How we age, why it sucks and how can we activate longevity?
Aging sucks. No more affairs, or extreme sports, and on top of that, in the last few decades before you die, you would probably feel how your body slowly shows its weakness, not letting you enjoy every second of life you are left with.
We all want the opposite, right?
But immersing more into aging, we would see another horrible statistic. Dreaming of never coming across hardly treatable diseases, we face the fact, that as we age the likelihood of having been diagnosed with them exponentially increases.
Who or what should be judged?
Nature. It is the cause that is blamed. That we will inevitably follow the same patterns as our ancestors did. We all will slowly become older, facing decreased physical capability and cognitive functioning, increased vulnerability to illnesses, and at the very end death.
But why do we live longer than they do? “Good medicine, a better quality of life”, would be my answer.
But doesn’t it mean, that now humankind is in a state where we can actually fight against drawbacks to extend our healthspan?
I am convinced that so.
Our body is an extremely complex mechanism, where every second occurs metabolic processes; where about 100 billion neurons are each firing messages in the range from 5–50 only per second; where every molecule, cell, tissue, and organ conducts a certain task to maintain the well-being of itself and whole mechanism(organism).
But ones we get older, more and more of these essential mechanism’s parts are becoming “broken”, because of numerous “accomplices of aging” (We will dive into it more after), that inflict big damage on the cellular, molecular, etc. levels and consequently accumulate a deterioration of the health to a lesser or bigger extent.
It is what we call AGING.
As how stated previously aging is NEVER contributing as one single problem in the functioning of our organism. It has its accomplices, such as:
- Senescence
- Lack of STEM cells ==> degradation of regeneration abilities of the body;
- Slowing of metabolism;
- NAD deficiency;
- Reduction in T and B cells production;
- A decline in mitochondrial function;
- Problems with homeostasis ==> Decreased ability to adapt to environmental and internal changes and to regulate the body’s reaction to them;
- Telomeres shortening;
- Epigenetic aging.
And many many more (I didn’t even approach half of the list).
Every human being is composed of cells. (There are approximately 37.2 trillion cells in the body). Cells serve several functions in the body, including providing structure, absorbing nutrients from food, converting these nutrients into energy, and carrying out specialized functions. And most significantly every cell has an essential for vital activity the nucleus, an organelle within a cell that contains the chromosomes. They, in turn, are structures made up of the most vital molecule that is a blueprint for all cellular functions and contributes to the building and maintenance of all living organisms — deoxyribonucleic acid (DNA).
As well as retaining the body’s genetic material, cells are capable of reproducing themselves by dividing.
There are two types of cell division: mitosis and meiosis. Meiosis is about the creation of reproductive cells(egg and sperm cells). Mitosis refers to the process of making brand-new cells in the body. When a cell undergoes mitosis, all of its contents are duplicated and the cell splits to produce two identical daughter cells. Since this process is so critical, certain genes are carefully coordinated to control the steps of mitosis. The failure of mitosis to be properly regulated may lead to health issues such as cancer.
Hence to sum up everything said above, we can create such simplified consistency.
The more cell divides => The more likely that DNA will be damaged.(It happens because of inevitable errors that occur in the proccess of DNA replication during each cell division.)
If the DNA is damaged => The more likelihood of next divisions(mitosis) will be not regulated accurately.
When the certain genes fail in regulation of mitosis => The cell eventually lose their ability to function properly.
When the cell evetually starts to dysfunction => We get more illnesess, start feeling week. In short, we age, with all of aging drawbacks.
Therefore for us to understand how to activate longevity, it’s essential to understand “accomplices of aging” in a cell. I’m here to guide you so I’ll be glad to introduce you to some of them.
Let’s plunge into cellular level! YOOHOO
Here is our test cell. His name is Bob.
When we zoom in Bob, we can see many organelles in there. But don’t get too overwhelmed, I will go into the deepth only of some of them (nuclues, ribosomes and mitochondrions are the most important).
Telomeres shortening
Meet our first “accomplice of aging” — telomeres shortening.
What is telomeres exactly and what role it plays in a cell?
To answer this question we should get back to the DNA and bring up an “end replication problem”.
DNA contains the four different nucleotides: adenine, thymine, cytosine and guanine. The sequence of the nucleotides creates genes, which are responsible for encoding information about specific molecules and proteins, which are necessary for human cells to function. These genes also control the growth and function of the body. As was mentioned before, DNA is orginized within a nucleus as separate linear chromosomes, hence the chromosomes have ends. Here comes an “end replication problem”. DNA in a way as it replicates during each cell division cannot replicate fully, so the proccess is incomplete. We don’t want that the vital gene won’t be replicated, right? Hopefully mother nature cares for us and we have telomeres on the chromosome edges, that appear in a way of repetitive nucleotide sequences [TTAGGG].
So telomeres are structures on the ends of chromosomes, that are essential for preserving the integrity of the genome (all the DNA contained in one cell or “the information repository of an organism” as many defines it) in a way of maintaing the chromosome stability and preventing unwanted DNA damage and end-joining.
And unfortunately again at each cell division, the telomeres shorten because of the incomplete replication of the linear DNA molecules by the conventional DNA polymerases. The limited extent(~50times) to which cell can deivide imposed by the shortening of telomeres with each division is called Hayflick Limit.
Telomere shortening can result in senescence, apoptosis, or oncogenic transformation of somatic cells, affecting a person’s health and life expectancy.
The shorter your telomeres, the older you are, biologically older.
Finally, the most exciting part: How can we prevent telomeric shortening?
My answer will be healthy lifestyle and improved environmental factors. From the side of healthy lifestyle, such factors as lower body max index, tobacco abstinence, a diet high in fruit and vegetables, high physical activity; from the side of environmental factors low stress exposion, social interaction, protection from ultra violet.
As supplements, it’s worth mentioning vitamin B12, folic acid and TA-65.
The importance that play these supplements:
TA-65 is a telomerase activator derived from the extract of the plant Astragalus. TA-65 supplements lengthen critically short telomeres in a telomerase-dependent manner and reduce both senescent and natural killer cells.
Vitamin B12 maintains genomic stability, thereby influencing telomere integrity and cellular aging.
Folic acid is required for the synthesis of deoxythymidine monophosphate (dTMP), which is a nucleotide that is used as monomer in DNA, from deoxyuridine monophosphate (dUMP), so it is important for DNA repair and synthesis.
Both vitamin B12 and folic acid could be found in a certain types of food, or consumed from dietry supplements.
Senescence and why senescent cells exist?
Here comes the other “accomplice of aging” — senescence.
Our cells are pretty good at repairing themselves. And it’s essential for our body since we are often exposed to the damage caused (the chemicals in the environment; sun etc)
But sometimes the cell could be irreparably damaged. And when it happens, it dies in a controlled manner to stop anything bad from occurring to surrounding cells. The cell becomes senescent. This “bad’ is often relates to cancer. So to answer the question of why senescence exists it will be easier to simplify it in such a manner: Senescence serves as a preventive measure against a tumor, by both preventing cancer cell proliferation and suppressing malignant progression when it’s impossible for the cell to successfully repair the damage.
Senescent cell stops dividing.
Can we state that the cell is “dead”? — Nope. These cells in reality turn out to be highly metabolically active, and they still produce senescence-associated secretory phenotype(SASP), that causes inflammation.
The senescent cells can be divided into two categories: short-term (acute), which is associated with positive effects, once they have completed their actions, immune cells are recruited to remove them; long-term (chronic), which is associated with disease, which secrete pro-inflammatory and pro-tumorigenic factors (SASP).
The number of senescent cells in a person’s body increases with age. With the onset of aging, the immune system becomes less efficient, resulting in an accumulation of senescent cells that can taint healthy cells. Hence, cellular senescence has been linked to numerous age-related diseases, such as cancer, diabetes, osteoporosis, cardiovascular diseases, strokes, Alzheimer’s disease and related dementias, as well as osteoarthritis. It has also been linked to declines in eyesight, mobility, and thinking ability.
To delay the appearance of many senescent cells we can recap everything that we mentioned when we talked about telomere shortening. But what we can do when a person already has a lot of them? In such cases, there’re a few strategies we can look at:
Senolytics
If chronic senescent cells are to be eliminated, a compound known as senolytics (small molecules aimed at selectively killing senescent cells) may be used to eliminate their negative effects. Senolytics target key proteins mainly involved in apoptosis, such as Bcl-2, Bcl-XL, p53, p21, PI3K, AKT, FOXO4, and p53.
SASP inhibitors (or senomorphics)
Another strategy to inhibit the functions of senescent cells is through the specific silencing of SASP, the complex mixture of soluble factors such as cytokines, chemokines, growth factors, proteases and angiogenic factors that mediates the high metabolic activity of senescent cells.
Improving immune system function
Immune function plays a fundamental role in eliminating senescent cells, and a decline in immune function is accompanied by an increase in senescent cells, and ultimately, disease. Therefore, a third strategy for targeting senescent cells would be to strengthen the immune system so that it would be capable of recognizing and eliminating these cells with greater efficiency, a process called immunosurveillance.
Decline in mitochondrial function
Let’s get back to Bob’s inners. When we will carefully have a look on a picture shown bellow, we would see the semi-autonomous (means organell has its own DNA which is capable of replicating independently) organelles called mitochondrias.
We all know from school that mitochondria plays essential role in generation of energy and adenosine triphosphate (ATP) synthesis. Besides this, this organnel is involved in amino acid and lipid metabolism and regulation of apoptosis(process of programmed cell death).
Mitochondrial function deteriorates with age. The freqent mutations and oxidative damaged caused by reactive oxygen species (ROS), lead to a descend in the volume, integrity, and functionality of mitochondrial DNA. Because of these factors, mitochondria is becoming dysfunctional, which includes a decrease in oxidative capacity, in antioxidant protection, and in ATP synthesis. With time, the function of cells in general declines causing aging and subsequent death.
How can we keep our mitochondrias in shape then?
Studies have shown that both suppression and stimulation of mitochondrial function can extend lifespan. One way to do this is caloric restriction; in a long run it may improve mitochondrial function, delay mitochondrial aging, and expand longevity.
In a nutshell, it happens so, that caloric restriction activates a few longevity pathways:
- Activation of SIRT1, which is an essential protein, that eventually leads to activation of PGC-1α, a transcription factor involved in mitochondrial respiration and biogenesis.
- Increasing in the activity of a binding protein (4E-BP) that stimulates the translation of genes encoding mitochondrial respiratory components, due to inhibition of the mammalian target of rapamycin (mTOR).
- Activation of NRF2, that is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes and therefore may lengthen lifespan through the reduction of oxidative stress and improving mitochondrial respiration.
Also, exercise training, either alone or in combination with CR, could be effective in preventing mitochondrial aging.
NAD deficiency
Welcome our last accomplice of aging for today — NAD defficiency.
First, let’s embrace the importance of this soo cool coenzyme (an enzyme binds with a coenzyme to catalyze a reaction).
Nicotinamide adenine dinucleotide(NAD) itself plays an essential role in the cell’s metabolic processes (turning nutrients into energy) and regulating some of the cell functions.
And what is more blow minding is that several components operate only thanks to NAD+ presence in the cell (NAD+ is the oxidized form of NAD).
And one of these components is sirtuins. As we already found out, sirtuins can be activated not only by NAD+ but also by caloric restrictions. However, the truth is, exactly NAD+ makes sirtuins function. There are 7 types of sirtuins (SIRT1, SIRT2, and so on), 3 of them are placed in mitochondria, 3 in a nucleus, and 1 in the cytoplasm. Sirtuins are proteins that regulate cellular health, physiological responses to metabolism, and stress. And lack of them can cause a bunch of problems. But we should keep in mind that sirtuins can only function in the presence of NAD+, hence increasing NAD+ levels through various strategies is the best way to enhance the activity of all sirtuins, improve metabolic function and increase longevity.
Over time, we are left with fewer NAD molecules. The other physiologic stressors linked to NAD depletion are excess alcohol consumption, excess UV exposure, sleep deprivation, poor diet, and infection.
How can we get more NAD then?
Unfortunately, NAD is too big to enter our cell, so here comes to rescue:
1. Nicotinamide mononucleotide (NMN)
2. Nicotinamide Riboside (NR)
There are plenty of dietary supplements, that consist of NMN and NR.
Conclusion:
There are a lot of pathways that can activate longevity and in the future, we will discover even more of them.
To recap briefly, aging is damage at a cellular level that leads to the deterioration of body functions. And the few damage build-ups that can be named here as an example are senescent cells; telomeres shortening; decline in mitochondrial function and NAD deficiency.
The broad implementation of other technologies, such as nanotechnologies, that are already used in the medical field, artificial intelligence, synthetic biology, etc. that is combined with the knowledge of the biological side of aging is likely to be highly successful in order to improve our health or eliminate already existing “accomplice of aging”.
It’s undoubtedly impossible to follow the pattern of immortality, and we don’t have to. However, what we can do is work hard on extending our healthspan.
So let’s take aging as a disease that could be treated. And using all of the knowledge of the human body we have, more and more new technologies that develop at a rapid pace of human evolvement we can live up to a hundred, feeling full of energy for the last cool adventure before the definite end.
And even if it is not going to happen, which I’m definitely sure is wrong, we can always remain healthy as long as we can by improved lifestyle, consuming the number of vitamins and minerals our body requires, and just feeling happy, I guess, stress is never a good thing. And all of the mentioned before is completely under our control.
Thank you for reading my first ever article! I would be more than happy to receive any feedback on it. If you have any further questions, feel free to reach out to me by:
Email: 4e4otkakathrine@gmail.com
Or
LinkedIn: https://www.linkedin.com/in/kateryna-chechotka-6a9b00246
Few more resources if you got interested in a field:
