What Are Senescent Cells and How Do They Accelerate Aging?

The accumulation of senescent cells is a hallmark of aging and chronic disease development. Many researchers are looking to slow down cellular senescence in order to increase longevity. Keep reading to learn exactly what senescent cells are, how they accelerate aging, and the best ways to slow down this process.

What is Cellular Senescence? 

Simply put, senescence is when cells stop dividing and lose their function. This irreversible growth arrest occurs in response to various stressors, such as DNA damage, telomere shortening, and exposure to reactive oxygen species that cause oxidative stress, according to a paper published in the Annual Review of Physiology.

Telomeres and senescence go relatively hand in hand. Telomeres, which can be imagined as the plastic casing protecting the tip of a shoelace, function to protect our chromosomes from damage. However, telomeres shorten with each and every cell division, thereby acting as a proxy for biological age. When a cell reaches the end of its telomere, it can no longer replicate and is considered senescent.  

In addition to losing their function, senescent cells can also damage nearby tissues and cells, as they secrete pro-inflammatory cytokines, compounds, and growth factors, a feature which is called the senescence-associated secretory phenotype (SASP).

Cellular senescence was first described by Leonard Hayflick in 1965. Named the Hayflick Limit, he proposed that normal human cells are only able to replicate and divide between 40 and 60 times before they will not divide anymore. After that, the cell will essentially “kill itself” through apoptosis, which is programmed cell death. When cells reach their Hayflick Limit, they become senescent. 

As described in a May 2014 review in Nature, senescent cells aren’t always bad — it’s believed that senescence may have evolved to suppress abnormal cell growth. Cells exposed to oncogenes (mutated genes with the potential to promote tumor growth) can activate tumor suppressor pathways, thereby inducing senescence to kill the abnormal cell.

In addition, the SASP feature of senescent cells can also repair and regenerate tissues after injury through stimulating cell proliferation and growth factors. 

However, it’s a bit of a catch-22. Senescent cells and SASP may also promote abnormal cell growth, contribute to chronic diseases, and accelerate the aging process. The paradox between these tumor-suppressing and disease-promoting aspects comes down to acute versus chronic senescence. 

Acute senescence is the helpful kind, as it responds and repairs wounds and tissue damage. However, when senescent cells are chronically present, the accumulation creates a hyper-inflammatory environment for disease to manifest and aging to progress.

Senescent Cells and Aging: Recent Research

Similarly to how telomere length can be used to estimate biological age, a higher number of senescent cells is linked to increases in biological and chronological age. 

In a 2020 systematic review and meta-analysis published in Aging Cell, researchers summarized that the magnitude of senescence varies in the body — tissue by tissue. This indicates that different organs in the body may age more quickly, depending on the level of senescent cells each contains. 

The mechanisms behind how accumulated senescent cells contribute to aging are multifactorial. Two of the triggers of senescence are exposure to oxidative stress and inflammatory conditions, which then damage DNA and mitochondria. Oxidative stress and inflammation occur from exposure to dietary or environmental toxins, inadequate intake of antioxidants, smoking, mental stress, or inadequate sleep and exercise. 

Metabolic stress also induces senescence, which occurs in cases of obesity and type 2 diabetes. In a study published in Cell Metabolism in May 2019, obese mice experienced a buildup of senescent glial cells related to neurodegenerative disorders. Importantly, clearing out the senescent glial cells restored brain activity in the mice. 

Senescence, oxidative stress, and inflammation can create a vicious cycle in cases of neurodegenerative disorders. Oxidative stress and neuroinflammation contribute to the development of neurodegenerative diseases, and oxidative stress can also trigger senescence in the brain. This is followed by senescent cells stimulating the production of additional pro-inflammatory cytokines, furthering the neuroinflammatory condition. 

In addition to accelerating aging through their contribution to chronic diseases, senescence can also directly shorten lifespan. In several animal studies, as described in a paper published in April 2020 in Cells, injecting senescent cells into mice led to tissue dysfunction and shortening of their lifespans. 

How to Slow Down Senescence 

The inability to clear senescent cells is an important aspect of how these dysfunctional cells accelerate aging. Many researchers are interested in how to better eliminate senescent cells — from both pharmaceutical methods or lifestyle interventions — in order to increase longevity and reduce the risk of chronic diseases. 

1. Senolytics 

Senolytics are a class of molecules that can eliminate senescent cells from the body, with the goal of reducing the inflammation, tissue damage, and shortening of lifespan that is associated with senescence.

As described in an April 2020 review in Advances in Therapy, the leading pharmaceuticals that function as senolytics are metformin (a glucose-lowering drug for type 2 diabetes), the immunosuppressant drug rapamycin, and dasatinib, which is used in leukemia intervention. In addition, the bioflavonoids quercetin and fisetin, which are found in fruits in vegetables, also act as senolytics.

In a trial published in EBioMedicine in September 2019, a combination of dasatinib and quercetin in individuals with diabetic kidney disease reduced the number of senescent cells in adipose tissue after 11 days, with no adverse effects. 

A study from August 2018, published in Nature Medicine, administered dasatinib and quercetin to both naturally-aged mice and young mice transplanted with senescent cells. They found that both sets of mice had improvements in their physical dysfunctions and had increased survival rates by 36%. 

However, the research on senolytic usage in humans is still in its infancy. While senolytics have been shown to extend lifespan in animals, it’s unknown yet if that will translate to humans. 

2. Boost NAD+ Levels

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme needed by all cells in the body for survival that naturally declines with age. Preventing or slowing down this decline can be used to mitigate the accelerated aging that comes along with lower levels of NAD+.

One of the ways to boost NAD+ levels is through supplementation with one of its precursors, NMN (nicotinamide mononucleotide). 

In a study published in Stem Cells in December 2016, restoring mitochondrial NAD+ levels in human stem cells delayed senescence and extended the lifespan of the cells. This indicates that restoring NAD+ levels could reverse the typical signs of aging, mediated through the prevention of senescence. 

With age, the visual system tends to decline in function; it’s thought that both senescence and reduced NAD+ levels play a role in that dysfunction. In a cellular study, the addition of NMN was able to effectively prevent senescence in the RPE (retinal pigment epithelium). Dysfunction of the RPE is associated with several eye disorders. 

3. Caloric Restriction

Caloric restriction, or time-restricted eating, activates two other mechanisms that can slow down cellular senescence: autophagy and increased expression of sirtuins. 

Autophagy is our body’s internal recycling program that promotes health and longevity through the removal of toxic, damaged, or dysfunctional compounds — including senescent cells.

Fasting or restricting calories activates a signaling pathway (AMPK) that inhibits mTOR (mammalian target of rapamycin). Inhibiting mTOR, which can also be achieved via the senolytic drug rapamycin, increases the activity of autophagy and helps to clear out senescent cells. 

Sirtuins, which are a family of proteins that are linked to increased longevity, are upregulated by caloric restriction and have been shown to prevent cellular senescence, as detailed in a March 2019 review in Cell Metabolism. As sirtuins are dependent on NAD+, boosting NAD+ through NMN supplementation can also increase sirtuin expression.

Lastly, caloric restriction reduces levels of the inflammatory reactive oxygen species that trigger cellular senescence. 

Key Takeaway:

• Cellular senescence occurs when cells reach the end of their replication ability, which renders them dysfunctional and inflammatory. 
• Studies have shown that an increase in senescent cells contributes to the development of chronic diseases and accelerates the aging process. 
• Three ways to slow down senescence include using senolytic drugs or supplements, boosting NAD+ levels via NMN, and utilizing caloric restriction or time-restricted eating to induce autophagy and sirtuin expression. 

References:  

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