Exploring the Relationship Between Cellular Senescence and Aging: Mechanisms, Consequences, and Therapeutic Insights

Author: BalanceGenics Anti-aging Research Team (How100.com)

 

Cellular senescence is a fundamental biological process that plays a crucial role in aging and age-related diseases. This phenomenon, characterized by the irreversible arrest of cell division, was first discovered by Leonard Hayflick and Paul Moorhead in the 1960s. Since then, extensive research has shed light on the mechanisms, consequences, and potential therapeutic interventions targeting cellular senescence.

 

Mechanisms of Cellular Senescence

 

Cellular senescence can be triggered by various intrinsic and extrinsic factors. Currently, there are numerous hypotheses regarding the mechanism of cellular aging, and a consistent viewpoint has not yet emerged. The main hypotheses include:

 

• Genetic Determinism Theory suggests that aging is a programmed process determined by genetics, with its driving force and determining factors being the genetic genome. Genes that control growth, development, and aging are systematically activated and deactivated at specific times.

• Free Radical Theory posits that reactive oxygen species lead to cellular damage and aging. Under normal conditions, the body generates free radicals from two sources: external sources such as high temperatures, radiation, photolysis, and chemicals, and internal sources such as various metabolic reactions.

• Telomere Clock Theory proposes that telomeres shorten with each cell division, primarily causing aging. This theory suggests that under normal circumstances, the special structures at the ends of chromosomes, called telomeres, gradually shorten with each cell division. When telomeres shorten to a certain extent, cell proliferation stagnates, leading to cellular aging.

• Accumulation of Cellular Metabolic Waste can cause cellular aging. This theory suggests that as cellular functions decline, cells cannot promptly eliminate metabolic waste or degrade and digest it. As a result, metabolic waste accumulates, occupying increasing space within the cell, hindering the transport of cellular metabolic waste, and ultimately disrupting normal cellular physiological functions, leading to cellular aging. Examples include lipofuscin accumulation.

• Errors in Gene Transcription or Translation lead to cellular aging. As age increases, the efficiency of DNA replication decreases, and errors in the synthesis of large molecules such as nucleic acids, proteins, and enzymes often occur. The gradual accumulation of these errors ultimately leads to reduced cellular function and gradual cellular aging and death.

Source: www.the-scientist.com

 

Although cellular aging is an inevitable physiological process, many external factors can accelerate this process:

 

Diseases and Medications:  

Disease progression and medication use may disrupt the balance between cellular aging and clearance, thus accelerating cellular aging. A typical example is cancer patients undergoing chemotherapy, which induces cellular aging in normal tissues and triggers pro-inflammatory stress responses, leading to adverse reactions such as fatigue, cancer recurrence, and metastasis.

 

• Lifestyle Habits:
• Poor lifestyle habits such as unhealthy diet, lack of exercise, and irregular sleep patterns may also accelerate cellular aging. Unhealthy dietary habits and lack of exercise can cause chronic inflammation and oxidative stress, while irregular sleep patterns disrupt the body's circadian rhythm, affecting normal cellular function.

• Environmental Pollution:
• Pollution of the natural environment such as air and soil can also accelerate cellular aging. Pollutants can cause oxidative stress and inflammatory responses, damaging cells. Long-term exposure to environmental pollution can have negative effects on cell health, accelerating the process of cellular aging.

 

Cellular Senescence and Aging

 

Normally, the inflammation produced by senescent cells is sufficient to activate the immune system to clear senescent cells within days or weeks. However, according to the threshold theory of senescent cell accumulation, once the abundance of senescent cells reaches a threshold, the immune system can no longer keep up with removing them. In turn, the cells of the immune system become senescent, which can further exacerbate senescent cell accumulation. These accumulating senescent cells gradually lose their vitality and function, which in turn causes degeneration of tissues and organs at the macroscopic level where it can be directly observed, ultimately leading to various forms of disease and aging.

 

The accumulation of senescent cells is considered a hallmark of aging and a driving force behind age-related diseases. Senescent cells can disrupt tissue homeostasis and impair regenerative processes through several mechanisms:

 1. Impaired tissue regeneration:

Senescent cells lose their ability to proliferate and contribute to tissue repair and regeneration, leading to a decline in tissue function and integrity.

 2. Inflammation and tissue dysfunction:

The SASP（Senescence-Associated Secretory Phenotype）secreted by senescent cells can promote chronic inflammation, disrupt the extracellular matrix, and contribute to tissue dysfunction and age-related pathologies.

 3. Stem cell exhaustion:

Senescent cells can induce senescence in neighboring cells, including stem cells, leading to stem cell exhaustion and impaired tissue regeneration.

 4. Metabolic dysregulation:

Senescent cells can alter metabolic pathways, contributing to age-related metabolic disorders such as insulin resistance and type 2 diabetes.

 5. Immune system dysfunction:

The accumulation of senescent cells can impair immune function, increasing susceptibility to infections and autoimmune diseases.

 

Targeting Cellular Senescence: Therapeutic Approaches

Given the detrimental effects of cellular senescence on aging and age-related diseases, targeting senescent cells has emerged as a promising therapeutic strategy. Two main approaches have been explored:

 

Senolytics: These are compounds that selectively induce apoptosis (programmed cell death) in senescent cells, effectively eliminating them from tissues. Various senolytic agents, including natural compounds, small molecules, and peptides, have been identified and are being investigated in preclinical and clinical studies.

 

Senomorphics: These are compounds that modulate the SASP and other senescence-associated phenotypes without inducing cell death. Senomorphics aim to suppress the pro-inflammatory and tissue-disruptive effects of senescent cells, potentially mitigating their harmful effects.

Source: NAD.com

 

One promising senomorphic compound is nicotinamide mononucleotide (NMN), a precursor of NAD+. Several studies have demonstrated the potential of NMN in targeting cellular senescence:

 

• NMN supplementation has been shown to alleviate NAD+ deficiency-induced senescence in mesenchymal stem cells (MSCs) by restoring mitochondrial homeostasis and NAD+/SIRT1 pathway activity.

 

• In a study on retinal pigment epithelial (RPE) cells, NMN pretreatment ameliorated oxidative stress-induced senescence by improving mitochondrial function, reducing oxidative damage, and modulating SIRT1 activity.

 

• NMN treatment increased cell viability, reduced apoptosis, and restored tight junctions in high-glucose-treated human corneal epithelial cells, potentially through the SIRT1/NRF2/HO-1 pathway.

 

• In animal models, NMN administration has been found to extend lifespan, improve physical function, and reduce the burden of senescent cells in various organs, including the liver, kidney, and skeletal muscle.

 

In recent years, the anti-aging effects of NMN or NAD+ supplements have been widely recognized by consumers. Incorporating the best NMN supplements such as Balancegenics’ Pure NMN into your anti-aging regimen will bring you a healthier and longer life!

 

 

 

 

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Guo, P. Q., Hu, X. X., Li, J. J., Li, A. L., Li, G. G., & Yu, X. (2022). Nicotinamide mononucleotide increases cell viability and restores tight junctions in high-glucose-treated human corneal epithelial cells. Biomedicine & Pharmacotherapy, 147, 112653. [https://doi.org/10.1016/j.biopha.2022.112653]