Unraveling the Secrets of Cellular Senescence for Healthy Aging

Cellular senescence triggers a biological process that causes cells to enter an irreversible state of growth arrest with no opportunity for further division. Understanding senescence properties and processes allows researchers to develop treatments that reduce adverse effects and utilize senescence's protective characteristics.

Fig. 1 This section explains how senescent cell characteristics function and identifies the elements that constitute the senescence-induced secretory phenotype (SASP). (Xiao S, et al., 2023)

What Is Cell Senescence?

Cells stop dividing permanently when they are affected by various stress conditions like DNA damage and telomere shortening along with oxidative stress, and this state of permanent growth arrest is called cellular senescence. Senescent cells exhibit several distinct characteristics:

• Morphological Changes: Senescent cells have larger dimensions and a flatter appearance than cells that are actively dividing. Cells undergo shape transformation due to structural changes occurring in the cytoskeleton.
• Increased Senescence-Associated β-Galactosidase (SA-β-Gal) Activity: Researchers can detect senescent cells by identifying their increased SA-β-Gal enzyme activity through specialized staining techniques. Researchers use this particular marker regularly to detect senescent cells in laboratory settings.
• Altered Gene Expression: The gene expression of senescent cells shows a notable increase in cell cycle inhibitors like p16INK4a and p21CIP1 while displaying a decrease in genes associated with cell proliferation.
• SASP: Senescent cells produce pro-inflammatory cytokines as well as growth factors and proteases, which together are referred to as the SASP. The molecules secreted from cells influence the activities of nearby cells, which results in tissue structural modifications and inflammatory responses.
• Resistance to Apoptosis: These cells show resistance to apoptosis, which allows them to remain in tissue even when damage exists.

Why Does Senescence Occur?

Cellular senescence acts as a defense mechanism to protect against possible cancer risks when cells encounter various stressors and damaging stimuli. The fundamental causes of senescence will be described in this section.

Replicative Senescence and Hayflick Limit

This senescence occurs as a natural consequence of repeated cell division. The Hayflick limit defines the specific maximum number of cell replications before division comes to a stop. Human somatic cells can generally divide between 40 and 60 times before they encounter their division limit. The natural defense mechanism functions to stop excessive cellular multiplication, which prevents cancer formation.

During cell division, telomeres become progressively shorter. Telomeres function as protective end caps on chromosomes that keep their ends from deteriorating. Once telomeres reach critically short lengths, they trigger a DNA damage response, leading to cell cycle arrest and senescence.

DNA Damage-Induced Senescence

Multiple stress factors create DNA damage, which triggers cellular responses that lead to senescence development. DNA damage occurs through environmental factors, including UV radiation and chemicals, as well as replication mistakes and oxidative stress. The detection of cellular damage triggers the activation of p53 and p21 pathways, which then start cell cycle arrest and senescence processes.

Damaged DNA replication halts through cellular response, which minimizes the mutation likelihood that could cause cancer development. Senescent cells following DNA damage demonstrate elevated SA-β-Gal activity alongside SASP characteristics, which affect nearby cells and their tissue performance.

Oncogene-Induced Senescence (OIS)

Specific oncogenes trigger a senescence response, which serves to protect cells against tumor development. Mutated oncogenes or those with excessive expression trigger unrestricted cellular growth. Oncogene activation generates cellular stress, which leads to DNA damage while also initiating a senescence response. When oncogenes become active, they trigger signaling pathways through both p16INK4a and p53.

Senescence and Aging

Fig. 2 Comparative representation of the aging and senescence processes. (Schmeer C, et al., 2019)

• Accumulation of Senescent Cells: Senescent cells increase in number across multiple tissues during an organism's entire lifespan. Senescent cells build up through replicative senescence as well as oxidative stress and chronic inflammation. Senescent cells disrupt the regular functioning and equilibrium of tissues.
• Impact on Tissue Regeneration: Senescent cells create impairment, which leads to a decrease in tissue regenerative capabilities. Younger individuals maintain effective tissue regeneration following injury. Senescent cells limit healthy cell multiplication in older people, which leads to reduced tissue repair abilities and delayed healing functions.
• Inflammatory Environment: Senescent cells release a set of molecules that include pro-inflammatory cytokines, growth factors, and proteases known as SASP. Persistent inflammatory conditions created by senescent cell secretions bring about multiple age-related diseases, including cardiovascular disorders, neurodegenerative diseases, and frailty.

Senescence and Cancer

Fig. 3 Role of senescence in cancer. (Xiao S, et al., 2023)

Senescence functions to halt the division of damaged cells, yet its relationship with cancer reveals significant intricacies.

• The induction of senescence functions to protect against the emergence of pre-cancerous lesions. The release of SASP factors from senescent cells creates a tumor-promoting microenvironment. Inflammatory cytokines and growth factors from senescent cells boost tumor development by destabilizing neighboring cells genetically and supporting the survival and expansion of cancer cells.
• Specific cancer therapies activate senescence in tumor cells as a means to halt their development. The risk of senescent tumor cells escaping their growth-inhibitory state and regaining their proliferative abilities creates a significant barrier to successful cancer therapy.

During aging and cancer progression, cellular senescence serves dual roles as a protective process while simultaneously posing risks. Though senescence serves critical protective roles, it can initiate age-related diseases and speed up cancer progression when it builds up. The investigation of senescence processes alongside their health implications continues to be essential for developing treatments that reduce adverse effects while using these mechanisms to prolong life expectancy. CD BioSciences works with clients to discover innovative approaches for improving healthspan and enhancing the quality of life among aging populations. If you are interested in our services, please feel free to contact us or make an online inquiry.

References

1. Xiao S, et al. Cellular senescence: a double-edged sword in cancer therapy. Front Oncol, 2023, 13: 1189015.
2. Schmeer C, et al. Dissecting Aging and Senescence-Current Concepts and Open Lessons. Cells, 2019, 8 (11): 1446.
3. Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol, 2021, 9: 645593.