Why Do We Age? The 12 Hallmarks of Aging

Aging seems pretty simple—you just grow older each day, month, and year, right? While everyone understands the basic concept of aging, it gets a little more complicated when considering the different types of aging and what causes it. 

There is no simple answer to the question, “Why do we age?”, as many things—including genetic, lifestyle, and environmental factors—all play a significant role in aging.

In this article, we’ll explore some of the reasons why humans age, including the top hallmarks of aging recognized by longevity researchers.

What Is Aging? Biological Vs. Chronological Aging 

As researchers published in the book Developmental Biology put it, “Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility.”¹

Essentially, aging causes the structure and function of our cells, tissues, and organs to degrade with time, which can be accelerated or slowed based on what we eat, drink, and expose ourselves to in our daily lives. 

However, there is a difference between biological and chronological aging. 

Although most people consider their age the number of candles on their birthday cake each year, how fast our cells and organs are aging is another story.

Chronological age is the age most people use to define themselves, based on when they were born and how many years have passed since. Conversely, biological age marks internal aging, including damage and dysfunction to cells and organs.

There are several ways of assessing biological aging to see how quickly your cells, organs, and tissues are deteriorating, including telomere length, epigenetic changes, or certain blood biomarkers. 

While biological and chronological age tend to line up during our younger years—a 20-year-old typically has cells of about the same age, for example—they can drift further apart as we grow older. 

With a biological age greater than your chronological age (i.e., you are 50 years old, but your cells match up more with someone who is 70), you’re more likely to experience accelerated aging and an earlier onset or progression of age-related disorders. 

You will probably also experience more of the external ways we characterize aging—like wrinkles, graying hair, sagging skin, stooped posture, and muscle loss—which tend to mirror internal aging. 

What Causes Aging? 

Longevity researchers often refer to the “Hallmarks of Aging” as the cellular factors that cause or accelerate aging.

The original 2013 paper published in Cell theorized a set of nine characteristics that define why we age, which was updated by the same authors in 2022 with three additional hallmarks.^2,3 

According to the authors of this paper, a hallmark of aging must meet three criteria:

1. It arises during the normal aging process. 
2. It will accelerate aging when upregulated in experiments.
3. It will slow down aging and improve health if it is downregulated. 

Although there are many theories of why we age, it mainly comes down to these 12 hallmarks of aging, which we’ll describe here. 

The 12 Hallmarks of Aging

1. Genomic Instability

The accumulation of genetic or DNA damage over the years is a leading cause of aging and leads to errors in our genetic sequences (i.e., genomic instability). This damage can occur from both endogenous and exogenous sources.²

Endogenously—coming from within the body—DNA is damaged through replication errors, mutations, or reactive oxygen species (ROS) buildup. ROS or free radicals are inflammatory and unstable molecules that cause oxidative damage to cells and DNA. Oxidative stress significantly contributes to aging and age-related disease (known as the free radical theory of aging).⁴ 

Exogenously, outside sources of genetic and DNA damage can arise from a myriad of places, including smoking, UV radiation, environmental toxins, or unhealthy food, water, and air that we eat, drink, and breathe.

Young and healthy people have systems in place to deal with this damage and facilitate DNA repair. However, accelerated aging and disease can occur when these systems break down from repeated mutations. 

As genomic instability is at the root of several other hallmarks of aging, including telomere attrition, mitochondrial dysfunction, and cellular senescence, it is considered by some to be the most essential and primary characteristic of aging. 

2. Telomere Attrition

Telomeres are the protective structures at the ends of our chromosomes. These endcaps are repetitive DNA sequences that shorten with every cell division to protect our genetic information from snipping off. Once a cell reaches the end of its telomere, it can no longer replicate. At this point, the cell either dies off (apoptosis) or becomes senescent, which we’ll get into more later in the article.

As telomeres “keep track” of how many times cells divide (i.e., how old they are), they are considered a proxy for measuring biological age—kind of like the rings inside a tree trunk. Studies have shown that shortened telomeres are linked to accelerated aging and reduced lifespans in both humans and animals.^5,6 

The enzyme telomerase, responsible for creating telomere DNA, is inactive in most adult human cells, which is why telomeres don’t naturally regenerate. Although research has found that stimulating telomerase production in mice delays aging and extends lifespan, it’s unknown if this will safely translate to humans.⁷ 

3. Epigenetic Alterations

The epigenome is a code that dictates which parts of the genome are expressed at certain times. Essentially, it’s a network controlling which genes get turned on or off. As longevity researcher David Sinclair, Ph.D., puts it in his book Lifespan, “If the genome were a computer, the epigenome would be the software.” 

With age, environmental factors, or unhealthy lifestyle habits, gene expression can get mixed up and dysfunctional—a gene that should be turned off gets turned on, or vice versa. DNA methylation—the addition or removal of a methyl group from a DNA molecule—also occurs more frequently with age. After repeating these mistakes over time, these epigenetic alterations can contribute significantly to aging.

Unlike DNA mutations, epigenetic alterations can be reversed, showing promise for extending both lifespan and healthspan—the years lived healthfully without developing chronic disease.⁸ 

4. Loss of Proteostasis

Proteostasis, or protein homeostasis, maintains proteins in their correctly folded states. Loss of protein maintenance causes misfolded proteins that can’t function properly, thereby altering cellular function. As proteins are required for cell structure and just about every chemical reaction in the body, proteostasis is a necessary function. 

A good example of a loss of proteostasis in action involves Alzheimer’s disease. Misfolded proteins called tau and amyloid-beta accumulate in the Alzheimer’s brain, causing plaques that disrupt neuron functioning and cause cognitive decline.⁹ While a loss of proteostasis mostly impacts age-related neurodegenerative diseases, this hallmark of aging is also linked to cataracts and certain cancers. 

One of the leading ways our bodies respond to a loss of proteostasis is through autophagy, an internal recycling system that clears out dysfunctional or toxic molecules—including misfolded proteins. However, as we’ll see, autophagy’s activity decreases with age, leading to a buildup of these damaged proteins that contribute to aging and disease. 

5. Dysregulated Nutrient Sensing

Nutrient sensing systems are involved with metabolic processes and evolved to protect us during times of food scarcity. When nutrients are abundant, the body places focus on energy storage and reproduction, while nutrient scarcity allows the body to prioritize cellular repair and maintenance, including processes like autophagy. 

Manipulating the body to think it’s in a state of nutrient scarcity, like caloric restriction, has been shown to increase lifespan. 

The main nutrient-sensing pathways are IIS (‘insulin and IGF-1 signaling’), sirtuins, mTOR, and AMPK. Briefly, IIS senses high glucose levels, mTOR senses high amino acid levels, and AMPK and sirtuins sense states of low energy. Boosting the activity of sirtuins and AMPK while inhibiting the activity of IIS and mTOR is linked to improved health and longevity. 

6. Mitochondrial Dysfunction

You probably remember mitochondria as the “powerhouse of the cell” from 7th-grade Biology class, as they are the organelles primarily responsible for producing energy via ATP (a process called mitochondrial respiration).

However, they also naturally produce free radicals and reactive oxygen species during the process of turning food into fuel. When mitochondrial function declines, we see reduced energy production and cellular turnover combined with increased free radical damage. 

This buildup of ROS in the mitochondria is also linked to several other hallmarks of aging, including loss of proteostasis, genomic damage, epigenetic alterations, and cell senescence.

7. Cellular Senescence

Cellular senescence was first described by Leonard Hayflick in 1965. Named the Hayflick Limit, he proposed that normal human cells are only able to replicate and divide between 40 and 60 times before they will not divide anymore.

After that, the cell will essentially “kill itself” through apoptosis, which is programmed cell death. When cells reach their Hayflick Limit (which is also the end of their telomere), they become senescent.¹⁰

Senescent cells have stopped dividing but remain in the body. These cells damage nearby tissues and surrounding cells as they secrete pro-inflammatory cytokines, compounds, and growth factors. This inflammatory damage that senescent cells produce is known as the senescence-associated secretory phenotype (SASP), which contributes to aging and age-related diseases. 

Not all senescence is bad: acute and short-lived senescence is beneficial, as it responds to and repairs wounds and tissue damage and can kill off some cancer cells. However, when senescent cells are chronically present, the accumulation creates a hyper-inflammatory environment for diseases to manifest (including cancer, cardiovascular disease, neurodegenerative disease, and more) and aging to progress.

8. Stem Cell Exhaustion

Stem cells are a blank canvas that can grow into any other cell type, which is necessary to repair and regenerate damaged tissues and other cells. 

With age, the supply of healthy stem cells is depleted, leading to many of the problems associated with aging, including disease, frailty, organ dysfunction, and low immune system functioning. 

Other causes behind the depletion of stem cells include cellular senescence and inflammatory damage from the SASP, genetic mutations, and telomere shortening of the stem cells.  

9. Altered Intercellular Communication

Appropriate communication between cells is necessary to maintain the health and integrity of the tissues and organs. The aging body is more prone to dysfunctional communication, most often due to chronic and low-grade inflammation, senescence, free radical accumulation, and DNA damage. 

Many other mechanisms play a role in inhibiting this cell-to-cell crosstalk, including senescence and SASP, free radical accumulation, and DNA damage. These processes create cascades of pro-inflammatory compounds that accelerate aging and disease. Referred to as “inflammaging,” these pathways inhibit stem cell function, reduce the immune system’s ability to fight pathogens and drive aging.

10. Compromised Autophagy

Autophagy is our cellular trash and recycling system that clears out dysfunctional or toxic cells, proteins, mitochondria, and other cellular components.¹¹ Autophagic activity decreases with age, leading to a buildup of these damaged cells and organelles that contribute to aging and disease. 

Conversely, research shows that increasing autophagic activity in animals and cells extends lifespan or improves markers of health.¹²

11. Chronic Inflammation

Inflammation is both a cause and a symptom of many of the other hallmarks of aging. Chronic release of pro-inflammatory compounds accelerates aging and disease, a process referred to as “inflammaging.” Chronic inflammation inhibits stem cell function, reduces the immune system’s ability to fight pathogens, and drives the aging process. 

People of increasing age or with chronic inflammatory diseases often see high blood levels of inflammatory markers, including IL-1, IL-6, C-reactive protein, IFNα, and others.¹³

12. Gut Microbiome Disturbances

Dysbiosis is a state of imbalance in the gut microbiome characterized by too few beneficial microbiota with too many harmful or pathogenic bacteria.

Aging is characterized by a loss of gut microbial species and diversity, as well as compromised gut barrier integrity that drives inflammation.¹³

It’s now known that the gut microbiome plays a much more important role in human health and longevity than just digestion—it has also been shown to affect cardiovascular, cognitive, neurological, metabolic, immune, and digestive health. 

The Bottom Line

Overall, human aging is an inevitable and natural part of life that is caused by a multitude of factors—both modifiable factors (like diet and lifestyle) and not (like genetics).

Keep an eye out for the next articles in this series to learn more about healthy aging, reversing the signs of aging, and the best foods to eat to help you live longer.

Causes of Aging FAQs