The Nine Hallmarks of Aging

In 1991, the book Evolutionary Biology of Aging defined aging as “a persistent decline in the age-specific fitness components of an organism due to internal physiological deterioration.”

It’s a rather broad definition to describe the aging process.

The challenge with trying to define aging is that aging is a complicated journey. There is no single answer that explains why we age. 

But interest within the scientific community around aging research accelerated significantly within the past 30 years, looking deeply at the cellular and molecular basis of life. 

In a review published in Cell, Carlos Lopez-Otın and a team of researchers proposed nine hallmarks of aging considered to contribute to the aging process. 

The nine hallmarks are the following:

Genomic Instability
Telomere Attrition
Epigenetic Alterations
Loss of Proteostasis
Deregulated Nutrient Sensing
Mitochondrial Dysfunction
Cellular Senescence
Stem Cell Exhaustion
Altered Intercellular Communication

1. Genomic instability

Your DNA is pretty important, and it’s not surprising to know that your DNA is worth protecting. 

Acting as the blueprint of your body, your DNA is responsible for providing all the intricate plans on how every operation in your body should function.

Your cells know DNA’s importance as well, harboring them with thick walls to keep them safely tucked away from damaging forces. 

Despite your cell’s best efforts, your DNA is constantly under attack. Free radicals, pollutants, pesticides, and UV rays from the sun are all exposing your DNA to damage. 

According to the American Federation of Aging Research, your DNA undergoes damage one million times per day. 

Luckily, your DNA also encodes a set of instructions to repair itself from such aggressors, but this repair can only go so far. With age, damage to your DNA (or genome) accumulates—known as genomic instability. 

You can also inherit mutations during the DNA repair process as well, an added detriment to your DNA.

The correlation between aging and genomic instability is much like the lifespan of a well-maintained car. You can be incredibly meticulous in rotating your tires, changing your oil, checking your tire pressure, and driving more fuel-efficient. But like all cars, your DNA can eventually break down from the simple passage of time. 

2. Telomere attrition

Telomere attrition is a specific type of genomic instability that has received so much attention in recent research; it bears mentioning separately amongst the nine hallmarks of aging.

Telomeres are protective caps at the end of each chromosome, like the plastic caps at the end of a shoelace.

To understand why telomeres are studied so closely in aging research, we have to look at how your DNA replicates.

Every time your cells undergo cell division, a fraction of your telomeres is lobbed off, making them shorter and shorter every time your cell replicates.

Eventually, your telomeres run out of runway, and there’s no room to cut. Your cells are unable to divide at this stage, accelerating the aging process.

Due to the finite nature of telomere length, researchers looked into their correlation to determine lifespan. A research article published in the Proceedings of the National Academy of Sciences investigated telomere length in various species.

The article concludes,

“The results shown here indicate that the telomere shortening rate of a species can be used to predict the life span of that species…”

The discovery of telomeres shifted the way we think about aging, challenging researchers to think beyond our chronological age. The work was so profound that the researchers were awarded the Nobel Prize.

3. Epigenetic alterations

Aging research is not only focused on your DNA. After all, several different functions work with your DNA to operate, like the epigenome.

Every cell in your body has the same DNA. But how is it that a liver cell functions differently from a brain cell?

The answer lies in your epigenome.

An epigenome is a multitude of chemical compounds that tell your DNA what to do. If DNA is the blueprint of your body, your epigenome is the contractor. They call the shots and decide what to build. This function is also known as gene expression.

For example, for your liver cells, the epigenome “turns on” certain parts of your DNA to assign it as a liver cell.

Unfortunately, as we age, your epigenome can be affected by environmental exposures and disease. These changes can change how your epigenome operates gene expression, affecting the way the epigenome processes your DNA.

An article published in the Journal of Applied Physiology outlines that epigenetic alterations such as mutations, deletions, and translocations are among the leading causes of genomic instability.

Your epigenome and your DNA cannot operate without the other. Research in epigenetic alterations and aging further highlights how all the hallmarks of aging are intrinsically tied.

4. Loss of proteostasis

Proteostasis comes from the root words “protein” and “stasis,” meaning a state of balance.

It’s the process of maintaining a stable production of proteins in your body without any issues. A loss of proteostasis describes when this vital protein-building machinery doesn’t function properly.

Proteins are precious molecules. They hold essential jobs in the cell, anywhere from gatekeeping the cellular wall to acting as enzymes for all the major chemical reactions on the body.

Your body maintains proteostasis via a network of proteins but can sometimes create too few or too many proteins when errors occur. These errors may create folds within the network, disrupting order and creating misshapen and dysfunctional proteins, almost like a paper jam in a printer.

A review in the journal Nature Reviews Molecular Cell Biology states that environmental factors can cause stress on this protein-building system, causing these errors to occur more frequently over time.

The abstract reads,

“Sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity.”

Periods of oxidative stress, an imbalance between your free radicals and antioxidants in your body, can cause these protein-production mishaps to occur more frequently. And like in oxidative stress, there must be a balance in protein production and protein degradation.

A research article published in the Proceedings of the National Academy of Sciences affirms,

“the tipping point...occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage.”

5. Deregulated nutrient sensing

Your cells need nutrients to operate, and they get their nutrients from the food you eat.

But your nutrients aren’t always steady. You aren’t eating every waking hour of the day (if you are, that’s a whole separate set of issues). So how do your cells know when nutrients are available and when they aren’t?

Your cells have sensors that can respond to the fluctuations of nutrient levels in your body. But your cells have to be careful. They need to take just the right amount. Why? Because metabolism, the process of turning your food into energy, is a double-edged sword.

Every time your body turns food into energy, your body creates damaging byproducts like free radicals. Imagine a gasoline engine. It produces efficient power for our cars but produces carbon emissions out of the exhaust.

Your cells’ nutrient sensors ensure it doesn’t take too much or too little of the food you eat. However, over time, as your cells accumulate damage from oxidative stress, these sensors have trouble regulating your nutrient intake.

An article published in Communications Biology denotes that these nutrient sensors provide the molecular basis for the association between lifestyle habits and aging.

The more damage your nutrient sensors take, the more damage they create by over metabolizing. It becomes a vicious cycle of damage.

But it isn’t all bad news. Continued study of nutrient-sensing concerning caloric deficits can have a profound impact on aging research, as a review published in Nature highlights:

“On the other hand, one of the most successful interventions against the onset of aging is limitation in nutrient intake, or caloric restriction. Hence, understanding normal nutrient sensing mechanisms is a prerequisite for designing better interventions…”

6. Mitochondrial dysfunction

The mitochondria are the “powerhouse of the cell.” They generate all the necessary energy your cells need, working as the primary component of metabolism. Your mitochondria produce 90% of your body’s energy.

But the energy comes at a cost. As shown in a review published in the Journal of Signal Transduction, mitochondria make most of the cell’s free radicals, a byproduct of their metabolic engines.

The vicious cycle of damage that occurs in your cell’s nutrient sensors also appears in the mitochondria. Free radicals damage your mitochondria’s efficiency, overworking their systems and creating more free radicals in the process.

Also, research from the School of Kinesiology and Health Science from York University shows you make fewer mitochondria as you age, making the few mitochondria you do have left work that much harder.

Integrative Medicine highlights that the loss of function in your mitochondria can result in excess fatigue, a common symptom associated with aging.

However, your mitochondria are very responsive to the energy demand of the body.

Like a power grid, if there is a decline in power demand, some power plants will shut off for greater efficiency. Likewise, sedentary lifestyles lead to further mitochondrial decline as the body responds to a lower energy need.

Fortunately, the inverse is also true. A study by David A. Hood from York University shows that exercise can promote mitochondrial biogenesis, the process where the body creates more mitochondria to meet the new energy demand.

7. Cellular senescence

Cellular senescence is a condition in which a cell no longer has the ability to divide, leading to its inevitable demise.

Cellular senescence is a natural process. Typically, your body can produce enough new cells to outweigh senescent cells. However, the number of senescent cells increases with age.

Think of cellular senescence as a natural protective mechanism. When a cell endures irreparable DNA damage or telomere dysfunction, cellular senescence prevents those damaged traits from proliferating further.

It’s your body’s “last-ditch” approach to an accumulation of environmental stressors. A review published in Nature Reviews Molecular Cell Biology notes, “cellular senescence occurs in response to endogenous and exogenous stresses.”

However, a review article in Nature Reviews Endocrinology highlights evidence that cellular senescence has a causative role in conditions associated with aging.

Without the replacement of new cells, a proliferation of cellular senescence can be problematic. For example, a review published by Nature Medicine outlines emerging evidence that suggests senescence causes a loss of tissue-repair capacity and proinflammatory molecules.

However, research investigating cellular senescence hopes to unlock the senescence mechanism for positive therapies, particularly in preventing the proliferation of problematic cells.

The same review from Nature Reviews Endocrinology points to the beneficial effects of cellular senescence for tumor suppression. But there is much to be studied to unlock the control of these benefits.

8. Stem cell exhaustion

Stem cell research consistently hits the airwaves and newsreels for its buzzworthy science in the past few decades.

There’s a good reason for it. Stem cell research is shrouded with a sense of both promise and controversy.

In particular, stem cell research can unlock potential growth for new tissue in humans. However, in the early stages of research, the use of embryos created political dissension for its continuation.

Thankfully, recent research has been able to circumvent this controversial practice by using adult stem cells.

So how do stem cells work?

To understand stem cell function, we need to look back to the epigenome and its ability to turn specific genes on and off.

The epigenome is responsible for assigning roles for our cells.

All of your cells have one function. Skin cells, liver cells, brain cells, heart cells—they are all assigned one role. But stem cells are like fresh college graduates that are ready to join your body’s cellular workforce. They don’t have a specialized job yet and are eager to be given some responsibility.

Based on your body’s needs, stem cells can assign themselves to become a specific cell. Think of them as reinforcements to all the cells in your body. For example, if there’s a need for more liver cells, stem cells will adjust their specialty to become liver cells.

This cycle of cell replenishment is vital for tissue homeostasis and regeneration. Stem cell exhaustion occurs when this new, budding workforce cannot replace the retiring cells fast enough to maintain peak tissue function.

Stem cell exhaustion is closely tied with the other hallmarks of aging. The imbalance between stem cells and retiring cells can occur from the proliferation of senescent cells, caused mainly by DNA damage.

A review published in Cell Metabolism highlights,

“Replication stress caused by age-related cell-cycle defects (e.g., DNA damage or chromosome disorganization) can diminish HSC functional activity, leading to decreased blood production and impaired therapeutic potential in transplantation assays.”

There is still a lot more research left to be done to unlock the potential capabilities of stem cells, but its relation to aging is clear. And aging research requires scientists to consider stem cells in tandem with the other hallmarks of aging.

9. Altered intercellular communication

Your cells love to chat. They use an intricate network of chemical signaling molecules to communicate with each other. Your cells use these networks to work together in adapting to environmental changes and manage the complex mechanisms that a multicellular organism (like humans) requires.

However, as you age, this vast communication network suffers signal degradation. The signals weaken, and communications run haywire, also known as altered intercellular communication.

One of the main culprits of this signal degradation is inflammation.

Inflammation is your body’s natural response to clear away threats and damaged cells. However, sometimes, inflammation can extend beyond its desired short-lived output and cause significant damage to nearby healthy cells.

Why is the inflammation triggered?

One of the main reasons is the existence of senescent cells, old cells that can no longer replicate. Senescent cells exert inflammation-causing chemicals, and in turn, create more damage to the cell environment.

Some studies suggest senescent cells can use these same intercellular communication signals to transform nearby healthy cells into senescent cells. A review in Trends in Cell Biology hypothesizes,

“One of the consequences of ageing and related diseases is the accumulation of senescent cells and their active intercellular communication profile.”

Studies around altered intercellular communication challenge the perception that autonomous cells are the sole subject of molecular aging.

Although there is still much we don’t know about how this vast network of chemical signaling works, research around intercellular communication illustrates how aging can be a consequence of cells in their environment.

Why should you care about the nine hallmarks of aging?

The nine hallmarks of aging help us understand that the process of aging is very complicated.

The answer to why we age does not equate to one answer. It doesn’t even equate to a multitude of answers. It looks more like a multitude of answers closely intertwined with another, like a ball of rubber bands.

And the research behind why we age is still very young. Scientists worldwide continue to find new findings, expanding our understanding of the nine hallmarks of aging. Likely, our knowledge of the aging process may not be limited to these nine in the future.

But our understanding of why we age should conclude the same. In every hallmark, science continually reveals how much our everyday habits and environment can impact the way we age on a microscopic level.

Remember that it’s never too late to make a healthier dedication to your body—a commitment to healthy aging.