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Cellular Senescence: Difference between revisions
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Cellular senescence, a state in which cells lose their ability to divide and function properly, is a pivotal concept in the study of aging and longevity. This phenomenon is intricately linked with the Hayflick limit, named after biologist Leonard Hayflick, who discovered in the 1960s that most somatic cells have a limited capacity to divide, typically around 40 to 60 times, before they enter senescence. The limitation arises primarily due to telomere shortening—the protective ends of chromosomes that diminish with each cellular division. Once telomeres reach a critical length, the cell perceives it as DNA damage, prompting cell cycle arrest and thereby preventing potential genetic instability. Cellular senescence serves as a double-edged sword. On one hand, it acts as a protective mechanism against cancer, ensuring that damaged cells don't proliferate uncontrollably. On the other, the accumulation of senescent cells contributes to aging and various age-related diseases. As the field of longevity research advances, understanding and addressing the nuances of cellular senescence will be key. Strategies that target senescence, either by removing these cells or modulating their effects, offer promising avenues for enhancing healthspan and potentially extending lifespan. | '''Cellular senescence''', a state in which cells lose their ability to divide and function properly, is a pivotal concept in the study of aging and longevity. This phenomenon is intricately linked with the Hayflick limit, named after biologist Leonard Hayflick, who discovered in the 1960s that most somatic cells have a limited capacity to divide, typically around 40 to 60 times, before they enter senescence. The limitation arises primarily due to telomere shortening—the protective ends of chromosomes that diminish with each cellular division. Once telomeres reach a critical length, the cell perceives it as DNA damage, prompting cell cycle arrest and thereby preventing potential genetic instability. | ||
Cellular senescence serves as a double-edged sword. On one hand, it acts as a protective mechanism against cancer, ensuring that damaged cells don't proliferate uncontrollably. On the other, the accumulation of senescent cells contributes to aging and various age-related diseases. As the field of longevity research advances, understanding and addressing the nuances of cellular senescence will be key. Strategies that target senescence, either by removing these cells or modulating their effects, offer promising avenues for enhancing healthspan and potentially extending lifespan. | |||
== Definition and Characteristics == | == Definition and Characteristics == | ||
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# '''Replicative Senescent Cells''': These cells have become senescent due to repeated cycles of replication and the consequent telomere shortening. When telomeres reach a critically short length, the cell undergoes replicative senescence. | # '''Replicative Senescent Cells''': These cells have become senescent due to repeated cycles of replication and the consequent telomere shortening. When telomeres reach a critically short length, the cell undergoes replicative senescence. | ||
# '''Oncogene-Induced Senescent (OIS) Cells''': These cells enter senescence due to the activation or overexpression of oncogenes, which are genes with the potential to cause cancer. This senescence acts as a protective mechanism, preventing potential tumorigenesis. | # '''Oncogene-Induced Senescent (OIS) Cells''': These cells enter senescence due to the activation or overexpression of oncogenes, which are genes with the potential to cause cancer. This senescence acts as a protective mechanism, preventing potential tumorigenesis. | ||
# '''DNA Damage-Induced Senescent Cells''': Exposure to agents or factors that cause DNA damage, such as radiation, certain chemicals, or oxidative stress, can induce cells to enter a senescent state as a response to protect against potential malignancies or functional aberrations. | # '''DNA Damage-Induced Senescent Cells''': Exposure to agents or factors that cause DNA damage, such as radiation, certain chemicals, or [[Oxidative Stress|oxidative stress]], can induce cells to enter a senescent state as a response to protect against potential malignancies or functional aberrations. | ||
# '''Stress-Induced Premature Senescence (SIPS)''': Various forms of cellular stress, other than DNA damage or oncogene activation, can lead to premature senescence. This includes factors like oxidative stress, mitochondrial dysfunction, or even certain drugs and therapeutic treatments. | # '''Stress-Induced Premature Senescence (SIPS)''': Various forms of cellular stress, other than DNA damage or oncogene activation, can lead to premature senescence. This includes factors like [[Oxidative Stress|oxidative stress]], [[Mitochondrial Dysfunction|mitochondrial dysfunction]], or even certain drugs and therapeutic treatments. | ||
# '''Wound Healing-Associated Senescent Cells''': These cells arise as a part of the wound healing process. They can help in tissue repair but might need to be cleared afterward to restore tissue functionality fully. | # '''Wound Healing-Associated Senescent Cells''': These cells arise as a part of the wound healing process. They can help in tissue repair but might need to be cleared afterward to restore tissue functionality fully. | ||
# '''Developmentally Programmed Senescent Cells''': These are cells that become senescent during embryonic development and play a role in shaping tissues and organs. After fulfilling their function, they are typically cleared from the body. | # '''Developmentally Programmed Senescent Cells''': These are cells that become senescent during embryonic development and play a role in shaping tissues and organs. After fulfilling their function, they are typically cleared from the body. | ||
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During early to mid-life, several factors contribute to the exponential accumulation of senescent cells: | During early to mid-life, several factors contribute to the exponential accumulation of senescent cells: | ||
# '''Natural Aging Process''': As individuals advance in age, cellular stresses, such as DNA damage, telomere shortening, and oxidative stress, become more prevalent, pushing more cells into the senescent state. | # '''Natural Aging Process''': As individuals advance in age, cellular stresses, such as DNA damage, [[Telomere Attrition|telomere shortening]], and [[Oxidative Stress|oxidative stress]], become more prevalent, pushing more cells into the senescent state. | ||
# '''Compounding Effects''': As more cells become senescent, the senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, creating a compounding effect where the rate of new cells entering senescence increases over time. | # '''Compounding Effects''': As more cells become senescent, the senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, creating a compounding effect where the rate of new cells entering senescence increases over time. | ||
# '''Environmental and Lifestyle Factors''': Repeated exposure to stressors like ultraviolet radiation, toxins, or an unhealthy lifestyle can further accelerate the accumulation of senescent cells during these years. | # '''Environmental and Lifestyle Factors''': Repeated exposure to stressors like ultraviolet radiation, toxins, or an unhealthy lifestyle can further accelerate the accumulation of senescent cells during these years. | ||
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However, it's not well-established that the growth rate of senescent cells declines substantially in advanced age. The reasons for a potential stabilization or slowdown include: | However, it's not well-established that the growth rate of senescent cells declines substantially in advanced age. The reasons for a potential stabilization or slowdown include: | ||
# '''Depleted Stem Cell Pools''': With age, the body's pool of stem cells, responsible for tissue regeneration and repair, diminishes. Since there are fewer actively dividing cells in very elderly individuals, there may be fewer cells to enter a senescent state. | # '''[[Stem Cell Exhaustion|Depleted Stem Cell Pools]]''': With age, the body's pool of stem cells, responsible for tissue regeneration and repair, diminishes. Since there are fewer actively dividing cells in very elderly individuals, there may be fewer cells to enter a senescent state. | ||
# '''Natural Cellular Attrition''': Over time, some senescent cells might undergo natural cell death, even if they are initially resistant to apoptosis. | # '''Natural Cellular Attrition''': Over time, some senescent cells might undergo natural cell death, even if they are initially resistant to apoptosis. | ||
# '''Tissue Atrophy and Reduced Cellularity''': Some tissues lose cell density with advanced age, potentially contributing to the reduced absolute numbers of senescent cells. | # '''Tissue Atrophy and Reduced Cellularity''': Some tissues lose cell density with advanced age, potentially contributing to the reduced absolute numbers of senescent cells. | ||
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== Implications for Age-Related Diseases == | == Implications for Age-Related Diseases == | ||
[[File:Incidence Rate of Age-Related Diseases.png|thumb|Incidence Rate of Age-Related Diseases | [[File:Incidence Rate of Age-Related Diseases.png|thumb|Incidence Rate of Age-Related Diseases{{pmid|33559235}}]] | ||
Age-related diseases are the main causes of death and disability. These diseases include cardiovascular disease, cancer, Alzheimer's disease, diabetes, kidney failure, and osteoarthritis. They affect different organ systems and have different origins, including mutations, dysregulated homeostasis, fibrosis, and degenerative processes. | Age-related diseases are the main causes of death and disability. These diseases include cardiovascular disease, cancer, Alzheimer's disease, diabetes, kidney failure, and osteoarthritis. They affect different organ systems and have different origins, including mutations, dysregulated homeostasis, fibrosis, and degenerative processes.{{pmid|33559235}} | ||
Despite the differences between these pathologies, they have certain universal features in terms of their incidence rate. The [[wikipedia:Incidence_(epidemiology)|incidence rate]] of a disease is defined as the number of new cases per year divided by the size of the population. The incidence rate of each age-related disease rises roughly exponentially with age. For many of the diseases, the incidence rate then drops at very old ages. Interestingly, the slope of the rising part of the incidence curve is similar for many age-related diseases, in the range of 6–8% per year (see Figure) . This similarity hints at a common biological process of aging that governs the onset of these different diseases. It is thus of interest to develop theories for the origin of the incidence of age-related diseases, in order to detect such a common process. | Despite the differences between these pathologies, they have certain universal features in terms of their incidence rate. The [[wikipedia:Incidence_(epidemiology)|incidence rate]] of a disease is defined as the number of new cases per year divided by the size of the population. The incidence rate of each age-related disease rises roughly exponentially with age. For many of the diseases, the incidence rate then drops at very old ages. Interestingly, the slope of the rising part of the incidence curve is similar for many age-related diseases, in the range of 6–8% per year (see Figure) . This similarity hints at a common biological process of aging that governs the onset of these different diseases. It is thus of interest to develop theories for the origin of the incidence of age-related diseases, in order to detect such a common process.{{pmid|33559235}} | ||
== Implications for Aging and Disease == | == Implications for Aging and Disease == | ||
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== Therapeutic Approaches Targeting Senescence == | == Therapeutic Approaches Targeting Senescence == | ||
# '''Senolytics''': These are drugs designed to selectively remove senescent cells from the body, thus reducing their negative impact. Examples include dasatinib and quercetin. | # '''[[Senolytics]]''': These are drugs designed to selectively remove senescent cells from the body, thus reducing their negative impact. Examples include dasatinib and quercetin. | ||
# '''Senomorphics''': These compounds aim to modulate the SASP, reducing the harmful effects of senescent cells without necessarily removing them. | # '''Senomorphics''': These compounds aim to modulate the SASP, reducing the harmful effects of senescent cells without necessarily removing them. | ||
# '''Lifestyle Interventions''': Factors like diet, exercise, and stress reduction can potentially influence the onset and accumulation of senescent cells. | # '''Lifestyle Interventions''': Factors like diet, exercise, and stress reduction can potentially influence the onset and accumulation of senescent cells. | ||
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== See also == | == See also == | ||
* [[ | * [[Senolytics]] | ||
* {{SeeWikipedia|Cellular senescence}} | |||
== Todo == | == Todo == | ||
* | * {{pmid text|33559235}} | ||
* | * {{pmid text|31792199}} | ||
* {{pmid text|31379458}} - Senescent cell biomarkers | * {{pmid text|31379458}} - Senescent cell biomarkers | ||
== References == | == References == | ||
<references | <references/> | ||
[[Category:Molecular and Cellular Biology]] | [[Category:Molecular and Cellular Biology]] | ||
[[Category:Aging]] | [[Category:Hallmarks of Aging]] | ||