Scientists have identified a set of cellular and molecular changes that accumulate over time and are thought to play a major role in the aging process. These changes, known as the “hallmarks of aging,” were first coined in 2013 and were set to provide a framework for understanding the complex mechanisms that contribute to aging and age-related diseases. Science, however, has continued to reveal more.
The nine hallmarks of aging were first identified in 2013.
Scientists have included three additional biological processes in the list of hallmarks of aging.
Each hallmark may accelerate the rate of aging independently, but many are connected through a series of mechanisms.
For a decade, it was understood that there were nine hallmarks of aging. However, scientists expanded that list this year and added three more factors that may accelerate aging.
While each of these hallmarks impacts aging on its own, they are not mutually exclusive and can often overlap. Nothing in the human body works in isolation, and it is a complex and interconnected set of mechanisms that have been found to contribute to the aging process.
The 12 hallmarks of aging
The first step toward finding ways to slow down aging is to define what factors contribute to its process. Knowing how certain mechanisms on the cellular level impact how fast we age will help develop ways to combat that and, as a result, age more gracefully.
From genomic instability and telomere shortening to stem cell exhaustion, these 12 hallmarks provide a roadmap to the aging process, shedding light on how our bodies change over the years.
1. Genomic instability
Genomic instability refers to the accumulation of genetic damage or changes in DNA that occur over time. Both external and internal factors may influence the level of DNA damage that takes place. Endogenous examples are DNA replication errors and oxidative stress, while exposure to radiation or toxins is exogenous.
When your cells age, their capacity to repair DNA damage may also deteriorate, which can further cause DNA instability leading to mutations and other alterations in the DNA sequence.
According to the National Cancer Institute, many types of cancer are a result of such defects.
2. Telomere attrition
Telomeres are small protective caps on the ends of chromosomes that help to maintain the stability and integrity of your genes. However, each time a cell divides, its telomeres become shorter due to the incomplete replication of the telomere sequence during DNA synthesis. The shorter they get, the less protection there is for the chromosomes, which eventually will result in cellular senescence or programmed cell death (more on this below).
The shortening of telomeres has been found to accelerate aging due to limiting the ability of cells to divide and replenish damaged tissues. Additionally, telomere attrition has been linked to chronic inflammation. According to a study in Nature Cell Biology, “senescent cells secrete a complex set of proinflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation, and can spread the senescence phenotype to surrounding cells, thereby causing chronic systemic inflammation.”
A variety of factors impact telomere attrition, including oxidative stress, inflammation, and exposure to toxins. However, studies have found that exercise, particularly aerobic activity, may help to improve telomere length. The explanation lies in the telomerase enzyme that adds telomere sequence to the ends of chromosomes. Such physical activity has been found to increase telomerase activity and reduce the rate of telomere attrition.
Telomere attrition has been linked to a number of age-related diseases, such as cardiovascular disease, cancer, and neurodegenerative disorders.
3. Epigenetic alterations
Epigenetic alterations are characterized by changes in the regulation of gene expression. While these changes do not impact the DNA sequence itself, they may trigger modifications in whether a gene switch is turned on or off.
Factors such as your environment, diet, lifestyle choices, and stress management can all contribute to how certain genes are expressed over the course of your life. However, as we age, the patterns of these epigenetic alterations can become more pronounced, leading to undesirable changes in gene expression that can contribute to age-related diseases and conditions.
A review published in the International Journal of Molecular Sciences concluded that epigenetic alterations may result in the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, and neurodegenerative disorders.
Since epigenetics refers to all things external that impact gene expression, these are largely reversible, and we can control what we do and surround ourselves with to protect our genes from developing diseases.
4. Loss of proteostasis
Proper cellular functioning requires a state of homeostasis, the process that regulates proteins within the cell. A balance between protein synthesis, folding, and degradation is essential for maintaining cellular function and preventing the accumulation of damaged or misfolded proteins. The loss of proteostasis refers to the gradual decline in the ability of cells to maintain that protein homeostasis or proteostasis.
The efficiency of cells to maintain proteostasis declines over time, leading to a build-up of damaged or misfolded proteins, which have been found to contribute to aging and disease.
Scientists have identified that a common pathological hallmark among different neurodegenerative diseases is the accumulation of aggregated proteins that might cause cellular dysfunction and, eventually, lead to cell death.
"Amyloid-beta, Tau, alpha-synuclein, TDP-43, or the prion protein, are just a few examples of proteins that can aggregate and contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS),"Frontiers in Molecular Neuroscience
5. Deregulated nutrient sensing
Deregulated nutrient sensing is defined by the decline of the cell’s ability to sense what nutrients are at hand and communicate to the other inner systems for further mechanisms to occur. Nutrient sensing pathways play a critical role in regulating cellular metabolism, energy balance, and growth and are essential for supporting the proper functioning of cells and tissues.
One of the most profound nutrient-sensing pathways relates to how our cells behave in the presence of insulin and insulin-like growth factor (IGF-1).
"Nutrient signaling through insulin/IGF-1 was the first pathway demonstrated to regulate aging and age-related disease in model organisms."Sub-cellular Biochemistry
The popular dietary intervention, called intermittent fasting, works through this pathway that has been found to be beneficial in animal models. However, its role in human aging and age-related disease needs more research to be conclusive.
6. Mitochondrial dysfunction
The mitochondria are often referred to as the powerhouse of the cell due to their role in producing energy in the form of Adenosine 5′-triphosphate or ATP. The more energy it can produce, the more energy the cell will have to work properly across all tissues and organs. Additionally, it plays a role in cellular metabolism.
A dysfunctional mitochondrion has been found to lead to an increase in reactive oxygen species that fuel inflammation and oxidative stress, triggering a cascade of maladaptations and accelerating aging. Studies have found mitochondrial dysfunction to be associated with a wide range of human pathologies, such as cancer and metabolic and cardiovascular diseases.
7. Cellular senescence
As cells continue to divide through our lifespan, many will eventually reach a point of senescence when they cannot divide anymore but are still metabolically active. However, in that “zombie” state, they become of little use and more of a burden.
On the one hand, research has shown that small amounts of senescent cells can be beneficial for recruiting tissue repair factors to damaged areas, such as wounds, or repairing cancerous cells. On the other hand, however, accumulating “zombie” cells can contribute to chronic inflammation and may lead to age-related diseases. Such accumulation is often referred to as “inflammaging.”
Senescence can be triggered by a variety of stresses that were also part of a few other hallmarks of aging, such as telomere shortening, reactive oxygen species, and the activation of cancerous cells due to potential epigenetic alterations.
8. Stem cell exhaustion
Stem cells are the type of cells that can turn into any kind of tissue in the body. Thus, they are key to replenishing dying cells to maintain normal tissue function and regenerating injured tissues.
A wide range of factors, some related to other hallmarks of aging, may promote stem cell exhaustion, such as DNA damage, telomere shortening, oxidative stress, and epigenetic factors. As the function of stem cells declines over time, it is more likely that an organism will develop age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancer.
Studies have found that failure to trigger appropriate responses to DNA damage, for example, is strongly associated with cancer initiation and progression.
9. Altered intercellular communication
As mentioned above, nothing within an organism, like the human body, occurs in a vacuum or in isolation. Cells constantly communicate with each other through a variety of mechanisms.
When this communication gets altered, however, the signaling between cells can be lost, misinterpreted, or even ignored, interrupting normal tissue function and repair, and may contribute to the development of age-related diseases.
10. Chronic inflammation
Chronic inflammation refers to a constant, lingering, and low-grade inflammatory response that, over time, wrecks havoc on the body. Think of being poked by a small needle for a very long time. You might not even notice it for the first few hours, but as days, weeks, months, and years go by, it will cause great damage beneath your skin.
Going beyond molecular inflammation and inflammaging, a group of researchers has identified multiphase inflammatory networks and proinflammatory pathways that may contribute to aging and, as a systemic response, may exacerbate age-related chronic diseases.
11. Disabled macroautophagy
Macroautophagy, or autophagy, is the body’s natural process through which cells get rid of damaged or dysfunctional organelles and proteins to help to maintain cellular homeostasis.
Age, oxidative stress, epigenetic factors, and mitochondrial dysfunction may decrease our cells’ ability to perform autophagy, leading to the accumulation of damaged cells and proteins and accelerating aging.
Additionally, the inhibition of this inner “healing” mechanism has been linked to Alzheimer’s disease, type 2 diabetes, and cardiovascular disease.
Dysbiosis is characterized as a disruption in the gut microbiota. Many studies have emerged in the past few years regarding the importance of balance among the complex ecosystem of trillions of microorganisms in the gut microbiome.
Scientists have concluded that “this sophisticated intestinal microbial ecosystem plays a pivotal role in an array of physiologic activities that are critical to human development and support health.”
Adding this to the list of hallmarks of aging further explains how dysbiosis can lead to negative health outcomes, increase systemic inflammation and speed up aging.
Furthermore, when the cooperation between our cells and the gut microbes falters, the microbial community within the gut can become a source of infection and, at times, can lead to serious health conditions and age-related diseases, such as obesity, diabetes, inflammatory bowel disease, allergies, and even neurological disorders such as depression and Alzheimer's disease.
Aging is a complex physiological process still being studied in animal and human models. However, these 12 hallmarks of aging may bring us a little closer to understanding the interconnectedness of how it occurs. By understanding these mechanisms, researchers hope to develop interventions to slow or even reverse the aging process and improve healthspan.
- Cell. Hallmarks of aging: An expanding universe.
- Nature Cell Biology. Telomere dysfunction in ageing and age-related diseases.
- Medicina. Does Exercise Affect Telomere Length? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
- The Journal of Clinical Investigation. Telomeres and age-related disease: how telomere biology informs clinical paradigms.
- International Journal of Molecular Sciences. Epigenetics of Aging and Aging-Associated Diseases.
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- Frontiers in Molecular Neuroscience. Editorial: Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases.
- Subcellular Biochemistry: Ascorbic Acid: Biochemistry and Biomedical Cell Biology. Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease.