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Hallmarks of aging provide clues for disease prevention

What are the changes that occur in the body with age? Twelve hallmarks of aging are key to understanding the cellular changes for disease prevention.

12 Hallmarks of aging

February 16, 2023

21 min read

Key Take Aways

  • Aging is the progressive loss of tissue and organ function that occurs over time, which can lead to the development of chronic diseases.
  • 12 biological hallmarks of aging have been identified. They provide clues for how the body ages and how we may prevent disease.
  • Much of our knowledge is based on pre-clinical trials. It is still unclear what strategies will be the most effective in prolonging life and health span in humans.
  • Mitopure (Urolithin A) can stimulate mitophagy, one of the 12 hallmarks. Urolithin A is mentioned as a strategy to improve health span.

How does the body age?

Aging is defined as a progressive loss of tissue and organ function over time, which can lead to the development of chronic disease. There are a number of ways the body changes with age, and understanding this is an important part of promoting healthy aging.

Ten years ago, the “Hallmarks of Aging” was originally published in Cell, with the goal of creating a framework for future studies on longevity and aging, and to drive the discovery of future interventions.

Since its initial publication, close to 300,000 articles on the subject of aging have been published, prompting the release of a new edition of the landmark paper. Three new hallmarks were identified, including macroautophagy, which incorporates mitophagy. The authors also include Urolithin A’s ability to stimulate mitophagy and improve muscle endurance and performance in humans in the list of interventions that target disabled autophagy.

Read on to discover what some of the most significant changes in the body are with age and what implications they have for health promotion and disease prevention.

Genomic instability

Genomic instability is thought to be one of the top drivers of the aging of cells. Genetic damage builds up throughout life and contributes to aging. Genomic instability refers not only to DNA damage, but also to the mutations that may occur as a result. These mutations may accumulate in organs and tissues with age. There are different types of mutations which may affect cellular function and contribute to aging.

Genomic instability can be caused by a variety of external factors that are physical, chemical, or biological in nature, as well as actors originating inside the body such as DNA replication errors and free radicals. Free radicals are molecules that can be made as part of the body’s normal processes and can build up and cause damage.

Telomere attrition

Telomeres are DNA structures that protect information-carrying DNA in the cell. They work to maintain the integrity of chromosomes, which carry genetic information from cell to cell, to sustain health. As cells divide, telomere length decreases to the point at which cellular division can no longer occur, causing the death of cells. This may explain the decline in organ function that characterizes aging. Shorter telomere length is associated with many chronic conditions, such as cancer, diabetes, atherosclerosis, and heart failure.

The contribution of telomere attrition to the aging process has been well characterized, and it is known that telomere attrition leads to cell senescence. In this state of cell senescence, damaged cells resist removal and may harm nearby cells.

Epigenetic alterations

Morris et al. provide a useful description of terms associated with the genetic basis of longevity. They define the genome as the “hardware” we are born with, and the epigenome as “software” influencing gene expression.

Epigenetics refers to the changes that occur in an organism due to modification of gene expression, as opposed to changes to the genetic code.

There are many epigenetic changes that affect cells and tissues throughout life. Various environmental and biological factors influence the epigenetic response, such as aging, nutrient availability and physical exercise. Factors like diet are able to modify the epigenome and influence health outcomes with age. Drugs that are able to affect the epigenome in beneficial ways to slow aging are also being studied as an area of interest.

Epigenetic changes during aging have a large effect on cellular functioning and stress resistance. These changes contribute to the progression of aging.

Epigenetic changes are thought to be particularly important in the aging process for several reasons. One reason is that changes in gene regulation may impact the functioning of cells and give rise to disease. Another reason is that studies suggest that epigenetic changes can occur early in the aging process and have a causative role in aging. These, among other reasons, make epigenetic mechanisms in aging an important area of focus.

Loss of proteostasis

Our cells require tight control over the maintenance or homeostasis of proteins. This protein homeostasis is referred to as proteostasis, and with age, there may be dysregulation of this process, which may contribute to Alzheimer's disease, Parkinson's, and Huntington's disease.

Proteostasis is maintained by a network that controls protein synthesis, folding, transport, and clearance of misfolded proteins. When these functions cease to operate well, damaged proteins may accumulate, and negative effects may occur.

Under normal conditions, cellular surveillance systems can detect and repair damaged structures to eliminate them from inside the cell. When there is dysfunction in these systems, there may be a buildup of abnormal proteins in cells, leading to proteotoxicity. Proteotoxcity can contribute to cell death.

Preserving these systems is a key part of slowing the aging process, and the functions responsible for protein homeostasis are very important for cellular adaptation to stress. Research has established numerous links between protein homeostasis and longevity.

Various strategies have been implemented to restore proteostasis and promote healthy aging. One example is protein replacement therapy, which involves administering a deficient protein intravenously.

Deregulated nutrient sensing

Nutrient sensing pathways offer a way for cells to detect an abundance or scarcity of nutrients, forming a link between diet and aging. With age, these pathways become deregulated and lose effectiveness.

Nutrient sensing has been studied in relation to some of the problems associated with age, such as cognitive decline. These pathways play a role in the maintenance of the cells of the central nervous system and how they age.

Changes in nutrient sensing pathways can be impacted both pharmacologically and through dietary intervention. Given this, caloric restriction has been suggested as one way to promote healthy aging. However, additional research is needed to determine whether long-term caloric restriction is safe, particularly in the elderly, people with diabetes, and other groups.

Mitochondrial dysfunction

Mitochondrial dysfunction occurs when the mitochondria do not work as they should. This generally occurs with increased production of free radicals, which are molecules that can build up in the body and cause damage to cells. The functioning of the mitochondria declines with age, and there is an associated impairment in the removal of these dysfunctional mitochondria (mitophagy).

Impairment of mitochondrial function has been associated with aging and many chronic conditions, such as cancer, neurodegenerative diseases, metabolic diseases, kidney diseases, and others.

It is still unclear what the primary driver of mitochondrial dysfunction is during cell senescence and whether it is possible to restore mitochondrial function in senescence and aging.

Cellular senescence

Mitochondrial dysfunction and cell senescence are closely related hallmarks of aging. Cell senescence was first defined as the irreversible loss of the ability of cells to replicate. While the cell is no longer able to divide, it does not die.

Senescent cells accumulate in the tissues as the body ages, leading to a decline in functioning. These cells can accumulate at sites of age-related pathologies, such as in osteoarthritis and atherosclerosis, and can impact the normal functioning of tissues. Cell senescence has been implicated in the development of other conditions as well, such as osteoporosis, glaucoma, diabetes, and neurodegenerative diseases.

Triggers of cellular senescence include genetic alterations that may result from oxidative stress, DNA, or telomere damage. The immune response may also promote cell senescence. A pro-inflammatory state that characterizes the aging process, known as "inflamm-aging," may trigger cell senescence as well. This may lead to the development of chronic inflammatory conditions such as osteoarthritis.

Senescent cells have a variety of characteristics, including deregulated nutrient signaling and the inability to remove dysfunctional parts of the cell.

Stem cell exhaustion

Stem cells can develop into many different cell types during early life and growth and are among the longest-living cells within an organism. In adults, stem cells are found in tissues and organs and can differentiate to produce the specialized cell type of a particular tissue or organ. The various types of stem cells include hematopoietic, intestinal, satellite cells of the skeletal muscle, neural, skin, and germline. Adult stem cells serve as a repair system in the body and act as replacements for lost cells due to wear and tear, injury or disease.

Given the role of stem cells in the body, they are important in preventing the aging of tissues and organs. However, during the aging process, these cells undergo changes such as a decline in the regenerative capacity and loss of function. As stem cell function becomes impaired, there is a gradual loss of tissue homeostasis and regeneration of injured tissue. This corresponds with the development of chronic conditions and other aging concerns, such as hair loss and graying, memory problems, anemia, and muscle weakness. It appears that all stem cell populations decline in function with age.

It has been suggested that reversing stem cell aging at the cellular level may be important for preventing aging. This holds promise in the area of regenerative medicine and the treatment of age-related diseases, such as loss of muscle mass and strength, heart failure, impaired immune function, and neurodegeneration.

One way to reverse stem cell aging is exercise. Exercise has been found to increase the number of hematopoietic stem cells, which are cells that develop into blood cells. This can be a marker for the repair and health of blood vessels. Exercise has also been found to activate neural cells, resulting in improved regenerative capacity of the brain and cognitive functioning.

Altered intercellular communication

The various problems that occur as the body ages can be considered to be a result of changes at the cellular level, as well as changes in intercellular interactions. Communication between cells is crucial in living organisms, and intercellular communication refers to the different ways cells transmit information to each other and transfer different types of messages. How cells communicate involves a variety of processes that may occur individually or simultaneously and change depending on the physiological or pathological context.

A number of different means of intercellular communication are involved during aging, including changes at the neuroendocrine, endocrine, and neuronal levels.

To provide an example of the problems associated with intercellular communication with age, senescent cells may be considered. Senescent cells are highly proactive and communicate with nearby cells via different types of intercellular communication. This can be potentially detrimental to tissue homeostasis. It is thought that one of the consequences of aging and related disease is the accumulation of senescent cells and the active intercellular communication that characterizes them.

Exercise may help to restore intercellular communication. Moderate exercise increases the expression of antioxidant enzymes and decreases the production of reactive oxygen species that can damage cells. Researchers have noted that further studies are needed to better understand the benefits of exercise with regard to various conditions and diseases, such as aging, obesity, and type 2 diabetes.

Disabled macroautophagy

In the latest publication, “Hallmarks of Aging: An Expanding Universe,” the authors indicate that disabled macroautophagy is a hallmark of aging.

“Autophagy” refers to the breakdown and recycling of various parts of the cell, whereas “macroautophagy” refers more specifically to diverse and often large cargo such as proteins, lipids, organelles, and pathogens. This is an important part of maintaining cellular health with age. Mitophagy is listed as a type of macroautophagy, targeting the removal of dysfuntional mitohcondria.

There are various steps involved in macroautophagy. The process first involves the breakdown of the contents of the cell. After degradation, the resulting products are released back into the cell for recycling to generate energy and to protect the cell when it undergoes stress. These processes may fail during aging and in age-related diseases.

Several strategies are known to mitigate the decline in autophagy that occurs with age, such as fasting and exercise. As dysregulated autophagy also includes mitophagy, consumption of natural compounds such as Urolithin A is also of interest when it comes to improving health span. Urolithin A has been shown to play an important role when it comes to the clearing and recycling of dysfunctional mitochondria.

Chronic inflammation

Inflammation plays an important role in the body in regard to tissue repair and regeneration. However, if inflammation is abnormally intense or continually present, this may have a negative effect.

With age, damage that occurs to the cells triggers a persistent proinflammatory state in the body, often referred to as “inflammaging.” This may promote the development of numerous chronic conditions associated with aging and a decline in physical and cognitive function.

Senescent cells have been identified as key in inflammaging and age-related diseases such as atherosclerosis, osteoarthritis, and cancer, among others. The accumulation of senescent cells increases the release of molecules that drive inflammaging. Senescent cells similarly accumulate in the immune system, promoting further senescence and inflammation.

Impaired mitochondrial function is also thought to drive inflammation, and this is intertwined with the other hallmarks of aging. However, additional research is needed to provide sufficient evidence of this in humans.

Emerging evidence indicates that inflammation is implicated in the aging of the brain and neurodegenerative disease. Additional research on inflammaging is needed to better understand how to treat such conditions and promote healthy aging.


Gut microbes play an important role in maintaining health, providing protection against pathogens, regulating metabolism, and promoting the development of immunity, among other functions. With age, changes in the gut microbes can negatively affect health. “Dysbiosis” refers to the loss or gain of bacteria that either promote health or disease, respectively. Dysbiosis has been associated with the development of disease within several organ systems, including the cardiovascular, immune, neurological, and respiratory systems.

Numerous changes that occur in the gut microbes with age have been identified, such as reduced diversity of bacteria and changes in the predominant bacterial groups. However, these changes are not fully understood, and additional research is needed in this area.

Some research has shown that dysbiosis of the gut microbiome may contribute to a chronic inflammatory state. The inflammation may promote chronic diseases such as Alzheimer’s and Parkinson’s disease. Thus, researchers have postulated that these conditions may actually begin in the gut.

Additional research is needed to determine how the microbiome may be manipulated to address disease. Probiotics show promise in this regard and need to be further tested in the elderly. Consumption of a healthy diet has also been shown to be of importance in maintaining gut health with age and preventing disease.

Urolithin A and the hallmarks of aging

Urolithin A is a molecule that can improve mitochondrial function through its role in optimizing mitophagy. It is a postbiotic made in the gut upon consuming antioxidant compounds from pomegranate and other fruits and nuts, yet studies have shown that only 40%* of the population has the right microbiome to make it.

Mitopure is a highly pure form of Urolithin A that has been shown to stimulate the removal of damaged mitochondria from cells.* Numerous research studies have been conducted on Mitopure, including clinical trials, which have demonstrated benefits in terms of mitochondrial health. It provides more than six times as much Urolithin A than you could get from diet alone, and research suggests that it can improve muscle strength and performance. A recent study conducted in untrained adults between 40 and 64 years of age, for example, showed that supplementation with Mitopure increases muscle strength and improves exercise-performance measures.**

Last words

As López-Otín et al. note, the 12 hallmarks of aging are interconnected. Thus, anti-aging interventions often simultaneously target several of the hallmarks. This new framework provides direction in regard to development of interventions to slow the aging process. Additional research will reveal the extent to which such interventions should be based on avoidance of detrimental environmental factors (such as pollution, insufficient physical activity and unhealthy diets), performing health-promoting behaviors (consuming a healthy diet, exercising, sleeping sufficiently), administration of particular drugs, or other interventions.

Understanding the aging process is the first step in determining how best to prevent disease and promote health. Changes in the body with age affect the cells in various ways, including cellular communication and the ability to perform their usual functions. Dietary components, as well as exercise, play a key role in maintaining health as we age. Considering compounds that promote health of the mitochondria of the cells, such as Urolithin A, is also key when it comes to healthy aging.

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. References: *Nutrition studies: 500mg Mitopure® have been shown to (1) induce gene expression related to mitochondria function and metabolism and (2) increase the strength of the hamstring leg muscle in measures of knee extension and flexion in overweight 40-65 year olds. Data from two randomized double-blind placebo-controlled human clinical trials. **Nutrition NOURISH Study: 500mg Mitopure® have been shown to deliver at least 6 times higher Urolithin A plasma levels over 24 hours (area under the curve) than 8 ounces (240ml) of pomegranate juice in a randomized human clinical trial.


Jinan Banna

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