The Nine Hallmarks of Aging

The Reasons You Age and Eventually Die

The Depressing Truth

Since childhood, every single one of us is aware that our time on this planet is running out. The same aging process that we celebrate early in our life with birthdays and parties, will be the cause of our demise in our later life.

And this fact has shaped our entire society and the way we live. For example, when we’re children, the chances of us dying because of age are nonexistent. So, we frolic around with no worries.

As teenagers, we become mature and aware of the approaching end to life, so we study and prepare for our adult life. Yet, death is likely still far, so we still play around and have fun. The same remains true in our twenties. Some of us continue to prepare by going into post-secondary education, or we might get our first job and work diligently, but our carefree spirit remains.

But by our thirties and forties, our concern for death grows much larger. We begin our journey into the later years of our life. Because of this, most settle down and start families. And, for the first time, we start experiencing the side effects of aging. We don’t have the same amount of energy as we did before. Our body starts hurting. Hair starts turning gray.

Our fifties and sixties are very similar, but the side effects get more and more serious. We have even less energy. Our bodies hurt more. Hair completely starts graying. Injuries don’t heal as fast.

By our seventies, we know we’re nearing the end. Many of us retire, no longer having the energy to work the same jobs we did until now. Most develop some kind of problems with their body, ranging from poor eyesight and hearing to dementia, to recurrent heart attacks.

For the average person, the eighties are the end. The disorders and diseases they had developed over the past decades finally take their toll. They’re admitted into hospitals, where they spend the last few days of their life in pain.

For those that are lucky, they move into the nineties and the hundreds. But life is hard now. They can barely walk. Everything hurts. Many are only being kept alive by medicine and machines at the hospitals. Until… even they lose the fight.

Regardless of how depressing this may be, we know it’s true. The clock is ticking, and our time is slowly running out. I’m only a teenager right now, and even I’m aware of this (and it freaks me out!).

But… what if this didn’t have to happen? What if we could live much longer? Or… what if we could live… forever?

What Is Aging? 👴🏽

For something that governs so much of our life, most of us don’t even know what aging is. We know it’s when we get older, but what does that mean? Why are we getting older?

Aging is just a series of processes that incurs direct damage to our body, leads to the accumulation of cellular waste, and causes genetic errors, followed by improper responses to and repairs of these errors.

Ok. That still doesn’t give us a good idea of what aging is. What are these damages? What cellular waste is being accumulated? Why do the genetic errors take place and why does the body respond improperly?

According to scientists, there are nine main hallmarks of aging, or reasons we age. The hallmarks are as follows:
- Genomic Instability
- Telomere Attrition
- Epigenetic Alterations
- Loss of Proteostasis
- Deregulated Nutrient Sensing
- Mitochondrial Dysfunction
- Cellular Senescence
- Stem Cell Exhaustion
- Altered Intercellular Communication

The first four hallmarks are known as the primary hallmarks of aging, since they are responsible for the remaining five hallmarks on the list. So, essentially, they are the causes behind the processes that lead us to age.

To understand aging at a deeper level, let’s explore every one of these hallmarks and how they control our lives.

Why Is The Genome Unstable 🧬?

I mean, that doesn’t sound like something that should happen, right? Our DNA is so important and well-regulated, so how come genomic instability is one of the hallmarks?

Well, despite all of the different processes our cells have developed over eons to protect and maintain our DNA, inefficiencies still exist.

It’s like a car 🚗. I mean, you could obsess over maintaining your car and making sure it’s kept running properly. Getting the oil exchanged perfectly on time, using the best quality of fuel, driving it at a safe speed, and everything else that people recommend. You could treat it as if it’s your child for all I know. Even then… it will break sooner or later. Things will still go wrong, and unfortunately, they’re mostly out of your control.

It’s the same with DNA. Our cells obsess over keeping the DNA safe and making sure no damage takes place. Mutations are fixed as soon as they’re identified. They’re even kept inside the nucleus, away from all the dangers of the cytoplasm. But… despite all of this, there are thousands of attacks on our DNA every single day. From UV radiation from the sun to reactive oxygen species floating around the body, and even the many reactions that go on inside our cell, our DNA is exposed to so many sources of damage. I mean, the DNA experiences tens of thousands of different lesions every day.

The mechanisms in the cell are hard at work to prevent DNA damage from different agents like UV radiation, oxygen species, and enzymes, while DNA repair mechanisms work hard to maintain the integrity of DNA and reverse mutations

Except, our heroic genome repair mechanisms are perfectly trained to edit and repair all of these base-pair mutations. They work tirelessly, trying their best to repair every single mutation as it is detected. But, in some cases, mutations are either never detected, or they can’t be repaired. For example, DNA repair mechanisms usually rely on both strands of DNA to conduct repairs. If only one strand is damaged, they can use the other one as a template and properly repair the mutation. But, if both strands are damaged, the repair mechanisms basically have to play a guessing game, which has essentially the same chances of inflicting lots of damage as leaving the mutation as it is.

It’s in these cases the genome begins becoming unstable. The first few mutations don’t usually do anything. But over time, these mutations can accumulate and really start inflicting damage. For example, if enough mutations do take place in genes known as proto-oncogenes, cells can become cancerous, and divide without control. Now, cancer isn’t the reason behind aging.

Aging takes place when these cells gather so many mutations that they are rendered dysfunctional. At this point, they should die through a self-suicide method known as apoptosis, but many cells avoid this fate and slip into another stage known as cellular senescence (which we’ll go into a bit later). And even for the cells that do commit apoptosis, if there are no cells to replace them, this eventually just leads to degeneration of the tissues and organs they make up. This is the case with neurons, for example, which halt any cellular division since the day they form as neurons, and often don’t get replaced upon death, especially later in life.

If these mutations occur in the DNA of mitochondria (yes, the powerhouses of the cell), on the other hand, it can lead to mitochondrial dysfunction (which is also another one of the hallmarks).

Because genome instability has so many effects on the process of aging, and even in the development of some of the other hallmarks of aging, it is considered the most important primary hallmark.

So What The Hell Is A Telomere?

Put simply, telomeres are just caps on the ends of chromosomes consisting of thousands of repetitions of a specific DNA sequence.

The telomeres (in pink) protect the coding regions of the chromosomes (purple) by acting as protective caps

So why do they matter? Well, they carry out two main functions: protecting coding DNA and keeping track of cellular age.

So how do they protect the DNA? Well first, the building blocks of DNA, also known as nucleotides, are highly reactive and run the risk of bonding to other molecules. To protect against this, the telomere caps are formed at the ends of chromosomes, to prevent the bonding of chromosomes to other chromosomes or cellular elements.

The DNA at the ends of chromosomes is also much more susceptible to mutations through random base-pair mutations. Once again, the noncoding telomere caps also protect the coding regions in the middle of the chromosome by limiting these mutations. Even if mutations do take place in these regions, they have hardly any impact and are much easier to fix because of the repeating sequences.

And lastly, every time a chromosome is copied during the S phase of the cell cycle, the ends of the chromosomes are shortened/cleaved. If this were to happen to a coding region, it would lead to massive amounts of information loss that would eventually lead to complete dysfunction in a cell. The telomere caps, thus, also protect against this by instead sacrificing themselves during replication, preventing loss of coding information.

That’s simple enough. But how do these simple caps at the ends of chromosomes play a role in keeping track of age? It has to do with that shortening of the chromosome every cell division.

In most cells, as these telomeres are cleaved division after division, they are not lengthened to their original length. This means that as a cell goes through more and more divisions, the length of the telomeres continues decreasing until we finally run out of them. When this happens, the cell has to stop dividing to prevent cleaving coding DNA and transform into a senescent cell. In this way, telomeres essentially limit cellular age or the number of cell divisions that can happen.

The problem with this is the fact that, as a person grows older, the number of senescent cells in their bodies increases as more and more cells reach their age division limit. Not only are these senescent cells dysfunctional, but they also inflict damage to surrounding tissues. As such, as more and more senescent cells accumulate, the body is seriously damaged, while the regeneration of the damaged tissues ceases because of the lack of cellular division.

Because of this, older patients might experience organ failures, and severe health issues, which, unfortunately, eventually lead to their demise.

Epigenetic Alterations

Throughout the field of biology, genetics gets all the hype. To be fair, DNA does code for every trait for every cell in the body.

But, if DNA was followed strictly as it is, life as we know it today wouldn’t exist. Multi-cellular organisms like humans would be much much different. You might be wondering… why?

Well, think of it like this. You know of the different types of cells in your body. There’s liver cells, neurons, muscle cells, immune cells, and whatnot. Each of them has a different function, and different characteristics necessary to achieve those functions. But… all of them have the same genetic code. The DNA is the same for every single one of the trillions of cells in our body. So then, why do some cells act as neurons, and others act as muscle cells?

The credit for that goes to the epigenome. In programming terms, if DNA was the digital hardcode in our cells, the epigenome would be the analog code necessary to make sense of the DNA and use it.

“If the genome were a computer, the epigenome would be the software” — David Sinclair, Longevity Researcher at Harvard Medical School

Essentially, the epigenome is the highly flexible code that controls what part of the genome is expressed, or turned on, and what part of it is turned off. And it does this by alterations to the structure of the chromosome.

The epigenome regulates the genome by turning certain genes on and others off, by making the DNA more or less accessible, respectively

In the chromosome, the DNA is wrapped around proteins known as histones, where sections of DNA wrapped around eight histones are collectively referred to as nucleosomes and resemble beads on a string. These nucleosomes are compressed into more and more fibres, which eventually arrange themselves into the chromosomes. In fact, this packaging is done so tightly, that if you unwound all the DNA inside your body, it would be about 1.2 x 10¹⁰ miles, which is about 70 trips to the Sun and back.

Our genome is wrapped very intricately to fit inside our tiny nuclei

The epigenome controls DNA by altering how tightly the strands are wound around the histones. By adding acetyl groups to certain histones, DNA is made to wind around them more loosely, leading to more transcription, while removing acetyl tags reduces transcription.

Similarly, the epigenome can also act on the DNA molecules themselves, by adding or removing methyl groups to the DNA molecules. Adding a methyl group to a specific nucleotide prevents transcription machinery from binding with the DNA in that region, and prevents transcription. Removing this tag again allows the DNA to be transcribed.

The epigenome uses combinations of mechanisms including these two to regulate what genes are expressed and what genes aren’t. In this way, it can determine cell types by making sure that genes specific to a cell type are only expressed in those cell types.

Except, as we age, this epigenetic information can be lost. Different enzymes that regulate this information can stop carrying out their function effectively, leading to misregulation of the genome. Because of this, the genes that need to be repressed sometimes become activated, and vice versa. At this point, the cell is said to have been ex-differentiated.

“A skin cell starts behaving differently, turning on genes that were shut off in the womb and were meant to stay off. Now it is 90 percent a skin cell, and 10 percent other cell types, all mixed up, with properties of neurons and kidney cells.” — David Sinclair

And this loss of information and cell function serves as a major cause for aging.

Loss of Proteostasis

You’re probably aware that proteins are super important. They catalyze and enable every single reaction in the body, and play a major role in maintaining homeostasis. So, you might guess, maintaining protein quality and structure is crucial to keeping the body healthy.

This state of keeping proteins stable in the body is known as proteostasis, and it is controlled by the proteostasis network, made up of other proteins themselves. Some of the members of this network include the ribosomes that produce the proteins, the chaperonins that correctly fold them, and the protein degradation enzymes that destroy malfunctioning or old proteins.

When you’re young, all of these members of the network work properly to maintain proteostasis and keep the body healthy. But, as you age, this network begins to break down.

Proteins might begin to misfold because of environmental stressors, preventing them from achieving their functions.
Mutations in DNA and RNA can cause incorrect protein sequences that can cause proteins to be dysfunctional, or even harm cells.
Chaperonins can experience these mutations themselves, leading to a loss of function, or they can become stuck in protein aggregates, preventing them from correctly folding newly-made proteins.
And degradation mechanisms fail, leading to aggregation of malfunctioning proteins. These can prevent other proteins from being degraded, or they can even leave the cell and harm the body in different regions, like prions in the brain.

Overall, the loss of proteostasis leads to extremely negative health effects throughout our cells and body, and serves as yet another main cause towards aging.

Deregulated Nutrient Sensing

In our cells, there are four main nutrient-controlled pathways that regulate metabolism in our cells and contribute to aging. The four key-protein groups associated with these pathways are IGF-1, mTOR, sirtuins, and AMPK.

IGF-1 and the IIS Pathway

IGF-1, or the Insulin-like Growth Factor, inhibits growth hormone secretion by binding to receptors on the cell surface, and, like insulin, IGF-1 also takes part in glucose sensing. Because of this similarity, insulin and IGF-1 are collectively said to be part of the IIS (insulin and insulin-like growth factor) pathway.

The IIS pathway in Haemonchus contortus

In numerous studies, suppression of this pathway has been found to be associated with longevity. For example, PI3K mice, which are mice engineered with a weakened IIS pathway, have been found to live much longer than normal, control mice. Furthermore, FOXO, a transcription factor, has been found to increase lifespan by attenuating IIS signalling pathways.

Some studies have also linked increased damage/harm when IGF-1 activity is high, which has been associated with an increase in risk for some types of cancer.

So, you might think, that as you age, the IIS pathway is activated much more in older organisms, right? Well… it’s actually suppressed in older individuals as well.

What? I know. Scientists think the main difference then, between their tests and older individuals, is the timespan during which the pathway is inhibited. For the body, they believe the body ditches the pathway as a last chance, trying to stop aging. But, scientists believe that this sudden inhibition of the pathway can actually be harmful to the body instead, to the point that IGF-1 supplementation is beneficial during this time. Instead, what actually works is the inhibition of the pathway over the long-term, since it controls metabolism levels and reduces the body’s “wear and tear”.

mTOR Signalling

mTOR (mechanistic Target of Rapamycin) is a kinase that consists of the mTORC1 and mTORC2 protein complexes that sense amino acids, with the kinase being associated with nutrient abundance. The pathway is strongly involved in the regulation of various anabolic (building new proteins and tissues) reactions in our bodies.

It has been found that regulation of the mTOR pathway, like the IIS pathway, can also increase longevity in organisms. For example, knockdown of the mTORC1 has been found to increase the lifespan in fruit flies, yeast, and nematodes. Furthermore, rapamycin, a drug that regulates the mTOR pathway by inhibiting mTORC1, has been observed to extend lifespan in yeast, nematodes, fruit flies, and mice.

Similar effects were also observed with dietary restrictions in the same organisms, suggesting that the mTOR pathway is automatically inhibited in dietary restriction. This is one of the reasons many longevity researchers recommend restricting your diet, through intermittent fasting, for example.

Sirtuins

Sirtuins represent a family of proteins acting as NAD+ dependent histone deacetylases (involved in deacetylation of histones). By carrying out this function, the sirtuins more tightly wind up the DNA around the histones proteins, reducing the expression of certain genes.

In their normal state, the sirtuins are generally found on genes that must be silenced constantly to prevent cellular dysfunction, while more sirtuins are also floating around the nucleus. However, when damage occurs in any part of the genome, these sirtuins must relocate to that site and silence the damaged DNA while it is repaired, preventing transcription of mutated genes. In young cells, the extra supply of sirtuins in the nucleus carries out this relocation and allows cellular repair to be carried out efficiently. However, as one ages, the sirtuin and NAD+ levels in the body begin to decline, to the point where there aren’t enough sirtuins to repress damaged genes and silence their original genes. When this happens, sirtuins must leave their current locations and flock to the damage site, allow repair to occur, and then they have to return to their original position.

Except, the sirtuins don’t always make it back to the right spot. Sometimes, they can get lost along the way, and wherever they leave the genome to address damage, genes that should be switched off, switch on, and vice versa. Meanwhile, wherever they stop on the genome, they do the same altering the epigenome in ways that were never intended when we were born.

And that’s when the effects experienced with epigenetic alterations begin to take place.

AMPK

AMPK, or adenosine monophosphate-activated protein kinase, serves to maintain energy levels in cells. As you might be aware, the sugars, fats, and even proteins we intake with our food are converted into energy-storage molecules known as ATP (adenosine triphosphate). When this ATP is used to extract energy for various cellular reactions, one major end product is AMP (adenosine monophosphate). If the cell was to use all the ATP present, it would rapidly fill up with AMP molecules, and soon after, die because of the complete lack of energy for crucial reactions.

That’s where AMPK comes in. It detects high AMP levels (and thus high ATP usage), and activates lipid and glucose oxidation, to create more ATP in the cell to allow reactions to continue. By doing this, AMPK promotes energy-releasing processes and suppresses energy-storage processes, leading to vigorous and active individuals with lower blood glucose and fat levels, lowering the risk of developing heart disease, diabetes, and other similar disorders.

AMPK also promotes a process known as autophagy, in which cells consume and recycle worn out and old subcellular components, eliminating damaged DNA and misfolded proteins. As such, younger individuals that have higher AMPK activity have a lower risk of developing cancers and degenerative diseases associated with misfolded/damaged proteins.

Mitochondrial Dysfunction

Mitochondria. We’ve all heard of them, and memorized “Mitochondria are the powerhouses of the cell”.

And yes, they are the powerhouses of the cell. They convert all the food we eat into ATP, which can be used by the cell for energy. And surprisingly, they aren’t even normal organelles like everything else in our cells. Instead, mitochondria are bacteria themselves, with their own DNA and everything.

How could that be? We think that a very very long time ago (some millions or billions of years ago), one prokaryotic bacteria found itself inside another larger prokaryotic bacteria. However, instead of being digested like normal, this smaller bacteria managed to stick around and formed a relationship with the larger bacterium to provide it with energy. And that’s when eukaryotes emerged. Neat, huh?

Anyways, as we age, these mitochondria can become damaged and go through changes that harm their ability to produce energy for us, while enabling the release of harmful, reactive oxygen species, which, as we discussed before, can cause mutations in the cell’s DNA and even damage proteostasis. Reactive oxygen species have also been found to drive muscle weakness, inflammation, bone frailty, senescent cell load, and immune suppression, all characteristics of old age.

These oxygen species can also cause mutations in the mitochondrial DNA, further damaging their function. Normally, in healthy, young individuals, these malfunctioning mitochondria would be destroyed through a process known as mitophagy, leaving only healthy mitochondria behind. But, in older individuals, these mechanisms can become flawed and allow dysfunctional and harmful mitochondria to build up and harm the cell.

Cellular Senescence

Senescence is a cellular response that limits the proliferation of aged or damaged cells. Senescent cells neither divide nor support the tissues that they are a part of and kind of just stay dormant. However, senescent cells also release harmful chemical signals that encourage nearby healthy cells to also enter senescence, which leads to numerous health effects including reduced tissue repair, increased chronic inflammation, and even increased risk of cancer and other age-related diseases. Even though the number of senescent cells makes up only a small proportion of the total number of cells in the body, they secrete a wide range of chemokines, cytokines, and extracellular matrix proteases, which collectively form the senescence-associated secretory phenotype (SASP), which is thought to have a major impact on aging and cancer.

Researchers also discovered that the reason senescent cells are able to prevent apoptosis is high expression of pro-survival genes, which makes them highly resistant to apoptosis. Drugs that targeted these genes were soon developed, and now form a class of drugs known as senolytics.

Many longevity researchers have also investigated the idea of targeting and removing senescent cells to improve aging. They found that removal of just thirty percent of senescent cells was enough to slow-down age-related decline and ill health in mice, who had extended healthspans and lifespans.

However, there’s a catch. Researchers also found that senescent cells play a big role in tissue healing and that complete removal of senescent cells can significantly reduce healing capabilities in mice and make injuries more chronic.

Stem Cell Exhaustion

Remember how we talked about the epigenome and how it determines what function a certain cell will carry out (oxygen transport, muscular contractions, and whatnot)?

Stem cells are basically novel cells that don’t have the same level of epigenetic regulation and don’t have any specific functions at the moment. Instead, they wait for chemical signals from the environment that instruct them to differentiate into a specific type of cell and begin to carry out those functions. Because of this, stem cells are known as undifferentiated cells.

Well, though this might not seem that important at first glance, these cells play a huge role in the repair and maintenance of our bodies. Essentially, whenever certain cells are damaged, stem cells can differentiate into those cell types and replace them, allowing the body to stay healthy.

So why does stem cell exhaustion occur? There’s a wide variety of reasons.

One has to do with the SASP signalling from senescent cells, along with other inflammatory signalling pathways, which cause inflammation and reduce stem cell activity, leading to immune senescence and reduced tissue regeneration.

The stem cells can also experience telomere attrition and develop genetic mutations, both of which can eventually limit stem cell activity.

Lots of research is currently being done into either replacing exhausted stem cells, or enabling the body to regenerate stem cell levels, but more work still needs to be done for effective therapies.

Altered Intercellular Communication

As I’ve mentioned multiple times in previous sections, as we age, the signalling environment in the whole body changes to become more inflammatory and inhibit immune cell action, along with numerous other effects. Several factors contribute to this, including the SASP signalling pathway we discussed earlier.

This increase in inflammatory signalling across the body leads to increased activation of nucleic chemicals known as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), which regulates inflammation and production of proteins, enzymes, and cytokines. As such, the increase in NF-kB activation leads to the numerous harmful consequences found in aging.

Furthermore, studies found that, in the hypothalamus, NF-kB also inhibits the gonadotropin-releasing hormone (GnRH), which may result in bone frailty, muscle weakness, skin degradation, and other harmful effects.

So We’re At The End — Or Are We?

Well, yes, you are at the end of the article (phew, that was a long one wasn’t it?).

What I mean is that this isn’t the end of aging research. With the identification of these nine pathways, we’ve opened up a new pathway for possibly ending aging once and for all, with careful and specific targeting and prevention of each and every one of these hallmarks.

Do I think that ending aging is possible? Absolutely! In fact, I’m part of the growing population that believes aging is just a disease, like cancer, or Alzheimer’s, or even the flu. And just like all other disorders, I definitely see a future where aging doesn’t control society the same way it does today. Maybe that means we live much longer, or that we don’t die at all. I don’t know. I also don’t know when this will happen. But I’m optimistic that it will.

Until then, I’ll be going through university and continuing to be freaked out by the slowly approaching certainty of death.

Key Takeaways

  • There are nine total hallmarks of aging, which are as follows:
  • Genetic Instability — The collection of mutations over time can have massive repercussions
  • Telomere Attrition — Degradation of the telomeres can lead to cellular senescence
  • Epigenetic Alterations — Genes that are meant to be off get turned on, and genes that are meant to be on get turned off
  • Loss of Proteostasis — Proteins begin being produced incorrectly, and collect in protein aggregates
  • Deregulated Nutrient Sensing — Way too much to summarize, but essentially a bunch of different nutrient-level-regulated pathways
  • Mitochondrial Dysfunction — The powerhouses of the cell stop working properly and produce reactive oxygen species that damage the genome and proteostasis
  • Cellular Senescence — Dormant cells produce inflammatory signals that harm tissues and lead to tissue damage
  • Stem Cell Exhaustion — Stem cells begin to die off because of inflammatory signalling, and disallow tissue regeneration and repair
  • Altered Intercellular Communication — Inflammatory signalling increases, and NF-kB becomes activated, leading to tissue damage
  • Aging is a disease and can be prevented

Main Sources

  • Lifespan — Book By David Sinclair, PhD

On a Personal Note

This is my first article on Human Longevity, and I really appreciate you taking the time to read it. If you liked it, please clap for the article!

To stay updated with more of my articles (about technology, and definitely more on longevity), follow this Medium account, check out my personal website to find out a bit more about me, and follow me on my LinkedIn and Twitter to stay updated.

That’s it for me! See you next time!

18 y/o innovator working on reversing ageing and researching cancer vaccines. www.akshajdarbar.com

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