In 2013, Lopez-Otin et al. proposed the original nine hallmarks of aging in an article published in Cell. Since then, the field of longevity medicine has witnessed significant growth, with new research and studies enhancing our understanding of the cellular and molecular mechanisms involved in the aging process. In 2022, a panel of experts reviewed the latest advancements in aging research and suggested the inclusion of five additional hallmarks based on compelling evidence of their role in aging. Furthermore, in 2023, Lopez-Otin published further research building upon his previous work, proposing the addition of three more hallmarks, while in 2020 the Hallmarks of Health were also proposed.
It is important to acknowledge that there is no definitive consensus on which mechanisms should be included as hallmarks of aging. These mechanisms often interact with each other and are interdependent. In certain cases, one hallmark may be encompassed within another, but authors choose to highlight specific sub-mechanisms due to their significant importance. The hallmarks of aging represent an evolving framework that continually expands as our knowledge in the field progresses.
What are the hallmarks of aging?
The hallmarks of aging are a set of cellular and molecular mechanisms identified as key factors in the aging process, which are critical for developing interventions that can slow or reverse the aging process and delay or prevent age-related diseases.
Aging is a complex process that affects all living organisms, and has been a subject of scientific research for many decades. However, the hallmarks of aging represent a simplification of the complex aging process. Despite their limitations, they provide a useful framework for understanding the cellular and molecular changes that occur with age. By identifying and targeting these hallmarks, it is possible to develop therapies aimed at delaying or preventing age-related diseases.
As research in the field of longevity medicine progresses, we can expect to see more hallmarks being added or modified to better reflect our understanding of aging. It is important to keep in mind that aging is a highly interconnected and complex process, and no single hallmark can fully capture the full scope of aging. Thus, a comprehensive approach is needed to address all the factors that contribute to aging.
In the following paragraphs, I will explore and give an overview of the proposed hallmarks of aging and their significance in the context of longevity medicine.
The Hallmarks of aging in longevity medicine (2023)
The original 9 Hallmarks of aging proposed in 2013 were:
- Genomic instability
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Deregulated nutrient sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
To which recently were added the following 5 proposed hallmarks
- Altered mechanical properties of cells and extracellular matrix
- Compromised autophagy
- Dysregulation of RNA processing
- Microbiome disturbances
- Chronic Inflammation
To be included in the list, a hallmark of aging needs to fulfill the following 3 premises:
- Its manifestation has to be age-associated
- By experimentally and artificially accentuating the hallmark, you should also see accelerated aging
- By intervening therapeutically on the hallmark, you should also slow down, stop or reverse the aging process.
Hence, identifying these hallmarks allows the identification of possible targets for intervention against aging and age-related diseases. Although these were the set premises, not all hallmarks tick all 3 boxes as of today and more research is needed to validate them.
Genomic instability is a phenomenon characterized by the accumulation of damage within the genome of cells. Our cells are constantly exposed to various internal and external stressors that can lead to DNA damage. Factors such as exposure to chemicals, ultraviolet (UV) rays, reactive oxygen species (ROS), errors during DNA replication, and other sources of genetic stress can cause lesions and alterations in the DNA structure.
To combat this damage, organisms, including humans, have evolved intricate and sophisticated repair mechanisms. These repair processes are designed to identify and rectify DNA lesions, maintaining the integrity of the genome. However, as we age, the efficiency of these repair mechanisms tends to decline, resulting in the gradual accumulation of DNA damage over time.
The consequences of genomic instability can be far-reaching. DNA damage can lead to mutations, chromosomal rearrangements, and other genetic abnormalities. These changes can impact the functioning of genes and regulatory elements, leading to dysfunctional cells and tissues. Moreover, genomic instability can affect not only nuclear DNA but also mitochondrial DNA (mtDNA) and the integrity of the nuclear lamina, a structural component within the nucleus. Damage to mtDNA and the nuclear lamina further contributes to the overall genomic instability observed during aging.
The consequences of genomic instability extend beyond cellular dysfunction. It is a recognized driver of the aging process and a contributing factor to the development of various age-related diseases, including cancer. The accumulation of DNA damage compromises cellular function, impairs tissue homeostasis, and can ultimately lead to the onset of disease and decline in overall health.
With each cell division, the telomeres, the protective caps at the ends of chromosomes, undergo a gradual shortening process. This occurs because the DNA polymerase, the enzyme responsible for replicating DNA, is unable to fully copy these non-coding regions of DNA. As a result, telomeres progressively shorten with each replication cycle.
As telomeres reach a critically short length after multiple cell divisions, they cause genomic instability which leads to either cell apoptosis or cell senescence.
Telomerase, an enzyme with reverse-transcriptase activity, has the ability to counteract telomere shortening by elongating the telomeric DNA. However, most somatic mammalian cells, including human cells, do not express sufficient levels of telomerase. Consequently, telomeres in these cells gradually erode as we age.
Unlike genomic instability, which is generally associated with negative consequences, telomere attrition can also serve as a protective mechanism against the proliferation of cancerous cells. By limiting the replicative potential of cancer cells, telomere attrition helps to control their growth and prevent the development of tumors. This is why telomere attrition, although part of genomic instability, is considered as a separate hallmark of aging.
Epigenetic alterations encompass a variety of modifications that occur on the DNA and associated proteins, including DNA methylation, histone modifications, chromatin remodeling, and deregulation of non-coding RNA (ncRNA). These alterations play a crucial role in switching genes on and off, thereby regulating gene expression.
Unlike genetic mutations, epigenetic changes are largely reversible and can dynamically influence the activity of genes. By modulating gene expression, epigenetic alterations have far-reaching effects on various biological processes. For instance, they can impact inflammation, mitochondrial function, protein folding, and many other cellular pathways that are central to the development and progression of age-related diseases.
Loss of Proteostasis
Protein homeostasis, or proteostasis, is a critical cellular process that ensures the proper folding, assembly, and clearance of proteins. It plays a fundamental role in maintaining cellular health and function. However, as we age, proteostasis becomes increasingly compromised and less efficient, contributing to the development of various age-related diseases, including Alzheimer’s and Parkinson’s disease.
Proteins are highly dynamic molecules that can undergo structural changes due to various factors such as oxidative stress, glycation, and other post-translational modifications. In addition, errors can occur during protein synthesis or folding, resulting in misfolded or partially folded proteins. These aberrant proteins are prone to forming aggregates, both intracellularly and extracellularly, disrupting normal cellular processes and impairing cellular function.
Deregulated Nutrient Sensing
Deregulated nutrient sensing refers to the dysregulation of cellular pathways involved in sensing and responding to nutrient availability, leading to metabolic imbalances and altered cellular functions.
Our bodies rely on a delicate balance between nutrient intake, utilization, and storage to maintain optimal health and function. However, as we age, this balance becomes disrupted, impairing the ability of cells and tissues to respond appropriately to nutrient cues.
In times of nutrient abundance, our bodies are in an anabolic state, signaling cells to utilize available nutrients for growth, energy production, and storage. This includes processes such as protein synthesis, lipid accumulation, and glycogen formation. Anabolic pathways, driven by nutrient-sensing mechanisms, promote tissue regeneration and support overall growth and development.
Conversely, during periods of nutrient scarcity or fasting, our bodies shift into a catabolic state. Nutrient sensing pathways sense the limited availability of nutrients and trigger cellular responses aimed at conserving energy and promoting repair processes. These responses include autophagy and the activation of stress response pathways that enhance cellular resilience.
In aging, the dysregulation of nutrient sensing pathways disrupts this delicate balance between anabolic and catabolic states. Cells may fail to respond appropriately to nutrient availability, leading to impaired energy metabolism, compromised repair processes, and increased susceptibility to age-related diseases. This imbalance can contribute to the accumulation of damaged proteins, oxidative stress, and inflammation, further exacerbating the aging process.
Some of the key pathways and players involved in nutrient sensing are the mammalian target of rapamycin (mTOR) signaling pathway, insuling and IGF-1 signaling, AMPK, sirtuins and FOXO.
Understanding the mechanisms underlying deregulated nutrient sensing is crucial for developing strategies to promote healthy aging and prevent age-related diseases. Researchers are exploring interventions such as caloric restriction, intermittent fasting, and pharmacological agents that target nutrient sensing pathways to restore metabolic balance and improve healthspan.
Mitochondria, often referred to as the powerhouses of the cells, are vital for energy production, cellular metabolism, and the regulation of various cellular processes, including cell death. However, as we age, mitochondrial function undergoes a decline, giving rise to mitochondrial dysfunction. This dysfunction manifests through several interconnected processes, including the accumulation of mitochondrial DNA (mtDNA) mutations, increased permeability of mitochondrial membranes, elevated production of reactive oxygen species (ROS), reduced energy production, disrupted cellular signaling pathways involved in nutrient sensing, and increased inflammation.
On a larger scale, mitochondrial dysfunction in cells within organs like the brain and heart contributes to the development of age-related diseases such as neurodegeneration and cardiovascular disease. Impaired mitochondrial function within these organs leads to compromised energy production, disrupted cellular signaling, inflammation, and increased susceptibility to cellular damage, all of which contribute to the progression of age-related pathologies.
Cellular senescence is a complex and dynamic physiological response that occurs in cells exposed to various stressors, including mitochondrial dysfunction, DNA damage, microbial infections, nutrient imbalance, oxidative stress, and oncogenic signaling. It acts as a protective mechanism under normal conditions, preventing the proliferation of damaged or potentially cancerous cells and maintaining tissue homeostasis.
When cells undergo senescence, they enter a state of permanent growth arrest. This halts their ability to divide and prevents the propagation of genetic abnormalities. Additionally, senescent cells undergo profound changes in their gene expression and secretory profile. They release a mixture of bioactive molecules, including cytokines, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP). The SASP can have both beneficial and detrimental effects on surrounding cells and tissues.
In ideal circumstances, the immune system recognizes and clears senescent cells, allowing for tissue regeneration and restoration of normal function. However, when immune clearance mechanisms become compromised or overwhelmed, senescent cells can accumulate within tissues. The accumulated senescent cells continue to secrete SASP components, which contribute to localized fibrosis and chronic inflammation. These processes play a crucial role in the progression of aging and the development of various age-related diseases, including type 2 diabetes, lung fibrosis, kidney disease, liver steatosis, and Alzheimer’s disease.
Stem cell exhaustion
Stem cell exhaustion is defined as the decline in the regenerative capacity of tissues and organs over time. Stem cells are a unique population of cells with the ability to self-renew and differentiate into various specialized cell types. They play a crucial role in maintaining tissue homeostasis, repair, and regeneration throughout life.
During the aging process, stem cells gradually lose their regenerative potential. Several factors contribute to stem cell exhaustion, including changes in the stem cell niche, alterations in signaling pathways, accumulation of DNA damage, and the impact of systemic factors and chronic inflammation. These changes result in a decreased number of functional stem cells and a reduced capacity to generate new cells to replace damaged or lost cells.
The decline in stem cell function has significant implications for tissue maintenance and repair. It leads to compromised tissue regeneration and an impaired ability to respond to injury or stress. As a result, tissues and organs become less efficient in their functionality, contributing to the development of age-related diseases and the overall decline in physiological function.
Moreover, hematopoietic stem cells, which are responsible for the production of immune cells, also experience exhaustion with age. This results in reduced immune cell output and impaired immune responses, making older individuals more susceptible to infections, autoimmune disorders, and impaired wound healing.
Altered intercellular communication
Impaired intercellular communication is defined as the alterations in the communication pathways between cells and their surrounding environment. Cells rely on effective communication to coordinate their functions and maintain tissue homeostasis. However, with aging, this intricate network of intercellular communication becomes disrupted, resulting in cellular dysfunction and the development of age-related diseases.
One aspect of impaired intercellular communication is the accumulation of senescent cells which have been shown to secrete a variety of molecules known as senescence-associated secretory phenotype (SASP) factors, including cytokines, chemokines, growth factors, and proteases, which can have detrimental effects on neighboring cells and tissues, contributing to chronic inflammation and tissue dysfunction.
Additionally, the production and activity of hormones and growth factors decline with age, further impairing intercellular communication. Hormones play critical roles in regulating various physiological processes, including metabolism, immune function, and tissue repair. The decreased production and weaker activity of these signaling molecules disrupt the communication between cells and tissues, affecting their coordinated functions. Finally, changes in the extracellular matrix (ECM), a complex network of proteins and other molecules surrounding cells, also contribute to impaired intercellular communication and signaling.
Altered mechanical properties of cells and extracellular matrix (ECM)
Altered mechanical properties of cells and the extracellular matrix (ECM) are defined as changes in the physical characteristics of cells and their surrounding environment. With age, cells and the ECM undergo structural alterations, leading to increased tissue stiffness, decreased elasticity, and impaired cellular mechanotransduction. These changes affect cellular functions, including migration and motility, differentiation, and signaling, and contribute to age-related tissue dysfunction and the development of age-related diseases such as hypertension.
Compromised autophagy is defined as the decline in the efficiency and effectiveness of the cellular recycling process known as autophagy. In the context of longevity medicine it specifically refers to the process of macroautophagy which is the most studied and main autophagy pathway and which targets cell organelles and proteins. Autophagy plays a crucial role in maintaining cellular homeostasis by eliminating damaged organelles and proteins, clearing cellular debris, and providing a source of nutrients during times of stress. However, with aging, autophagy becomes less efficient, leading to the accumulation of cellular waste, dysfunctional organelles and cellular components, reduced elimination of pathogens, accumulation of protein aggregates and increased inflammation. This impaired autophagy contributes to the development of age-related diseases and the decline in cellular function.
Dysregulation of RNA processing
Dysregulation of RNA processing is characterized by disruptions in the intricate machinery responsible for the precise regulation of RNA molecules within cells. RNA processing encompasses a series of steps, including transcription, splicing, and post-transcriptional modifications, that are crucial for generating functional RNA molecules. During aging, this process becomes dysregulated, leading to altered RNA splicing patterns, aberrant RNA modifications, and impaired RNA stability and turnover. These abnormalities can result in the accumulation of defective transcripts, disrupted gene expression patterns, and impaired protein production. The dysregulation of RNA processing contributes to age-related changes in cellular function and is implicated in the development of various age-related diseases.
Microbiome disturbances, also known as dysbiosis, refer to alterations in the composition, diversity, and function of microbial communities residing in the human body, particularly in the intestinal tract. The intestinal microbiome plays a vital role in various physiological processes, including nutrient digestion and absorption, vitamin production, central nervous system signaling, and protection against pathogens. With aging, there is a decline in the diversity and function of the gut microbiota, influenced by factors such as lifestyle choices, medication use, and changes in immune function. These disturbances contribute to chronic inflammation and the development of diseases such as obesity, type 2 diabetes, cardiovascular disease, colitis, cancer, and neurological disorders.
Low-grade chronic inflammation, also known as inflammaging in the context of longevity medicine, refers to the persistent elevation of pro-inflammatory molecules in the bloodstream. This includes cytokines such as IL-1 and IL-6, as well as inflammatory biomarkers like CRP. Alongside increased inflammation, there is a concurrent decline in immune function as the body ages.
Inflammaging can be triggered by various factors, including cellular senescence and mitochondrial dysfunction. It plays a significant role in the development and progression of age-related diseases, including cardiovascular disease, neurodegenerative disorders, and metabolic syndrome. Furthermore, it actively contributes to the aging process itself by promoting tissue damage, impairing tissue repair mechanisms, and disrupting normal cellular functions and intercellular communication.
Possible future additions to the hallmarks of aging
In addition to the currently established hallmarks of aging, ongoing research has identified potential future hallmarks that are being investigated. One such area of interest is the resurrection of endogenous retroviruses (ERVs), which are remnants of ancient viral infections embedded within our DNA. Emerging evidence suggests that ERVs may become active and contribute to age-related diseases. Another mechanism under investigation is cell enlargement, which refers to the increase in cell size that occurs during aging. This phenomenon has been observed in various tissues and is believed to play a role in age-related functional decline. These potential future hallmarks, along with others that may be discovered in the future, hold promise for expanding our understanding of the aging process and developing novel strategies for promoting healthy aging.
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