Removal of Accumulated Senescent Cells with Quercetin

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Cellular Senescence

Cellular senescence is defined as the irreversible arrest of cell proliferation (growth) that occurs when cells experience any of the following triggers:

  • Telomere shortening that triggers a DNA damage response
  • Elevated reactive oxygen species (ROS) causing DNA damage
  • Activation of oncogenes
  • Cell-cell fusion  

Senescent cell are cells that are dysfunctional in the body since they are not dividing any longer and they cannot be reversed back into functioning dividing cells.  However, senescent cells are not dead cells since they have a built-in survival mechanism. 

These senescent cells remain metabolically active and unless eliminated by the immune system or destroyed in the form of programmed cell death, they will accumulate in the body and accelerate the aging process by harming surrounding cells over time.

Senescent cells can represent up to 10% – 15% of cells in the body and up to 20% in the skin.  1  2    Senescent cells can also be found all over the body and in may accumulate in certain body organs.  The most common areas of the body and organs that senescent cell accumulate are the following:

  • Skin – Senescent cells can often accumulate in the fibroblasts, which are cells in the skin that are essential for producing new skin tissue.  3
  • Joints – Old cartilage-producing cells (chondrocytes) in the joints can accumulate which can lead to osteoarthritis.  4  5
  • Brain – As the brain ages, it starts to accumulate senescent cells which secrete inflammatory cytokines.  This may then lead to the age related brain disorders like Alzheimer’s and Parkinson’s disease.  6 
  • Heart – Senescent cells accumulate in the heart tissue which may lead to cardiovascular disease.  The endothelium layers of the blood vessels can also accumulate senescent cells.
  • Lungs – Senescent cells have been discovered in the lungs of smokers.  7
  • Liver – Senescent cells can accumulate in the liver and compromise its function and lead to conditions like non-alcoholic fatty liver disease (NAFLD).  8  9
  • Lymph Nodes – The lymph nodes of aged individuals may accumulate senescent T cells.  10

The Problem with Senescent Cells – Their Accumulation in the Body and a Compromised Immune System

The problem with senescent cells is their accumulation in various body organs and tissue and not the fact they are produced by the body.  Scientists believe that senescent cells are similar to cancer cells and boasted an increased expression of so called pro-survival networks that help them resist apoptosis, or programmed cell death. 

Senescent calls increase with age due to changes in the age-related decline in the immune system.  This then makes it less likely that the senescent cell will be cleared from the body efficiently.  11 

Since senescent cells are produced at a higher frequency with age, these aging cells and tissues demonstrate a steady accumulation of cells that show DNA damage.  12  13 

Once the senescent cells accumulate in the body, they secrete pro-inflammatory cytokines, chemokines, and protein digesting extracellular matrix proteases, which together constitute the senescence-associated secretory phenotype or SASP.  14  15  16 

Senescent cells are removed from the body by a robust immune system.  The immune cells that participate in the clearance of senescent cells are natural killer cells, macrophages, and T cells.  However, as the body ages, the immune system becomes compromised through immune senescence which leads to the acceleration of aging. 

The Solution to Senescent Cells – Removal from the Body

To date, scientists have not found a way to stop the process and development of senescent cells in the body.  So instead of focusing on research on how to stop senescent cells from developing, the focus has been on identification of approaches to remove damaged, senescent cells.  By removing inflammation prone senescent cells from the body, it could lead to a state of longer healthspans and mindspans and a decrease of the diseases linked to these senescent cells.

Research scientists have invented the term “Senolytics” as drugs that selectively induce death of senescent cells.  In an article published in August 2015 in Aging Cell entitled The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs, the authors stated that:

“The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells.

These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.”  17

The authors of the Aging Cell article were able to find two compounds among the 46 they tested that would effectively induce the death of senescent cells.  These two compounds are:

  • Dasatinib, a cancer drug marketed under the name Sprycel, and
  • Quercetin, a natural compound.

Tests in cell cultures showed that these two compounds did selectively induce death of senescent cells, targeting different cells. The dasatinib eliminated senescent human fat cell progenitors.

Quercetin was found to be most effective in eliminating senescent:

  • Human endothelial cells
  • Mouse bone marrow stem cells

Quercetin

Quercetin caused a 50% reduction of senescent cells in the Aging Cell study.  The authors stated that:

“Note that at 10 μm Q, nonsenescent HUVECs achieved a 2-3-fold increase in cell number between days 0 and 3, while parallel cultures of senescent cells were reduced by 50%, indicating selective killing of senescent cells.”  18

The authors concluded their study by stating the following:

“The identification of approaches to remove damaged, senescent cells would have a tremendous impact on quality of life and burden of age-related chronic diseases. To identify agents able to kill senescent cells, we hypothesized that senescent cells, like cancer cells, are dependent on anti-apoptotic pathways to ensure their survival following stress and damage. Based on this hypothesis, here we demonstrate that senescent cells indeed are susceptible to selective clearance by targeting pro-survival mechanisms using siRNAs and drugs, even at doses insufficient to kill normal proliferating or differentiated, quiescent cells. This observation opens up new approaches to develop clinically relevant small molecules or biologics that selectively eliminate senescent cells from nongenetically modified individuals, acting as senolytic agents. The prototype senolytic agents identified here, dasatinib and quercetin, have the ability to alleviate multiple aging phenotypes, as would be predicted if they truly act by eliminating senescent cells.”  19

Forms of Quercetin

Quercetin is found in a variety of foods, especially raw capers, canned capers, lovage, sorrel and radish leaves.  The Phenol-Explorer database lists the content of quercetin in various foods.

Quercetin is also available as a supplement.  There are a number of forms of supplemental quercetin:

  • Quercetin dihydrate – The most common form of quercetin, yet it is insoluble in water and has poor bioavailability
  • Quercetin 3-O-beta-glucoside (Isoquercetin) – Isoquercitrin and isoquercetin are naturally occurring forms of quercetin with a glucoside side chain that enhances bioavailability.    
  • Alpha-Glycosyl Isoquercitrin – provides the benefits of the flavonoid quercetin with better absorption and superior bioavailability.  Alpha-Glycosyl Isoquercitrin has 3 times the bioavailability of isoquercetin and nearly 18 times the bioavailability of quercetin aglycone
  • Quercetin Phytosome (Sophora japonica concentrate) – sunflower sourced phosphatidylcholine for optimal absorption 

Recent research indicates that combining tocotrienols and quercetin may target cellular senescence. 20
An excellent article has just been published in the October 2016 edition of Life Extension magazine entitled: Natural Compounds that Remove Aging Cells


Resources:

Quercetin dihydrate

Quercetin 3-O-beta-glucoside (Isoquercetin)

Alpha-Glycosyl Isoquercitrin  

Quercetin Phytosome


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5 thoughts on “Removal of Accumulated Senescent Cells with Quercetin

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