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[[File:The Nine Hallmarks of Aging.jpg|thumb|The original nine hallmarks of aging as proposed by López-Otín and colleagues in 2013{{pmid|23746838}}]]
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{{pmid|23746838}} to conceptualize the essence of biological aging and its underlying mechanisms.
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{{pmid|23746838}} to conceptualize the essence of biological aging and its underlying mechanisms.


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|-
|-
|1
|1
|'''Genomic Instability'''
|'''[[Genomic Instability]]'''
| rowspan="4" |'''Primary Hallmarks'''
| rowspan="4" |'''Primary Hallmarks'''
(causes damage)
(causes damage)
|-
|-
|2
|2
|'''Telomere Attrition'''
|'''[[Telomere Attrition]]'''
|-
|-
|3
|3
|'''Epigenetic Alterations'''
|'''[[Epigenetic Alterations]]'''
|-
|-
|4
|4
|'''Loss of Proteostasis'''
|'''[[Loss of Proteostasis]]'''
|-
|-
|5
|5
|'''Deregulated Nutrient Sensing'''
|'''[[Deregulated Nutrient Sensing]]'''
| rowspan="3" |'''Antagonistic Hallmarks'''
| rowspan="3" |'''Antagonistic Hallmarks'''
(responses to damage)
(responses to damage)
|-
|-
|6
|6
|'''Mitochondrial Dysfunction'''
|'''[[Mitochondrial Dysfunction]]'''
|-
|-
|7
|7
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|-
|-
|8
|8
|'''Stem Cell Exhaustion'''
|'''[[Stem Cell Exhaustion]]'''
| rowspan="2" |'''Integrative Hallmarks'''
| rowspan="2" |'''Integrative Hallmarks'''
(culprits of the phenotype)
(culprits of the phenotype)
|-
|-
|9
|9
|'''Altered Intercellular Communication'''
|'''[[Altered Intercellular Communication]]'''
|}
|}


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=== The Twelve Hallmarks of Aging (2023) ===
=== The Twelve Hallmarks of Aging (2023) ===
The original authors of the nine hallmarks of aging update the set of proposed hallmarks after a decade.{{pmid|36599349}}
<div style="overflow-x:auto;">
{| class="wikitable"
{| class="wikitable"
!Level
!Level
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!Category
!Category
|-
|-
| rowspan="5" style="background-color:hsla(195, 100%, 85%);" |'''Molecular<br>Level'''
| rowspan="5" style="background-color:hsla(195, 100%, 85%);" |'''{{VerticalText|Molecular Level}}'''
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:DNA Structure+Key+Labelled.pn NoBB.png|frameless|76x76px]]
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:DNA Structure+Key+Labelled.pn NoBB.png|frameless|76x76px]]
| style="background-color:hsla(180, 100%, 85%);" |'''Genomic instability'''
| style="background-color:hsla(180, 100%, 85%);" |'''[[Genomic Instability|Genomic instability]]'''
| style="background-color:hsla(180, 100%, 85%);" |Accumulation of DNA damage over time leading to cellular dysfunction.
| style="background-color:hsla(180, 100%, 85%);" |Accumulation of DNA damage over time leading to cellular dysfunction.
|2013
|2013
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|-
|-
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:Telomeres transparent.png|frameless|88x88px]]
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:Telomeres transparent.png|frameless|88x88px]]
| style="background-color:hsla(180, 100%, 85%);" |'''Telomere attrition'''
| style="background-color:hsla(180, 100%, 85%);" |'''[[Telomere Attrition|Telomere attrition]]'''
| style="background-color:hsla(180, 100%, 85%);" |Reduction in the length of telomeres leading to cellular aging.
| style="background-color:hsla(180, 100%, 85%);" |Reduction in the length of telomeres leading to cellular aging.
|2013
|2013
|-
|-
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:Epigenome-transparent-upscale.png|frameless|85x85px]]
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |[[File:Epigenome-transparent-upscale.png|frameless|85x85px]]
| style="background-color:hsla(180, 100%, 85%);" |'''Epigenetic alterations'''
| style="background-color:hsla(180, 100%, 85%);" |'''[[Epigenetic Alterations|Epigenetic alterations]]'''
| style="background-color:hsla(180, 100%, 85%);" |Changes in DNA methylation and histone modification affecting gene expression.
| style="background-color:hsla(180, 100%, 85%);" |Changes in DNA methylation and histone modification affecting gene expression.
|2013
|2013
|-
|-
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |[[File:Stress signaling.png|frameless|95x95px]]
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |[[File:Loss of Proteostasis.png|frameless|118x118px]]
| style="background-color:hsla(210, 100%, 85%);" |'''Loss of proteostasis'''
| style="background-color:hsla(210, 100%, 85%);" |'''[[Loss of Proteostasis|Loss of proteostasis]]'''
| style="background-color:hsla(210, 100%, 85%);" |Disruption in protein folding and stability leading to cell damage.
| style="background-color:hsla(210, 100%, 85%);" |Disruption in protein folding and stability leading to cell damage.
|2013
|2013
|-
|-
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |[[File:Macro-micro-autophagy.gif|frameless|101x101px]]
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |[[File:Macro-micro-autophagy-transparent.png|frameless|101x101px]]
| style="background-color:hsla(210, 100%, 85%);" |'''Disabled autophagy'''
| style="background-color:hsla(210, 100%, 85%);" |'''[[Disabled Macroautophagy|Disabled macroautophagy]]'''
| style="background-color:hsla(210, 100%, 85%);" | Impaired cellular maintenance through the consumption of own components.
| style="background-color:hsla(210, 100%, 85%);" | Impaired cellular maintenance through the consumption of own components.
|2021{{pmid|34563704}}
|2021{{pmid|34563704}}
| rowspan="4" |'''Antagonistic Hallmarks'''<br>(responses to damage)
| rowspan="4" |'''Antagonistic Hallmarks'''<br>(responses to damage)
|-
|-
| rowspan="7" style="background-color:hsla(15, 100%, 85%);" |'''Cellular &<br>Organismal<br>Level'''
| rowspan="7" style="background-color:hsla(15, 100%, 85%);" |'''{{VerticalText|Cellular & Organismal Level}}'''
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |[[File:Aiga restaurant knife-fork crossed.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |[[File:Aiga restaurant knife-fork crossed.png|frameless|75x75px]]
| style="background-color:hsla(0, 100%, 85%);" |'''Deregulated nutrient sensing'''
| style="background-color:hsla(0, 100%, 85%);" |'''[[Deregulated Nutrient Sensing|Deregulated nutrient sensing]]'''
| style="background-color:hsla(0, 100%, 85%);" | Alterations in nutrient sensing pathways affecting metabolism and aging.
| style="background-color:hsla(0, 100%, 85%);" | Alterations in nutrient sensing pathways affecting metabolism and aging.
|2013
|2013
|-
|-
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |[[File:Mitochondrion mini.svg|frameless|92x92px]]
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |[[File:Mitochondrion mini.svg|frameless|92x92px]]
| style="background-color:hsla(0, 100%, 85%);" |'''Mitochondrial dysfunction'''
| style="background-color:hsla(0, 100%, 85%);" |'''[[Mitochondrial Dysfunction|Mitochondrial dysfunction]]'''
| style="background-color:hsla(0, 100%, 85%);" | Decrease in mitochondrial efficiency and increase in oxidative stress.
| style="background-color:hsla(0, 100%, 85%);" | Decrease in mitochondrial efficiency and increase in [[Oxidative Stress|oxidative stress]].
|2013
|2013
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:DALL·E 2023-10-15 05.28.43 - Photo of senescent cells magnified under a microscope, showing their characteristic enlarged and flattened morphology. The cells are stained with a bl.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:cellular-senescence-process.png|frameless|142x142px]]
| style="background-color:hsla(30, 100%, 85%);" |[[Senescent Cells|'''Cellular senescence''']]
| style="background-color:hsla(30, 100%, 85%);" |[[Senescent Cells|'''Cellular senescence''']]
| style="background-color:hsla(30, 100%, 85%);" |Accumulation of non-dividing, dysfunctional cells secreting harmful factors.
| style="background-color:hsla(30, 100%, 85%);" |Accumulation of non-dividing, dysfunctional cells secreting harmful factors.
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|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Stem cell differentiation.svg|frameless|106x106px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Stem cell differentiation.svg|frameless|106x106px]]
| style="background-color:hsla(30, 100%, 85%);" |'''Stem cell exhaustion'''
| style="background-color:hsla(30, 100%, 85%);" |'''[[Stem Cell Exhaustion|Stem cell exhaustion]]'''
| style="background-color:hsla(30, 100%, 85%);" |Decline in the regenerative capacity of stem cells affecting tissue repair.
| style="background-color:hsla(30, 100%, 85%);" |Decline in the regenerative capacity of stem cells affecting tissue repair.
|2013
|2013
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|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:202004 Gut microbiota.svg|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:202004 Gut microbiota.svg|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |'''Dysbiosis'''
| style="background-color:hsla(30, 100%, 85%);" |'''[[Dysbiosis (Microbiome Disturbance)|Dysbiosis<br>(Microbiome disturbance)]]'''
'''(Microbiome disturbance)'''
| style="background-color:hsla(30, 100%, 85%);" |Changes in gut microbiome affecting health and aging.
| style="background-color:hsla(30, 100%, 85%);" |Changes in gut microbiome affecting health and aging.
|
|
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Histopathology of acute and chronic inflammation of the gastro-esophageal junction, annotated.jpg|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Histopathology of acute and chronic inflammation of the gastro-esophageal junction, annotated.jpg|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |'''Chronic inflammation'''
| style="background-color:hsla(30, 100%, 85%);" |'''[[Chronic Inflammation (Inflammaging)|Chronic inflammation<br>(Inflammaging)]]'''
'''(Inflammaging)'''
| style="background-color:hsla(30, 100%, 85%);" |Systemic inflammation contributing to aging and related diseases.
| style="background-color:hsla(30, 100%, 85%);" |Systemic inflammation contributing to aging and related diseases.
|2023{{pmid|37329949}}
|2023{{pmid|37329949}}
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Forms of Cell Signaling.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[File:Forms of Cell Signaling.png|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |'''Altered intercellular communication'''
| style="background-color:hsla(30, 100%, 85%);" |'''[[Altered Intercellular Communication|Altered intercellular communication]]'''
| style="background-color:hsla(30, 100%, 85%);" |Changes in cellular communication leading to inflammation and tissue dysfunction.
| style="background-color:hsla(30, 100%, 85%);" |Changes in cellular communication leading to inflammation and tissue dysfunction.
|2013
|2013
|}
|}
</div>


=== Potential Hallmarks of Aging ===
=== Potential Hallmarks of Aging ===
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== The Hallmarks in Detail ==
== The Hallmarks in Detail ==
<div style="overflow-x:auto;">
{| class="wikitable"
{| class="wikitable"
!Hallmark
!Hallmark
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!Associated human diseases
!Associated human diseases
|-
|-
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |'''Genomic instability'''[[File:DNA Structure+Key+Labelled.pn NoBB.png|frameless|76x76px]]
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |'''[[Genomic Instability|Genomic instability]]'''[[File:DNA Structure+Key+Labelled.pn NoBB.png|frameless|76x76px]]
| style="background-color:hsla(180, 100%, 85%);" |Damange in the DNA are formed mainly through oxidative stress and environmental factors.{{pmid|15123782}} A number of molecular processes work continuously to repair this damage.{{pmid|15703726}}
| style="background-color:hsla(180, 100%, 85%);" |Damange in the DNA are formed mainly through [[Oxidative Stress|oxidative stress]] and environmental factors.{{pmid|15123782}} A number of molecular processes work continuously to repair this damage.{{pmid|15703726}}
|DNA damage accumulates over time{{pmid|23398157}}
|DNA damage accumulates over time{{pmid|23398157}}
|Deficient DNA repair causes premature aging{{pmid|19812404}}
|Deficient DNA repair causes premature aging{{pmid|19812404}}
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|
|
|-
|-
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |'''Telomere attrition'''[[File:Telomeres transparent.png|frameless|88x88px]]
| style="text-align:center; background-color:hsla(180, 100%, 85%);" |'''[[Telomere Attrition|Telomere attrition]]'''[[File:Telomeres transparent.png|frameless|88x88px]]
| style="background-color:hsla(180, 100%, 85%);" |Telomere attrition refers to the progressive shortening of telomeres, which are protective sequences at the ends of chromosomes. This occurs due to the inability of DNA polymerases to completely replicate the ends of linear DNA, and the absence of telomerase in most somatic cells. Shortened telomeres lead to cellular aging and reduced regenerative capacity, manifesting as replicative senescence or Hayflick limit{{pmid|17024208}}. Shelterins protect telomeres but may mask damage leading to persistent DNA damage and cellular stress{{pmid|18680434}}. Dysfunctions in telomere maintenance are linked to various age-related diseases{{pmid|22965356}}.
| style="background-color:hsla(180, 100%, 85%);" |Telomere attrition refers to the progressive shortening of telomeres, which are protective sequences at the ends of chromosomes. This occurs due to the inability of DNA polymerases to completely replicate the ends of linear DNA, and the absence of telomerase in most somatic cells. Shortened telomeres lead to cellular aging and reduced regenerative capacity, manifesting as replicative senescence or Hayflick limit{{pmid|17024208}}. Shelterins protect telomeres but may mask damage leading to persistent DNA damage and cellular stress{{pmid|18680434}}. Dysfunctions in telomere maintenance are linked to various age-related diseases{{pmid|22965356}}.
|Telomere shortening is observed during normal aging in humans and mice{{pmid|17876321}}.
|Telomere shortening is observed during normal aging in humans and mice{{pmid|17876321}}.
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| style="background-color:hsla(180, 100%, 85%);" |'''DNA methylation shift''': DNA methylation is a biochemical process involving the addition of a methyl group to the DNA molecule, specifically to the cytosine or adenine DNA nucleotides. This process is a form of epigenetic modification, which means it can affect gene expression and function without changing the DNA sequence itself.
| style="background-color:hsla(180, 100%, 85%);" |'''DNA methylation shift''': DNA methylation is a biochemical process involving the addition of a methyl group to the DNA molecule, specifically to the cytosine or adenine DNA nucleotides. This process is a form of epigenetic modification, which means it can affect gene expression and function without changing the DNA sequence itself.
|DNA methylation generally decreases with age in certain human and mouse tissues or cell cultures.{{pmid|3611071}}{{pmid|22689993}}{{pmid|35143257}}{{pmid|35501397}} The loss of methylation in CD4<sup>+</sup> T cells is proportional to age.{{pmid|22689993}}
|DNA methylation generally decreases with age in certain human and mouse tissues or cell cultures.{{pmid|3611071}}{{pmid|22689993}}{{pmid|35143257}}{{pmid|35501397}} The loss of methylation in CD4<sup>+</sup> T cells is proportional to age.{{pmid|22689993}}
|No direct evidence yet that altering DNA methylation patterns extends lifespan.
|No direct evidence yet.
|No direct evidence yet that altering DNA methylation patterns extends lifespan.
|No direct evidence yet.
|Progeroid syndromes exhibit DNA methylation patterns similar to normal aging, suggesting a link with aging-related diseases{{pmid|20961378}}{{pmid|16738054}}.
|Progeroid syndromes exhibit DNA methylation patterns similar to normal aging, suggesting a link with aging-related diseases{{pmid|20961378}}{{pmid|16738054}}.
|-
|-
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|
|
|-
|-
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |'''Loss of proteostasis'''[[File:Stress signaling.png|frameless|95x95px]]
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |'''[[Loss of Proteostasis|Loss of proteostasis]]'''
| style="background-color:hsla(210, 100%, 85%);" |
'''[[File:Loss of Proteostasis.png|frameless|118x118px]]'''
|
| style="background-color:hsla(210, 100%, 85%);" |Loss of proteostasis refers to the disruption of the body's ability to regulate its proteins effectively, a process in which chaperones play a crucial role. This encompasses the processes of protein synthesis, folding, transport, and degradation. Chaperones, specialized proteins that assist in the proper folding and stabilization of other proteins, are essential in maintaining proteostasis. As we age, or in certain diseases, the balance of these processes can be disturbed, leading to the accumulation of misfolded or damaged proteins, and a decrease in the ability to produce and maintain healthy proteins. The decline in the efficiency or availability of chaperones contributes to this loss of proteostasis, exacerbating the accumulation of dysfunctional proteins and cellular stress.
|
|Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis.{{pmid|19298183}}
|
|Mutant mice that  that lack a certain helper chaperone from the heat-shock protein family show accelerated aging.{{pmid|18411298}}
|
|Transgenic worms and flies overexpressing chaperones are long-lived{{pmid|14734639}}{{pmid|12882326}}
|Chronic expression of unfolded, misfolded or aggregated proteins contributes to the development of some age-related pathologies, such as Alzheimer’s disease, Parkinson’s disease and cataracts{{pmid|19298183}}.
|-
|-
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |'''Disabled autophagy'''[[File:Macro-micro-autophagy.gif|frameless|101x101px]]
| style="text-align:center; background-color:hsla(210, 100%, 85%);" |'''[[Disabled Macroautophagy|Disabled macroautophagy]]'''
| style="background-color:hsla(210, 100%, 85%);" |
[[File:Macro-micro-autophagy-transparent.png|frameless|101x101px]]
|
| style="background-color:hsla(210, 100%, 85%);" |'''Disabled macroautophagy''', often referred as impaired or dysfunctional autophagy, is a condition where the cellular process of autophagy—specifically the macroautophagy pathway—is disrupted or less effective. Autophagy is a critical cellular process for degrading and recycling damaged organelles, misfolded proteins, and other cellular debris. Macroautophagy involves the engulfment of these unwanted materials into vesicles called autophagosomes, which then fuse with lysosomes where the contents are degraded and recycled. When macroautophagy is disabled or impaired, cells accumulate damaged proteins and organelles, leading to cellular dysfunction and contributing to various diseases, particularly those related to aging and neurodegeneration. This loss of a crucial cellular "cleanup" mechanism can result in increased [[Oxidative Stress|oxidative stress]], disrupted cellular homeostasis, and an acceleration of the aging process.
|
 
While originally considered under hallmark '''altered proteostasis''', autophagy regulates a number of other hallmarks of ageing such as DNA repair and nutrient sensing/metabolism{{pmid|29626215}}, and hence it was proposed to be categorized as an integrative hallmark.
|Compromised autophagy is observed in numerous ageing conditions including neurodegeneration and immunosenescence{{pmid|31144030}}{{pmid|34901876}}.
|
|
|Activation of autophagy can increase mouse lifespan{{pmid|29849149}}, and even improve immune response to vaccination in older humans by overcoming immunosenescence{{pmid|33317695}}.
|
|
|-
|-
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |'''Deregulated nutrient sensing'''[[File:Aiga restaurant knife-fork crossed.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |'''[[Deregulated Nutrient Sensing|Deregulated nutrient sensing]]'''
| style="background-color:hsla(0, 100%, 85%);" |
[[File:Aiga restaurant knife-fork crossed.png|frameless|75x75px]]
|
| style="background-color:hsla(0, 100%, 85%);" |'''Deregulated nutrient sensing''' refers to the body's declining ability to properly manage and respond to nutrients, such as fats, sugars, and proteins, as we get older. Normally, our bodies have finely tuned systems that detect when we eat and use these nutrients efficiently for energy and repair. However, with age, these systems start to malfunction. This means our body might not handle sugars well, leading to conditions like diabetes, or it might struggle with managing fats, leading to issues like high cholesterol. Essentially, Deregulated Nutrient Sensing is when our body's 'nutrient management system' becomes less efficient and accurate with age, leading to various metabolic and health problems.
|
|Deregulated nutrient sensing ability takes place upon aging.{{pmid|31249645}}
|
|
|The significance of nutrient sensing throughout the aging process has been first established in the prominent observation that decreased food intake in rats prolongs lifespan relative to ad libitum fed controls.{{pmid|2520283}}
|
|
|-
|-
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |'''Mitochondrial dysfunction'''[[File:Mitochondrion mini.svg|frameless|92x92px]]
| style="text-align:center; background-color:hsla(0, 100%, 85%);" |'''[[Mitochondrial Dysfunction|Mitochondrial dysfunction]]'''[[File:Mitochondrion mini.svg|frameless|92x92px]]
| style="background-color:hsla(0, 100%, 85%);" |
| style="background-color:hsla(0, 100%, 85%);" |
|
|
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|
|
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[Senescent Cells|'''Cellular senescence''']][[File:DALL·E 2023-10-15 05.28.43 - Photo of senescent cells magnified under a microscope, showing their characteristic enlarged and flattened morphology. The cells are stained with a bl.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |[[Senescent Cells|'''Cellular senescence''']]
[[File:cellular-senescence-process.png|frameless|142x142px]]
| style="background-color:hsla(30, 100%, 85%);" |
| style="background-color:hsla(30, 100%, 85%);" |
|
|
|
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|
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|
|
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''Stem cell exhaustion'''[[File:Stem cell differentiation.svg|frameless|106x106px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''[[Stem Cell Exhaustion|Stem cell exhaustion]]'''[[File:Stem cell differentiation.svg|frameless|106x106px]]
| style="background-color:hsla(30, 100%, 85%);" |
| style="background-color:hsla(30, 100%, 85%);" |
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|
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|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''Dysbiosis'''
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''[[Dysbiosis (Microbiome Disturbance)|Dysbiosis<br>(Microbiome disturbance)]]'''
'''(Microbiome disturbance)'''[[File:202004 Gut microbiota.svg|frameless|75x75px]]
[[File:202004 Gut microbiota.svg|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |
| style="background-color:hsla(30, 100%, 85%);" |
|
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|
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|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''Chronic inflammation'''
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''[[Chronic Inflammation (Inflammaging)|Chronic inflammation<br>(Inflammaging)]]'''
'''(Inflammaging)'''[[File:Histopathology of acute and chronic inflammation of the gastro-esophageal junction, annotated.jpg|frameless|75x75px]]
[[File:Histopathology of acute and chronic inflammation of the gastro-esophageal junction, annotated.jpg|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |
| style="background-color:hsla(30, 100%, 85%);" |
|
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|
|
|-
|-
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''Altered intercellular communication'''[[File:Forms of Cell Signaling.png|frameless|75x75px]]
| style="text-align:center; background-color:hsla(30, 100%, 85%);" |'''[[Altered Intercellular Communication|Altered intercellular communication]]'''[[File:Forms of Cell Signaling.png|frameless|75x75px]]
| style="background-color:hsla(30, 100%, 85%);" |
| style="background-color:hsla(30, 100%, 85%);" |
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|}
|}
</div>
== Correlation to Age-Related Diseases ==
[[File:Relationship between the hallmarks of aging and the age-related diseases.jpg|thumb|Relationship between the hallmarks of aging and the age-related diseases as revealed by the number of corelated documents{{pmid|38095562}}]]
This section explores the correlations between the aging hallmarks and the age-related diseases, as reflected in the number of documents in the CAS Content Collection. Generally, cellular senescence, mitochondrial dysfunction, lipid metabolism disorders, and inflammaging appear as related to multiple pathologies.{{pmid|38095562}}
Some particular correlations are noteworthy:
*There is a strong correlation between documents related to cellular senescence and cancer, according to the CAS Content Collection. Cellular senescence is a state of a cell cycle arrest, so the entry of cells into senescence can act as a barrier to tumorigenesis thus being of special interest for anticancer therapies. It has been demonstrated however that, in certain conditions, malignant and nonmalignant senescent cells can develop protumorigenic properties and eventually trigger tumor relapse, evidencing contrasting roles of senescent cells in cancer still remaining to be explored.{{pmid|36045302}}{{pmid|34135460}}{{pmid|34458273}}
*The strongest correlation between diabetes mellitus and aging hallmarks is with the lipid metabolism disorders, according to the CAS Content Collection documents number. Glucose and lipid metabolism are correlated in multiple ways.{{pmid|26566492}} One of the notable manifestations of this correlation is diabetic dyslipidemia, with both being well established cardiovascular risk factors. The link between glucose and lipid metabolism is in fact rather complex with both lipids and glucose playing important roles in energy metabolism.{{pmid|26566492}}{{pmid|29858856}}{{pmid|17429039}}


* Hypertension–lipid metabolism disorders correlation: It has been reported that both hypertension and aging are associated with higher lipid peroxidation.{{pmid|26763852}} Aging is additionally associated with an increase in lipid peroxidation in cardiac muscle.{{pmid|10963736}}


* Inflammation–cellular senescence correlation: Aging is characterized by systemic chronic inflammation, linked to cellular senescence, immunosenescence, and age-related organ dysfunction. Senescence-associated secretory phenotype (SASP) factors secreted by senescent cells promote chronic inflammation. Meanwhile, chronic inflammation accelerates the senescence of immune cells, resulting in an inability to clear inflammatory factors, which creates a malicious cycle of inflammation and senescence.
*Altogether, there is significant correlation between cellular senescence and the majority of age-related diseases.{{pmid|26646499}} The disadvantages of senescence seem to be in, first, causing a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells and, second, in producing proinflammatory molecules in the senescence-associated secretory phenotype (SASP). Substantial pool of information about senescence in cells has been acquired recently; however, it is still poorly understood.
*Cognitive impairment–mitochondrial dysfunction correlation: The brain profoundly depends on mitochondria to produce energy, in order to maintain essential bodily functions. Upon aging, damaged mitochondria accumulate. They produce insufficient ATP and excessive ROS. It has been recently reported that mitochondria at dysfunctional synapses do not meet the energetic need and potentially trigger age-related cognitive impairment.<ref>Mitochondrial Dysfunction May Be a Cause of Age-Related Cognitive Impairment. https://www.genengnews.com/news/mitochondrial-dysfunction-may-be-a-cause-of-age-related-cognitive-impairment/#:~:text=During%20aging%2C%20damaged%20mitochondria%20that,cause%20age%2Drelated%20cognitive%20impairment. (accessed Jul 21, 2023).</ref>{{pmid|37122384}}
*Alzheimer disease–mitochondrial dysfunction correlation: Alzheimer’s disease is the most frequent source of age-related neurodegeneration and cognitive impairment. A growing body of evidence implicates mitochondrial dysfunction as a common pathogenic mechanism involved in many of the features of the Alzheimer’s patients brain, such as formation of amyloid plaques and neurofibrillary tangles.{{pmid|34063708}}
*Altogether, there is significant correlation between mitochondrial dysfunction and the majority of age-related diseases including diabetes, inflammation, obesity, neurodegenerative disorders, cardiovascular diseases, and cancer.{{pmid|29257072}} Mitochondria are vital in regulation of energy and metabolic homeostasis. Proper mitochondrial functions, including cellular energy production and control of [[Oxidative Stress|oxidative stress]], are in strong relation with the accurate performance of brain, cognition, and the overall health.{{pmid|33808109}}
*Liver fibrosis–lipid metabolic disorders correlation: Liver plays a key role in lipid metabolism; therefore alterations in hepatic lipid metabolism can be a factor in development of chronic liver disease. Furthermore, chronic liver disease can impact hepatic lipid metabolism causing alterations in circulating lipid levels contributing to dyslipidemia.<ref>Arvind A.; Osganian S. A.; Cohen D. E.E.; C K.. Lipid and Lipoprotein Metabolism in Liver Disease. In Endotext [Internet]; Feingold K. R., Anawalt B., Blackman M. R., Eds.; MDText.com, Inc.: South Dartmouth, 2019. [Google Scholar]</ref> Likewise, the liver plays an essential role in lipid metabolism, certain steps of lipid synthesis, and transport. Therefore, abnormal lipid profiles and liver dysfunctions are expectedly closely correlated.{{pmid|22312394}}
*Altogether, there is significant correlation between lipid metabolic disorders and the majority of age-related diseases.{{pmid|33924316}} Upon aging, body fat builds up with changes in the lipid metabolism. Considering lipid metabolism, excess body fat with enhanced lipotoxicity triggers various age-related diseases, including cardiovascular disease, cancer, arthritis, diabetes, and Alzheimer’s disease. Progress in lipidomic techniques has identified alterations in lipid profiles associated with aging. Lipid accumulation and impaired fatty acid processing are associated with pathophysiological aging phenotypes. Although it is still not well-known how lipid metabolism is regulated upon aging, data suggest a dynamic role for lipid metabolism in signaling and gene expression regulation.{{pmid|33924316}}{{pmid|31560163}}
==History==
==History==


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*'''2022''' It was proposed to expand the list of the nine hallmarks of aging with five more.{{pmid|36040386}}<ref>{{cite web|vauthors=Conway J|url=https://www.lifespan.io/news/researchers-propose-five-new-hallmarks-of-aging/|title=Researchers Propose Five New Hallmarks of Aging|work=[[Life Extension Advocacy Foundation|Lifespan.io]]|date=29 August 2022}}</ref>
*'''2022''' It was proposed to expand the list of the nine hallmarks of aging with five more.{{pmid|36040386}}<ref>{{cite web|vauthors=Conway J|url=https://www.lifespan.io/news/researchers-propose-five-new-hallmarks-of-aging/|title=Researchers Propose Five New Hallmarks of Aging|work=[[Life Extension Advocacy Foundation|Lifespan.io]]|date=29 August 2022}}</ref>
*'''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.{{pmid|36599349}} A review with overlapping authors merge or link various hallmarks of cancer with those of aging.{{pmid|36599298}}
*'''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.{{pmid|36599349}} A review with overlapping authors merge or link various hallmarks of cancer with those of aging.{{pmid|36599298}}
== Further Reading ==
* {{pmid text|23746838}}
* {{pmid text|38095562}}
* {{pmid text|36599349}}
== See Also ==
* [[Age-Related Diseases]]
* {{SeeWikipedia|Hallmarks of aging}}


==Todo==
==Todo==


*{{pmid text|23746838}}
*{{pmid text|37329949}}
*{{pmid text|37329949}}
*{{pmid text|38095562}}
*{{pmid text|35259281}}
*{{pmid text|35259281}}
*https://doi.org/10.1038/s41587-023-02024-y
*https://doi.org/10.1038/s41587-023-02024-y
*{{pmid text|36599298}}


==References==
==References==
<references />
<references />
[[Category:Aging]]
[[Category:Hallmarks of Aging|!Hallmarks_of_Aging]]
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