Almost everyone wants to live longer lives. But our lifespans are biologically capped at the cellular level. Our cells can only replicate a certain number of times until they are no longer able to. And the key factor that decides how many times a cell can divide is telomere length.
Table of Contents
- 1 What is a Telomere & Telomere Length?
- 2 How Cell Divisions Cause Shortened Telomeres
- 3 Cell Senescence – A Result of Shortened Telomeres
- 4 Slowing or Reversing Telomere Shortening for Life Extension
- 4.1 What Increases the Rate of Telomere Shortening?
- 4.2 What Slows Down Telomere Shortening?
- 4.3 What Makes Telomeres Grow Longer?
- 5 Related Links
What is a Telomere & Telomere Length?
But wait, what’s a telomere? What about a Telomere’s Length?
The telomeres are basically the gatekeeper to our DNA. Telomeres act as the end caps of a chromosome that protect the chromosome’s genetic contents from deteriorating, being lost, or fusing with adjacent chromosomes.
The length of a telomere decides how easily chromosome DNA is likely to become corrupted. That means chromosome mutations are in higher likelihood with shorter telomeres. A higher rate of mutations means a higher risk of acquiring cancer.
In human beings, the chromosome’s telomere sequence is TTAGGG.
In human beings, the average telomere length is 11 kilobases at birth. But when a human approaches seniority, the average telomere length decreases to less than 4 kilobases, with the decline being greater in men than in women.
The drastic decline in telomere length causes cells to eventually stop dividing and possibly lose their function, which helps explain why older people become weaker, are more susceptible to illnesses, as well as have increased cancer risk. Their body cells no longer work as efficiently as they used to. But why do telomeres become shorter in the first place?
How Cell Divisions Cause Shortened Telomeres
The Consequence of Many Cell Divisions and Shortened Telomeres
When chromosomes are replicated by certain enzymes, these enzymes do not duplicate all the way to the end of the chromosome. The result is that the end of the chromosome is shortened. So as your cells keep replicating to replace the dead & old ones, your chromosome telomeres become smaller and smaller, and become more vulnerable to defects, fusion, and genetic mutations. Each time a cell divides, as much as 25 to 200 base pairs may be lost from the ends.
After there are too many cell divisions, the cell’s chromosome’s telomeres shorten to a point where the cell either mutates into a cancer cell, or the cell become “senescent”- meaning that the cell stops dividing entirely.
Cell Senescence – A Result of Shortened Telomeres
What is Cell Senescence?
Cell senescence is a phenomenon where the cell stops dividing entirely, reaching what is known as “replicative senescence” or the “Hayflick Limit”. Hayflick found that cells stop dividing after a certain number of cell divisions, and that only cancer cells keep dividing without an observable limit. The anatomist Leonard Hayflick believes that his Hayflick Limit concept explains why human beings age, and explains aging at the cellular level.
This is Professor Leonard Hayflick, who discovered that “normal” human cells have a cell division limit.
Replicative senescence may be triggered when a cell’s telomeres have become too short. Another way that replicative cell senescence is triggers is through DNA damage. DNA can be damaged from the increased gene vulnerability from shortened telomeres, exposure to elevated levels of reactive oxygen species, the activation of oncogenes (a.k.a. “cancer genes”), and/or cell to cell fusion.
Purpose of Cell Senescence
One may interpret that the purpose of halting cell division is a safety measure that senescent cells takes to prevent themselves from accumulating more mutational genetic defects and thereby becoming cancerous. Specifically, senescent cells produce cytokines and other signaling chemicals that stop its growth:
Although a universal marker that is solely expressed in senescent cells has not been identified, most senescent cells seem to express p16Ink4a, a cyclin-dependent kinase inhibitor and tumour suppressor that enforces growth arrest by activating Rb [retinoblastoma protein]. Additionally, the expression of p16Ink4a is known to increase with ageing in several rodent and human tissues.
And although senescent cells do not replicate, they remain metabolically active. They do not die right away. So what normally happens is that the number of senescent cells in our body tissues rise with aging. Especially so given that our cells have experienced more number of divisions the older we get, meaning that there are high number of cells with shortened telomeres.
Cell Senescence Plays a Part in Aging
But the accumulation of senescent cells eventually starts to become a problem. These non-replicative cells no longer function normally and cannot efficiently play their roles in the body. They are a bit like the rust that starts to appear on a steel structure. Although the rust is still a part of the steel, they lose their functional strength and make the steel structure weaker than before. Likewise, senescent cells are the weak link in our body that puts the integrity of our health in danger.
Specifically, the accumulation of senescent cells in our body leads to many age-related diseases, such as type 2 diabetes & atherosclerosis. That’s because the senescent beta cells in the pancreas do not produce insulin, and senescent blood vessel cells are no longer as elastic as they used to be- deteriorating, growing bigger, and thickenings to cause atherosclerosis & atherosclerosis plaques.
Another consequence for the existence of senescent cells is that they secrete pro-inflammatory chemicals which adds up the level of chronic systemic inflammation present in the body. Chronic systemic inflammation is associated with further telomere deterioration.
The interesting thing is that the elimination of senescent cells leads to a delay and some reversal of age-related physiological disorders. For example, scientists have observed that killing off the senescent cells in a mouse progeroid model (progeroid refers to genetic disorders that mimic aging) in vivo can delay age-related tissue dysfunction, including cataract formation, lipodystrophy, and lordokyphosis. Other tissues, such as adipose tissue, skeletal muscle and eye, also show delays in age-related pathologies.
By delaying age-related pathologies through the clearance of senescent cells, you can conclude that cell senescence has a significant role in aging. So by reducing the senescent cell presence, you may be able to achieve some level of life extension and reduced symptoms of aging. One method is to induce apoptosis to those senescent cells. Another method would have to be figuring out ways to lengthen a chromosome’s telomeres- or at least slow down the rate at which telomeres shorten.
Slowing or Reversing Telomere Shortening for Life Extension
The length of our telomeres play a significant part in our aging. The rate at which telomeres shorten may indicate a person’s rate of aging.
If we can slow down, stop, or even reverse the shortening of our chromosome’s telomeres, it may be possible to extend our projected range of expected life.
So we need to identify 3 things. What speeds up the shortening of telomeres. What slows or stops telomere shortening. And what lengthens our telomeres. Perhaps its really 2 things, because if you can figure out what speeds up telomere shortening, then you can put in measures to actively avoid it, and thereby slow down telomere shortening.
Anyways, let’s dive into what speeds up telomere shortening.
What Increases the Rate of Telomere Shortening?
So the question is, what speeds up the rate at which telomeres become shorter? If we can answer this question, and figure out the factors that shorten telomere length quicker, then by avoiding those factors we may be able to achieve some level of life-extension.
Oxidative Stress & Free Radicals Shorten Telomeres
Well, let’s first consider that one factor that speeds up the shortening of telomeres is free radical exposure. Free radicals can cause damage to cellular DNA, thereby leading to senescence and apoptosis (programmed cell death) in cells.
Remember that oxidative stress means the stress that results from an aerobic metabolism (aerobic respiration) that produces free radicals from use of oxygen molecules. For example, the electron transport chain that is responsible for transferring electrons can leak electrons to oxygen molecules, generating superoxide free radicals and other free radicals that can lead to cellular damage from those free radical species reacting with neighboring cells.
Oxidative stress is also a result of inflammation, where white blood cells release free radical species to destroy foreign invaders.
How Oxidative Stress Damages Telomeres & DNA
In the case of telomeres, they are highly sensitive & easily damaged by oxidative stress due to telomeres having a high makeup of guanine nucleobases. Guanine has a high oxidation potential compared to other nucleobases. Additionally, damage to a cell’s nucleobases accumulates overtime, which contributes significantly to cellular dysfunction, mutations, and senescence.
Furthermore, oxygen free radicals (especially hydroxyl radicals like HO•) produce single-strand breaks in DNA. Although genomic DNA has repair mechanisms for single strand breaks, telomere DNA is observed by scientists not have any single strand break repair mechanisms. Furthermore, repairing lesions on the telomere DNA caused by Reactive Oxygen Species is inefficient compared to the rest of the genome.
Free Radicals shorten Telomeres by increasing Cell division.
So what’s a possible reason why increased free radical exposure leads to shorter telomeres? Well, consider that free radicals speeds up the rate at which cells are lost in the body. Which means that the remaining cells that survive are encouraged to replicate faster to replace the lost cells. And because telomeres are slightly shortened every time a somatic cell divides, increasing the rate of cell divisions increases the rate at which telomeres become smaller.
So we have established that generally anything that increases oxidative stress increases the rate at which telomeres are shortened on our chromosomes. For example, this includes high levels of psychological stress, smoking tobacco (and inhaling smoke in general), exposure to harsh sunlight, obesity, a sedentary lifestyle, and sleep deprivation.
You’ll notice that people who experience high levels of stress, or who suffer PTSD, can show signs of aging faster. Like developing more wrinkles & having their hair graying prematurely.
Additionally, chronic stress and high cortisol exposure decreases the body’s supply of telomerase, which is an enzyme that can re-lengthen telomeres.
Generally speaking, chronic psychological stress speeds up the rate at which a person’s telomeres are shortened by increasing the level of persistent inflammation in the person and thereby increasing oxidative stress. Oxidative stress damages cells, and increases the demand of cell replication to replace lost cells.
The body can recover from acute bouts of stress. But chronic stress causes the damage to the body cells to accumulate, and thereby having a much more significant effect on shortening a cell chromosome’s telomeres.
To counteract a person’s response to stress, one may exercise regularly. Exercising regularly causes the body to respond weaker to stressors. Whereas a sedentary person’s body responds much more strongly to stressors.
For sunlight, you’ll notice that a person’s skin ages faster when exposed to lots of harsh sunlight. This is especially true for Caucasians who do not tan as easily, as tanning is actually a protective mechanism in our skin- where the amount of a dark pigment called melanin increases in the skin as a means to protect against free radical damage by blocking UV rays.
That’s why you’ll notice that African Americans have darker skin tones as an adaptive measure to protect against high sunlight exposure. Whereas Caucasians have lighter skin tones because they are exposed to lower levels of sunlight.
One thing you should keep in mind is not to expose yourself to the sun during the zenith of the sun and a little while before & after. This is the time period when the sunlight is at its harshest, and has the highest probability to damage our skin cell’s DNA.
Of course, I’m not saying not to expose yourself to the sun at all. We do need some level of UVB sunlight exposure on our skin in order to manufacturer vitamin D.
In fact, having sufficient levels of Vitamin D in the body lowers the level of chronic systemic inflammation, reducing oxidative stress and thereby slowing the rate at which telomeres are shortened.
So what does obesity have to do with oxidative stress? At a glance, obesity is a major cause of morbidity & mortality. Obesity causes metabolic syndrome, diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer.
So as you can see, obesity isn’t only a matter of having too much energy reserves in the form of adipose tissue. Adipose tissue also acts like an active endocrine (hormone secreting) organ, releasing its own cell signaling molecules known as “adipokines” or “adipocytokines”. The problem is that when there are too many of these adipokine molecules present in the body, it results in a low grade chronic inflammation that increases the amount of oxidative stress the body experiences. Generally speaking, the increase in oxidative stress doesn’t disappear until the adipose tissue producing the extra adipokines disappears. Meaning the increase in oxidative stress is permanent until the person looses the extra body fat that makes him obese in the first place.
What Slows Down Telomere Shortening?
Slowing down the rate at which telomeres shorten is one way to possibly achieve life extension.
An interesting way to extend lifespan is through eating less or by restricting the number of calories that you eat. This has a 2 fold effect. First, metabolism may be slowed to some extent, such that the rate of cell division is lowered. Fewer cell divisions means that telomeres are shortened at a slower pace.
The other effect of caloric restriction is that the amount of adipose tissue or fat in the body decreases. Less fat means that there are less inflammatory cytokines released by the adipose tissue (adipokines). On the other hand, an obese person has too much adipose tissue, and subsequently higher levels of inflammatory adipokines.
Having more adipokines is inflammatory because it tells the immune system to be over-activated, leading to white blood cells releasing more free radicals to kill foreign invaders and pathogens (that may not necessarily be there). So simply reducing the amount of adipose tissue you have through fasting or caloric restriction is one way to solve this problem.
Excess free radical exposure is a problem, because it causes cells and cell DNA to be damaged more frequently. Damaging cell and their DNA is one way to induce apoptosis or programmed cell death as a safety mechanism for reducing cancer risk and for getting rid of non-functional cells. So increasing the rate at which cells are damaged requires a higher level of cell divisions from healthy cells to replace them. Thereby the rate at which telomeres are shortened is increased.
So we now understand that exposure to free radicals, or Reactive Oxygen Species (ROS), is something that can lead to shorter telomeres in our cell’s chromosomes. One way to reduce this negative effect of ROS exposure is by lowering the level of systemic chronic inflammation that may present in the body. Another way to reduce the negative effects of ROS exposure is by preventing ROS from reacting with our cellular machinery with free radical scavengers- also known as antioxidants.
Antioxidants are molecules that defend us from oxidative stress toxicity by preventing the oxidation of other molecules that make up our cells. Oxidation is a chemical reaction that produces free radicals as by products. Free radicals are atoms, molecules, or ions that have unpaired valence electrons. Because these electrons are unpaired and want to reach a balanced state, free radicals are highly chemically reactive.
Free radicals left to its own devices lead to chain reactions that may damage cells by reacting with them. Antioxidants such as thiols, vitamin C & E stop ROS chain reactions by acting as its electron acceptor to react with- thereby preventing the ROS from reacting with anything else.
For example, researchers tested the theory that antioxidants protect telomeres by supplementing birds, specifically the Wild Blue Tits (Cyanistes caeruleus) with antioxidants. Normally is observed that birds experience higher levels of oxidative stress during reproduction. The effects of oxidative stress are shown on the bird’s telomeres by them shortening faster during the bird’s reproductive phase.
So in this study, what the researchers found was that supplementing antioxidants, specifically Vitamin E and Methionine, caused the Wild Blue Tit birds to experience reduced telomere loss compared to the control, in addition to a healthy increase in body mass and higher fledgling success.
What Makes Telomeres Grow Longer?
Finally, another option for life extension from the cellular level is to bring the length of the telomeres back to normal.
One way that the body replenishes itself with long-telomere cells is through the introduction of stem cells to different parts of the body. Another way is by literally growing the telomere back from its shortened state with the help of an enzyme called telomerase.
Telomerase – The Enzyme that Lengthen Cell LifeThere is a mechanism that exists in some cells for growing back the length of chromosome telomeres and thereby extending the cell’s lifespan. Specifically, there is an enzyme called “telomerase” (a.k.a. Telomerase Reverse Transcriptase) that reverses telomere shortening by adding back the TTAGGG genetic sequences to the telomere.
But the cell life-extending telomerase enzyme isn’t available ubiquitously. Telomerase can be found present in the germline, hematopoietic cells, stem cells, and some other rapidly dividing cells. But telomerase presence is extremely low or absent in most normal somatic cells. That means that most of the cells in our body do not utilize telomerase; meaning that the telomeres of somatic cells progressively become shorter.
Telomerase & Cancer
Usually, when a somatic cell’s telomeres becomes too short, they either undergo apoptosis (programmed cell death) or senescence (stalling of cell division). But when the signals for apoptosis and senescence are absent, the somatic cell continues to divide. This leads to extremely shortened telomeres and increased genomic instability.
If the cell continues to survive with extremely short telomeres, then the cell experiences an activation of a telomere maintenance mechanism (either ALT or telomerase). But the risk is that the cell may become cancerous. You’ll notice that cancer cells have very short but stable telomeres, because they were once somatic cells that divided way too many times. And their telomeres are stabilized by ALT or telomerase.
So this leads to me to my next point; there are other cells that activate telomerase to maintain telomere length, namely cancer and immortalized cells. However, there is another group of cancer/immortalized cells that lack the telomerase enzyme, so they maintain telomere length through a different mechanism that involves genetic recombination- specifically the genes from one telomere is copied to another telomere. This is known as Alternative Lengthening of Telomeres (ALT) through homologous recombination.
So that means another method that can be investigated by scientists for extending cell-life through telomere extension is ALT.
Note that telomerase acts both as a risk factor and a preventative for cancer. I already mentioned that telomerase is what allows cancer cells to replicate indefinitely. But telomerase is a preventative for cancer by helping to prevent the telomeres from becoming so short that their genome becomes unstable and prone to cancerous mutations.
The Absence of Telomerase
When scientists engineered mice to completely lack the telomerase enzyme, their telomeres progressively shorten over several generations. The scientists observed that these mice aged at a faster rate than normal mice — the telomerase-absent mice were barely fertile and suffer from age-related conditions such as osteoporosis, diabetes and neurodegeneration. And they also died young. According to these observations, one may conclude that telomerase is a key player in extending the life of our cells- and thereby our own lives.
Some scientists hypothesize that activating telomerase is a way to reverse aging in mammals and other organisms.
Lowering Stress & Inflammation Improve Telomere Length…
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- Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders [Nature]
- Oxidative Stress, Oxygen Free Radicals and Telomere Shortening. A Biomarker of Ageing Determined by Environmental and Genetic Factors [ResearchGate]
- Ageing and reproduction: antioxidant supplementation alleviates telomere loss in wild birds. [J Evol Biol.]
- Telomeres, lifestyle, cancer, and aging [Curr Opin Clin Nutr Metab Care]
- Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice [Nature]