Hallmarks of Aging

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013^[1] to conceptualize the essence of biological aging and its underlying mechanisms.

Criteria

Each hallmark was chosen to try to fulfill the following criteria:^[1]

manifests during normal aging;
experimentally increasing it accelerates aging;
experimentally amending it slows the normal aging process and increases healthy lifespan.

These conditions are met to different extents by each of these hallmarks. The last criterion is not present in many of the hallmarks, as science has not yet found feasible ways to amend these problems in living organisms.

Overview

Scheme of the currently identified hallmarks of aging along with their classification.^[2]

The Nine Hallmarks of Aging (2013)

#	Hallmark
1	Genomic Instability	Primary Hallmarks (causes damage)
2	Telomere Attrition
3	Epigenetic Alterations
4	Loss of Proteostasis
5	Deregulated Nutrient Sensing	Antagonistic Hallmarks (responses to damage)
6	Mitochondrial Dysfunction
7	Cellular Senescence
8	Stem Cell Exhaustion	Integrative Hallmarks (culprits of the phenotype)
9	Altered Intercellular Communication	Integrative Hallmarks (culprits of the phenotype)

The 14 Hallmarks of Aging (2023)

#	Hallmark	Description
1	Genomic Instability	Accumulation of DNA damage over time leading to cellular dysfunction.	Primary Hallmarks (causes damage)
2	Telomere Attrition	Reduction in the length of telomeres leading to cellular aging.
3	Epigenetic Alterations	Changes in DNA methylation and histone modification affecting gene expression.
4	Loss of Proteostasis	Disruption in protein folding and stability leading to cell damage.
5	Deregulated Nutrient Sensing	Alterations in nutrient sensing pathways affecting metabolism and aging.	Antagonistic Hallmarks (responses to damage)
6	Mitochondrial Dysfunction	Decrease in mitochondrial efficiency and increase in oxidative stress.
7	Cellular Senescence	Accumulation of non-dividing, dysfunctional cells secreting harmful factors.
8	Stem Cell Exhaustion	Decline in the regenerative capacity of stem cells affecting tissue repair.	Integrative Hallmarks (culprits of the phenotype)
9	Altered Intercellular Communication	Changes in cellular communication leading to inflammation and tissue dysfunction.	Integrative Hallmarks (culprits of the phenotype)
10	Compromised Autophagy	Impaired cellular maintenance through the consumption of own components.	Proposed New Hallmarks
11	Splicing Dysregulation	Impaired RNA construction from DNA, leading to cellular dysfunction.
12	Microbiome Disturbance	Changes in gut microbiome affecting health and aging.
13	Altered Mechanical Properties	Changes in cellular and extracellular structure affecting tissue function.
14	Inflammation (Inflammaging)	Systemic inflammation contributing to aging and related diseases.

History

2013 The scientific journal Cell published the article "The Hallmarks of Aging", that was translated to several languages and determined the directions of many studies.^[1]
2022 It was proposed to expand the list of the nine hallmarks of aging with five more.^[3]^[4]
2023 In a paywalled review, the authors of a heavily cited paper on the hallmarks of aging update the set of proposed hallmarks after a decade.^[5] A review with overlapping authors merge or link various hallmarks of cancer with those of aging.^[6]

Todo

2013, The hallmarks of aging ^[1]
2023, Chronic inflammation and the hallmarks of aging ^[7]
2023, Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement ^[2]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 López-Otín C et al.: The hallmarks of aging. Cell 2013. (PMID 23746838) [PubMed] [DOI] [Full text] Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.
↑ ^2.0 ^2.1 Tenchov R et al.: Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem Neurosci 2023. (PMID 38095562) [PubMed] [DOI] Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.
↑ Schmauck-Medina T et al.: New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY) 2022. (PMID 36040386) [PubMed] [DOI] [Full text] Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.
↑ Researchers Propose Five New Hallmarks of Aging, https://www.lifespan.io/news/researchers-propose-five-new-hallmarks-of-aging/
↑ López-Otín C et al.: Hallmarks of aging: An expanding universe. Cell 2023. (PMID 36599349) [PubMed] [DOI] Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
↑ López-Otín C et al.: Meta-hallmarks of aging and cancer. Cell Metab 2023. (PMID 36599298) [PubMed] [DOI] Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
↑ Baechle JJ et al.: Chronic inflammation and the hallmarks of aging. Mol Metab 2023. (PMID 37329949) [PubMed] [DOI] [Full text] BACKGROUND: Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research. SCOPE OF REVIEW: This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases. MAIN CONCLUSIONS: The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

[pmid23746838-1] 1.0 ^1.1 ^1.2 ^1.3 López-Otín C et al.: The hallmarks of aging. Cell 2013. (PMID 23746838) [PubMed] [DOI] [Full text] Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.

[pmid38095562-2] 2.0 ^2.1 Tenchov R et al.: Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem Neurosci 2023. (PMID 38095562) [PubMed] [DOI] Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.

[pmid36040386-3] Schmauck-Medina T et al.: New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY) 2022. (PMID 36040386) [PubMed] [DOI] [Full text] Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

[4] Researchers Propose Five New Hallmarks of Aging, https://www.lifespan.io/news/researchers-propose-five-new-hallmarks-of-aging/

[pmid36599349-5] López-Otín C et al.: Hallmarks of aging: An expanding universe. Cell 2023. (PMID 36599349) [PubMed] [DOI] Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.

[pmid36599298-6] López-Otín C et al.: Meta-hallmarks of aging and cancer. Cell Metab 2023. (PMID 36599298) [PubMed] [DOI] Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.

[pmid37329949-7] Baechle JJ et al.: Chronic inflammation and the hallmarks of aging. Mol Metab 2023. (PMID 37329949) [PubMed] [DOI] [Full text] BACKGROUND: Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research. SCOPE OF REVIEW: This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases. MAIN CONCLUSIONS: The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

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