Senescent cells, Senolytics and renal and kidney disease

Senescent Cells, Their Role in Kidney Disease & How to Manage Them

What are Senescent Cells?

The definition senescent literally means the condition or process of deterioration with age. In biology, senescence is a process by which a cell ages and then permanently stops dividing but does not die. Senescent cells are undead cells (that should be dead) that are lacking a protein that tells them when to die. They’re one of the main reasons we age. Over time, large numbers of these old, senescent cells can build up in tissues throughout the body. These cells remain active and can release harmful substances that may cause inflammation and damage to nearby healthy cells. 

A healthy immune system is able to clear these senescent cells out of the body, which stops large amounts of them from accumulating. However, research is showing that in some people the inability to clear out these cells is a contributing factor to many of the chronic diseases we are seeing in the Western World, including diabetes, heart disease, Alzheimer’s disease, osteoporosis and of course kidney disease. 

You may have also come across another term for these types of cells and that is Zombie Cells. Why zombie cells you ask? Well, senescent cells won’t die and they have the ability to “infect” normal cells around them and turn them into the same type of zombie, senescent cells. Instead of dying like normal aged cells, senescent cells – or “zombie cells” – tend to live on, spewing a cocktail of inflammatory compounds linked to Alzheimer’s disease, arthritis, and other age-related maladies including cancer.

Senescent cells lack the ability to function as normal cells, these cells are not undergoing normal cellular repair or cell division or programmed cell death which is the normal cycle of a cell. Cells either go through apoptosis (the programmed death of a cell) or become Senescent cells. 

Senescent cells have thee three things in common:

  1. They are blocked from cell division and can’t become two new cells. This has a major impact on tissues that require stem cells to replace lost cells. For example, senescent cells contribute to age-associated cardiomyopathy (a disease of the heart muscle that makes it harder for the heart to pump blood to the body). In 70-year-old subjects, over half of the cardiac stem cells are senescent and can’t form healthy new heart cells. This contributes to cardiac failure.
  2. They cause a damaging bystander effect in neighbouring healthy cells, causing them to become senescent. In effect, one rotten apple spoils the barrel. In a 2018 study, the injection of a small number of senescent cells in young mice spread cellular senescence into host tissues. This led to physical dysfunction and a five-fold increased risk of death.
  3. They produce what’s called a senescence-associated secretory phenotype, or SASP. This is a witch’s brew of highly active substances, including a fearsome mixture of pro-inflammatory compounds. Various SASP phenotypes cause specific diseases.

https://www.lifeextension.com/magazine/2021/2/senolytics

Senescent cells almost work like an infection. Animal studies have shown that if you remove the senescent cells from an aged, diseased rat and then inject them into a younger healthy rat, the young healthy rat will develop whatever disease(s) the older diseased rat had.

 

Why Does Senescence Occur?

Senescence prevents the replication of cells harbouring damaged DNA, which serves an important anti-tumorigenic function. Senescence typically occurs in response to damaging stimuli, including telomere shortening (replicative senescence), DNA damage (DNA damage-induced senescence), and oncogenic signalling (oncogene-induced senescence).

So some level of senescence is actually required to keep the body healthy. The issue is when the number of senescent cells gets too high for the immune system to clear it then contributes to many of the chronic diseases I have previously mentioned. Also remember that senescent cells can infect neighbouring cells, meaning that they can destroy healthy tissues, this is what is thought to be happening in chronic diseases such as Alzheimer’s disease and of course kidney disease. 

Senescent Cells and Kidney Disease

https://www.cellsignal.com/science-resources/overview-of-cellular-senescence

Senescent Cells & Kidney Disease

A quick search in google using the words Kidney Disease and Senescent cells and you will find a plethora of research articles linking senescent cells to the onset of CKD. Here is a quick summary of what these studies are finding.

Chronic kidney disease can be viewed as a state of accelerated and premature aging. The aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. Chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). These SASP are major contributors to kidney fibrosis and of course fibrosis of the tissue in the kidneys is what stops the kidneys from functioning properly leading to a decreased GFR and eventual failure of the kidneys to work. 

https://www.frontiersin.org/articles/10.3389/fphar.2020.601325/full

Senescent cells accumulate in the kidney in three broad settings: with age, with any insult causing acute kidney injury, including post-transplantation, and in chronic kidney disease. In each case, higher levels of senescent cells associate with worsened kidney function and outcome.

https://www.frontiersin.org/articles/10.3389/fphar.2020.00755/full#:~:text=Senescent%20cells%20accumulate%20in%20the,and%20outcome%20(Figure%203).

These recent studies provide experimental evidence supporting the notion that the accumulation of senescent cells and their associated SASP is a main driver leading to structural and functional organ degeneration in CKD and other ageing-related disorders.

https://journals.lww.com/co-nephrolhypertens/Abstract/2022/05000/Ageing,_cellular_senescence_and_chronic_kidney.5.aspx

Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. This may decrease the decline found in CKD or even halt CKD in its tracks.

https://www.frontiersin.org/articles/10.3389/fphar.2020.00755/full#:~:text=Senescent%20cells%20accumulate%20in%20the,and%20outcome%20(Figure%203).

The main thing that all the studies that I read pointed to was that senescent cells drive fibrosis, and fibrosis is the hallmark of CKD. Senescent cells also drive inflammatory cytokines which cause further damage to the kidneys of course the ability of senescent cells to work almost like a virus infecting surrounding tissues means that when these cells are in abundance in the kidney tissue the cells of the kidneys are susceptible to huge amounts of inflammation, damage and fibrosis.  Anything that we can do to stop the process of fibrosis and inflammation within the kidneys will preserve kidney function and give us the chance to repair already damaged tissues.

chronic kidney disease caused by senescent cells

https://ars.els-cdn.com/content/image/1-s2.0-S0753332220313846-ga1_lrg.jpg

Two Types of Aging

Dr Alan Green a leading researcher and expert on all things senescent explains this really well in an interview he did with Life Extensions magazine.

Passive/Natural Aging 

This type of aging is the classic concept of aging. As a result of wear and tear over time, there is a slow accumulation of damage. The damaged parts include mitochondria, DNA, nuclear membranes, proteins, etc. In natural aging, the body does its best to repair the damage which accumulates.

Active Aging

In active aging, the organism’s own actions cause damage, decline, and death. This is the type of damage that causes age-related disease. Almost everybody dies from active aging. Senescent cells are involved in this type of aging.

https://www.lifeextension.com/magazine/2021/2/senolytics

How Would I Know If I Have a Build-up Of Senescent Cells?

The short answer is that there is no reliable test for senescent cells as the research is still new and in the exploratory stages. 

A telltale sign that you might have an accumulation of these cells is the diagnosis of any chronic health condition. We all have some level of senescent cells in us. Issues only arise when these cells reach a vital tipping point where the number of them overwhelms the immune system’s ability to clear them. When this happens we often see in clinical practice the quick and rapid onset of symptoms. Everything seems to go downhill very quickly. 

How Do Senescent Cells Occur?

Senescent cells are a naturally occurring phenomenon in the body to a degree, it is the overproduction and the inability of the immune system to clear them that causes age-related diseases. 

And guess what? It is all the things that we are always talking about here at the Kidney Coach that contributes to an accumulation of these senescent cells. Poor dietary habits, environmental toxins, excessive use of pharmaceutical medications, GMO foods, pollution, radiation, stress, viral infections (including Covid), bacterial infections, yeast infections, and heavy metals. Everything that we know contributes to chronic diseases is associated with an excessive build-up of senescent cells, which of course makes perfect sense.

Is It Possible To Treat Or Slow Active Aging?

Remember active aging is the type of aging that occurs due to the build-up of senescent cells. This type of aging is driven to a significant degree by two things: senescent cells and mTOR. They present targets for anti-aging treatments. Drugs or compounds that treat active aging must be able to prolong lifespan and prevent age-related diseases, including atherosclerotic heart disease, Alzheimer’s disease, and cancer. In mouse studies, removing senescent cells or lowering mTOR does both of these things.

https://www.lifeextension.com/magazine/2021/2/senolytics

Of course, then there are all the preventative things that you can do to prevent a build-up of these cells in the first place. Exercise, eat a healthy nutrient-rich diet, balance stress levels, stay hydrated, reduce your exposure to toxins and pollution and reduce the need for unnecessary medications. Prevention is always better than cure, but luckily if your senescent cell levels have surpassed the level at which your immune system can keep up then using senolytics can help to reduce the number of senescent cells in the body.

What Can We Do About Senescent Cells?

Senolytics are drugs or other compounds that remove senescent cells they are under research to see if they can cause the death of senescent cells without killing the healthy ones in the process. In mouse studies, the removal of senescent cells increases lifespan and ameliorates age-related disease. There is now a sufficient body of evidence to justify the introduction of senolytics into clinical anti-aging medicine.

The main three senolytics that are known and used by experts in this field include dasatinib, fisetin, and quercetin. Dasatinib is the generic name for Sprycel®, a drug approved in 1996 for the treatment of leukemia. Fisetin and quercetin are flavonoids present in fruits and vegetables. They’re sold over the counter and are known to be very safe with no real side effects.

Dr Alan Green treats using all three: 100 mg dasatinib for three days, 1,000 mg of regular quercetin for three days, 1,500 mg of regular fisetin for three days. That’s a maximum dose. Patients can begin with a smaller dose and determine sensitivity.

https://www.lifeextension.com/magazine/2021/2/senolytics

Treatments using senolytics are very short-term, also known as a shotgun approach, you don’t need to take these medications ongoing for a long time. It takes 2-6 weeks for senescent cells to reproduce, and studies have shown that short-term treatment over a few days is enough to lower the burden enough that the immune system can get back in control. Of course, if you don’t address the underlying cause of why you are getting a build-up of these senescent cells then you will need to keep doing this type of treatment every 3 – 6 months. 

What makes the most sense to me is to use something like the above or the peptide FOX04-DRI which I will get to shortly, but also address your diet and lifestyle. By improving your diet and lifestyle you are more likely to prevent a build-up of these cells from occurring again. This might include starting to exercise, eating more leafy vegetables, removing unhealthy hydrogenated fatty foods, and sugar which is known to reduce the effectiveness of the immune system, improving your sleep quality, managing your stress and doing all the things that we know contribute to a healthy lifestyle. 

This is what I call a holistic approach to treatment and makes the most sense to me.

There are now two human studies and more than 20 animal studies regarding dasatinib’s role as a senolytic. Quercetin has been used in two human studies, and all mouse studies with dasatinib included quercetin. Fisetin had an excellent result in a 2018 mouse study. It was even more effective than quercetin, and there are several human studies using fisetin now listed on: www.clinicaltrials.gov. There have been no apparent harmful effects from the long-term removal of senescent cells.

FOX04-DRI

FOX04-DRI is my favourite senolytic to use to reduce senescent cells, that is because it is a peptide that seems to have very few side effects.

FOXO4-DRI is a peptide (short chains of compounds part of the amino group linked by peptide bonds) that is injected into your body. It then finds the gene FOXO4 (short for forkhead box O4) and interacts with it to stop any communication with the p53 gene, initiating apoptosis (the destruction of cells) in senescent cells.

To clarify, the FOXO4 gene is a gene that is involved in the negative regulation of the cell cycle. The p53 gene is a gene that codes for a cell cycle-regulating protein and helps with tumour-suppressing functions.

FOX04-DRI and Renal Disease

FOXO4 can interact with p53, which is involved in the regulation of multiple target genes and controls a wide range of cellular processes, including metabolic adaptation, DNA repair, cell cycle arrest, apoptosis, and senescence. Studies have shown that FOXO4 can interact with p53, inhibit p53-mediated apoptosis, and thus maintain the vitality of senescent cells, leading to their accumulation. So in short the interaction of FOX04 and p53 is what creates senescent cells. The science suggests that getting FOXO4-DRI to separate FOXO4 and p53 would decrease the number of senescent cells you gain as you age and in chronic disease states. So FOX04-DRI has the ability to not only help the body mop up senescent cells but to also stop further accumulation of them.

I know that is all pretty scientific but really the takeaway is that FOX04-DRI stops the accumulation and helps mop up senescent cells. 

How Do I Get FOX04-DRI?

I suggest you work with a healthcare practitioner that is highly educated in using this peptide. FOX04-DRI only needs to be used short-term like any senolytic treatment and should not be used long-term, as we actually do need a certain number of senescent cells in our bodies. You can order FOX04-DRI from some peptide websites but I suggest doing your research to make sure you are getting good quality, better yet as I said above work with a well-educated healthcare provider.

Dosage

Due to the novel nature of this peptide, the optimal dose of FOXO4-DRI is extremely uncertain. Ben Greenfield who is an expert in the world of peptides suggests using 3mg injected subcutaneously every other day for six days, and repeating this cycle 1-3 times a year. That’s it! In the world of peptides and especially senolytics less is more.

Side Effects

As far as side effects go the only information comes from the pivotal Cell paper published in 2017 where FOXO4-DRI was introduced to the world, in which the peptide was well-tolerated without any side effects.

Jay Campbell on his website suggests that uncommon side effects may include:

  • Fatigue
  • Nausea
  • Muscle soreness

Drug Interactions

As far as drug interactions I am not aware that FOX04-DRI interacts with any medications.

Final Notes

If you want to read more about FOX04-DRI then I highly recommend looking at Jay Campbell’s website – https://jaycampbell.com/peptides/foxo4-dri-the-peptide/

Or have a read of this good scientific article – https://www.cell.com/cell/pdf/S0092-8674(17)30246-5.pdf

Remember you should always work with a healthcare provider when it comes to introducing new therapies, especially peptides like FOX04-DRI.

Hopefully, you have found this article useful and have learnt a little about the new and emerging world of senescent cells and senolytics

Feel free to share this article with friends and family or head over to our Facebook page and leave us a comment. 

You can hear more about Senescent Cells by listening to Dr Morgan Camp and myself on our YouTube channel.

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