Aging is a series of processes in which the body’s ability to perform functions gradually decreases. The Hallmarks of Aging includes such things as an increase in senescent cells and a decrease in stem cells, but decreasing NAD+ and increasing free radicals matter as well. This article covers a few root causes of aging and their total impact on humanity.
One root cause of aging is senescent cells. These are aged or damaged cells that normally would initiate the self-destruct sequence known as apoptosis to dispose of themselves, but, for some reason, they evade this process and stay alive in the body.
Normally, the immune system would dispose of these cells as part of apoptosis, but, as we age, this also slows down, and more and more senescent cells build up, causing chronic inflammation due to the harmful signals they send out.
Senescent cells do not support the tissues of which they are part; worse than that, senescent cells can also cause nearby healthy cells to also become senescent from the same harmful signals they produce.
One cause of cellular senescence is oxidative stress, which is the buildup of oxygen-containing molecules activating a protein called p53 . Another cause comes from mitogenic signals, which are sent during mitosis (cell division) . Cells can also become senescent for a variety of other reasons, many of which relate to aging.
Senescent cells are linked to the development of many aging-related diseases, including cancer, osteoarthritis, and heart disease. So, if we would get rid of them, we might then be able to reduce the amount of people who get these diseases.
Senescent cells have been a hot topic in the news in recent years, and there are many therapies in development to get rid of them, some of which are currently undergoing human trials. If the results of human trials are similar to mouse trials, this could revolutionize how we think about and treat aging.
One more root cause of aging is mitochondrial dysfunction, which is caused by free radicals, also known as reactive oxygen species. They’re molecules that lack an electron to complete their shells. They steal an electron from another molecule’s shell, and the cycle repeats. They cause oxidative stress, which can damage the mitochondria and induce cellular senescence.
The mitochondria are basically miniature power plants that live in every cell and use the nutrition we eat and drink and convert it into a type of universal cellular energy known as Adenosine triphosphate (ATP). Unfortunately just like real power plants the mitochondria produce pollution, in this case free radicals. These molecules bounce around the inside of the cell and can strike the mitochondrial DNA, which is outside the protective cell nucleus, and damage it which leads to dysfunction or cellular senescence.
There have been past attempts to try to fix this problem, and it was once thought that antioxidants were the solution. Antioxidants are molecules that have one extra electron to complete the free radical’s shell. They can come from foods such as oranges, blueberries, vegetables and high coca chocolate. However, you’d have to eat too many of these foods to get enough antioxidants to get rid of all of your free radicals, so this solution ends up being futile.
In biology, nothing works in isolation, and the old idea that antioxidants are good and oxidants are bad is outdated. The body needs a certain amount of oxidants to function and cells maintain a careful balance of antioxidants and oxidants; any major shift in that balance can lead to problems.
Some people also use antioxidant dietary supplements, but this is a minefield of knowing where to source pure products, which ones to use, and how much. Unless you have a lot of diagnostic equipment and can monitor your biomarkers and carefully adjust your dosage to maintain balance, this is once again a futile approach, as you’re taking these supplements’ effectiveness on faith rather than using the scientific method.
Fortunately, there are more robust solutions in development. The SENS Research Foundation in Mountain View, California is developing a therapy known as MitoSENS, which aims to remove the problem of damage to the mitochondrial DNA by free radicals by creating backup copies of the mitochondrial DNA inside the cell nucleus, where it will be safe from harm. Nature has already started doing this, as evolution has moved around 1000 mitochondrial genes into the nucleus so far; now, there are only 13 mitochondrial genes left outside to move over. The SENS Research Foundation has already succeeded in doing this with two mitochondrial genes and are very close to another two being done. If successful, this would mean that our mitochondria would basically be immune to the free radicals that they produce during energy production.
Stem cell exhaustion
Another root cause of aging is stem cell exhaustion. Stem cells can be likened to cellular factories, replicating themselves to create a constant supply of fresh, young cells. One of these types is tissue-resident stem cells, which are specific to a type of tissue and only create the cells that its particular tissue or organ needs. We are born with a “pool” of stem cells which, over time, begins to decline and, in some tissues, run out completely. Stem cell losses happen due to damage and even replicative senescence when their telomeres wear out. This exhaustion of the stem cell supply is thought to be another reason why we age. .
Early stem cell studies used embryonic stem cells, but these come with ethical concerns. This is because they are derived from human embryos, which are formed during pregnancy. This means that they’re potential babies, and doing research on them would involve destroying them. Embryonic stem cells are undifferentiated, meaning that they can turn into any other type of cell, making them very useful for scientific studies.
Fortunately there is a solution to the ethical issue, which is to use induced pluripotent stem cells (iPSCs). These are adult cells that have been epigenetically reprogrammed with four factors (Oct4, Sox2, Klf4, and c-Myc – also known as OSKM) in order to become like embryonic stem cells, meaning that we can do research on them without raising ethical questions. OSKM is often referred to as the Yamanaka factors after the scientist who first demonstrated that iPSCs were possible .
There are many potential uses for iPSCs, including replacing losses of stem cells in the hypothalamus, a part of the brain that regulates hormones, metabolism, and aging. Over time, these losses to the pool of hypothalamic stem cells cause our bodies to lose control of metabolism, hormone release and regulation, and our ability to regulate our body temperature effectively. Dr. Dongsheng Cai has also shown the connection that this small part of the brain has over development and aging via hormone secretion and the exosomes secreted by the tissue-resident stem cells there .
The thymus, additionally, loses its originally large pool of thymic stem cells, which decreases and erodes as we age which leads to immunosenescence. This is a result of stem cell exhaustion.
The solution to stem cell losses is to periodically top up the stem cell pool in the various tissues to ensure that the supply of fresh cells does not run out. Fortunately, since the early days of iPSCs, we have now become ever-more skilled at creating different cell types on demand using reprogramming, and it is not hard to see a time in the near future when we can potentially replace most if not all of the cells in our bodies.
Telomere attrition, another root cause of aging, also leads to cellular senescence. When our cells divide, they copy DNA from chromosome to chromosome. Unfortunately, this process isn’t perfect, and it cuts off a bit of DNA at the ends. We don’t want lose any valuable genetic information, so our bodies have created a solution.
Telomeres are like the aglets on the ends of your shoelaces, except these shoelaces are chromosomes and the aglets are dispensable bits of repeated DNA. With every cell division, they’re cut off a bit more. After about 50-70 cell divisions the telomeres run out and the cell ceases to divide having reached what is known as the Hayflick limit. At this point the cell enters replicative senescence, activates apoptosis and is destroyed.
Normally, this is not a problem, as we want aged and potentially damaged cells to stop dividing and remove themselves from the system, but this becomes a problem when there are no new cells to replace them and the stem cells supplying fresh cells run out. You see, even some stem cells that supply the tissues in the body eventually run out of telomeres and stop producing replacement cells; they can divide many more times than the 50-70 times that normal cells can, but even they have a limit and they also stop dividing, which is the basis of another reason we age: Stem cell exhausion. When there are no replacement cells, it can result in loss of tissue repair and fibrosis.
So you might be thinking: why don’t all cells just keep dividing indefinitely?
The number of times a cell can divide acts as a kind of clock, and it is thought that telomere loss is a protective measure to prevent cancer. Older cells are more likely to be damaged or possibly mutated, so limiting the amount of times that they can replicate before retiring them is possibly a safety measure; it is likely that cancer would happen more often if we did not have this telomere clock in place.
However, it seems that old cells with short telomeres might be rejuvenated. In the late 90s, researchers treated regular aged cells with telomerase, a protein that stem cells produce and that allows them to keep replicating for longer. What they found was that the old cells regained lost telomeres and became functionally like young cells again. This was also demonstrated in mice, and the mice lived longer with no increase of cancer incidence.
Some scientists hope to treat normal old cells in people very briefly with this protein so that their telomeres are lengthed a bit more, keeping the cells alive and healthy for longer. Another possible solution is to replace the stem cell losses so that the supply of replacement cells continues.
Deregulated nutrient sensing is another proposed cause of aging, and this includes decreasing levels of NAD+. This coenzyme is found in every living cell and both supports cellular functions and acts as a signaling molecule. Our NAD+ levels decrease as we get older due to rising chronic age-related inflammation . The result of declining NAD+ levels is a metabolism that doesn’t work as well as it used to, causing the onset of various metabolic conditions, such as diabetes and obesity.
There are currently a number of companies working on ways to increase our NAD+ levels, ranging from dietary supplements to more sophisticated approaches, such as gene therapy. There are also other methods, such as caloric restriction, that increase NAD+ and reverse its decline.
One precursor of NAD+, NMN, has been shown to increase NAD+ production when administered into the drinking water of mice . This is currently being tested in human trials, as researchers hope that the findings in mouse studies could be translated to people.
Aging’s impact on humanity
All of the root causes of aging lead to an enormous total impact. Aging is what causes your body’s performance of various functions, such as of physical activity, to go down. The causes of aging do terrible things to our bodies and end up causing many age-related diseases.
Our lifetime risk of getting dementia after the age of 55 is 1/6 for women and 1/10 for men. This is what happened to my grandfather and what motivated me to want to do something about aging: he had vascular dementia, and I was always curious and confused about what was happening to him.
If you were to make an impact in this field, think about the people who you’d help, the people who might have died due to one of those diseases, but, thanks to you, would survive for decades longer, making their mark on the world. Think about their families as well; age-related diseases affect patients, but they also strongly affect their families and close friends, because they’re the ones dealing with the aftermath of these diseases.
Aging is a difficult problem, but that doesn’t mean that we cannot defeat it. Our generation is the future, and if we don’t step up and do something about it, nobody will. We have the ability to eradicate aging, and if we don’t do it now, the number of people dying from aging-related diseases will increase, and our conditions will worsen.
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