Cellular Senescence

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

Cellular senescence is a cellular state characterized by a set of distinctive features that mark the end of a cell's ability to divide and function optimally. At the heart of this process is:

• Permanent Cell Cycle Arrest: In this halted state, cells lose their ability to undergo mitotic division. This is often a result of critical telomere shortening, DNA damage, or other stressors that signal the cell it should no longer replicate to prevent potential errors or malfunctions in future cell generations.
• Changes in Cell Morphology and Function: Senescent cells often undergo noticeable changes in shape, size, and internal structures. Additionally, their functionality diminishes, which can impact tissue integrity and the cellular microenvironment, leading to suboptimal organ and system performance over time.
• Senescence-Associated Secretory Phenotype (SASP): One of the defining features of senescent cells is their altered secretory profile. They release a mix of pro-inflammatory cytokines, chemokines, growth factors, and proteases. While the SASP can have beneficial roles, such as in wound healing and tissue regeneration, its chronic presence is associated with a pro-inflammatory environment, which is implicated in various age-related pathologies.

Causes of Cell Senescence

Several factors can induce cellular senescence:

1. Telomere Shortening: Every time a cell divides, its telomeres (protective ends of chromosomes) get shorter. Once they reach a critical length, the cell enters a state of senescence.
2. DNA Damage: Exposure to radiation, toxins, or oxidative stress can damage DNA, triggering senescence.
3. Oncogene Activation: Overactivity of certain genes can promote tumorous growth, and in response, cells may become senescent to prevent cancer.

Implications for Aging and Disease

• Tissue Dysfunction: Senescent cells can impair tissue function due to their loss of proliferative capacity and the secretion of SASP factors, which can cause inflammation and damage surrounding cells.
• Chronic Diseases: Increased senescent cell burden is associated with various age-related diseases, including osteoarthritis, atherosclerosis, and certain types of cancers.
• Reduced Regenerative Capacity: Senescence in stem cells can reduce the body's ability to repair damaged tissues, leading to slower recovery and reduced tissue functionality.

Therapeutic Approaches Targeting Senescence

1. Senolytics: These are drugs designed to selectively remove senescent cells from the body, thus reducing their negative impact. Examples include dasatinib and quercetin.
2. Senomorphics: These compounds aim to modulate the SASP, reducing the harmful effects of senescent cells without necessarily removing them.
3. Lifestyle Interventions: Factors like diet, exercise, and stress reduction can potentially influence the onset and accumulation of senescent cells.

Research and Future Directions

With the understanding of senescence's role in aging, there's a growing interest in developing strategies to modulate this process. Future research aims to:

• Understand the exact mechanisms driving senescence.
• Develop more targeted therapies for senescent cell removal or modulation.
• Explore the long-term effects and potential risks of senescence-targeting interventions.

Todo

• https://onlinelibrary.wiley.com/doi/10.1111/acel.13314