t perfect, so a few free radicals make it through the cracks and damage proteins or DNA. Stressful situations or environments (injuries, inflammation, etc) can also accelerate the production of free radicals because the body responds to stress by increasing its metabolic rate (which draws in more oxygen) and shutting down the mechanisms that produce antioxidants to conserve energy. Over time, this damage builds up until it begins to compromise the body’s functioning.
How exactly free radicals cause aging is a bit more complicated with several mechanisms whose relative importance are subjects of debate. One theory is that the primary avenue of damage is the destruction of the mitochondria. Mitochondria are organelles in the cell where oxygen is reacted with glucose and the resulting energy is captured for use by the cell. Since oxygen reactions occur inside the mitochondria, they are very prone to free radical damage. Additionally, losing mitochondria puts more stress on the remaining mitochondria, causing a feedback loop. Diseases linked to mitochondria damage include diabetes, heart disease, Alzheimers, and Parkinsons. Another theory is that proteins, sugars, and DNA damaged by free radicals can become stuck together by what’s called cross linkages. Damaged or dysfunctional proteins would normally be broken down and recycled by the cell, but cross-linked proteins can’t be broken down by the cell’s normal process. The buildup of these undisposable cross-linked molecules inhibits other cellular functions. Cross-linkages are linked to cataracts, kidney disease, hardening of blood vessels, and wrinkling of the skin. And of course, free radicals can damage the DNA directly to cause mutations that can lead to cancer or cellular senescence. Again, all of these theories are known to be factually true, the question is which ones are more responsible for aging for any given person.
DNA Methylation
This is perhaps the newest theory of aging, emerging in the past two decades along with the study of epigenetics. Epigenetics is the study of a particular mechanism of gene regulation. The mechanism is a tad complicated, but the short version is that DNA can be modified by adding molecules called methyl groups to the nucleotides. This modification serves a few purposes such as with DNA replication and repair, but there are regions of the genome that when fully methylated will allow proteins to attach to the chromosome and prevent nearby genes being transcribed. In essence, these genes are turned off for the long-term, to the point that epigenetic tags can last for a cell’s whole life or be passed down to daughter cells. Perhaps the biggest role they play for multicellular life is in differentiating cells. Every cell in your body contains the genes to function as every type of cell in your body; your blood cells have the genes to become nerve cells and vice versa. But once an undifferentiated cell becomes a particular cell type, all the genes it won’t need are permanently disabled with epigenetic tags.
Epigenetics is a rather new field with a lot of relevance for disease and development that scientists are just beginning to get the full scope of. But the relevant part here is how the epigenome changes over time. When DNA is damaged and repaired, there is some chance that epigenetic markers will be moved. Given enough time, the carefully calibrated regulation of active and inactive genes becomes unregulated; genes important to the tissue’s functioning are switched off while genes that would be disruptive for said tissue are switched on, making the tissue less functional overall. The role of epigenetics in aging is still being studied, but the link is so strong that scientists can accurately determine a random patient’s age, give or take 2.5 years, just by looking at whether 353 particular epigenetic markers are in the right place or not.
This is by no means a comprehensive list of the mechanisms that cause aging. There are theories regarding hormonal changes and direct DNA damage as well as a few genes that appear to have a direct impact on one’s speed of aging. And all these theories connect and feed off each other. Free radicals can damage and shorten telomeres as well as cause the DNA damage that shifts epigenetic tags. The chronic inflammation caused by a buildup of senescent cells puts stress on tissue which creates free radicals. Tissues made less functional by epigenetic dysregulation are less able to repair free radical damage. All these systems are interconnected in ways that once one becomes weakened, additional stress is put on the others until they’re weakened as well. For systems as complex as human physiology, it’s debatable if anything can truly have one cause.
What We Can Do About It
Fortunately, understanding these mechanisms means we now have targets for therapeutic intervention. Drugs and treatments are in development which selectively kill senescent cells or suppress their disease-causing traits. Ways to deliver telomerase to cells are being tested which could hopefully regenerate telomeres without removing the safeguard against cancer they provide. The scientists who developed the test for epigenetic age also identified three genes which when activated reset a cell’s epigenome to its younger state (mechanism unknown). Ways to deliver additional NAD+ antioxidants to cells to prevent free radical damage have also been tested. All of these drugs and therapies have been tested in mice and shown incredible promise.
So will these new therapies deliver us to an age of human immortality? Maybe. Figuring out what side effects these therapies will have and how to counteract them will be the next step before human testing can begin. And in order to have true immortality, we will need to develop a universal cure for cancer since that is what kills you if nothing else does. Besides, the goal of this research for now is to extend a person’s healthspan, meaning the portion of their life where they are healthy. This in and of itself would be huge, eliminating a lot of suffering. What happens as this technology is developed even further should be exciting to see.
I would like to thank Dr. Vikas Chandhoke, who’s Bio 426 course was where I started learning this information.
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