Senolytics and Cell Senescence

[Sue (Ayt)]

I stumbled upon the word "Senolytics" a few years back, and started a list of substances found in nature that have preventative components and possible age-reversing potential. I have been trying to incorporate them somewhat in my diet over the years.

Seems there has been lots of interest by the scientific community in researching and potentially figuring out ways to patent and use them for $ pharmaceutical purposes $, and recently this quest appears to have heated up.

The initial list I had accumulated included:
astragalus
fisetin
quercitin
Rhodiola
EGCG
Resveratrol
Curcumin/turmeric
lycopene
(likely most here have heard a little about the benefits of many of these, but their senolytic action kind of ties it all together)

What are Senolytics?

Senolytics are groups of compounds that remove senescent cells. Animal model studies have shown that these compounds can slow specific aspects of aging. 
When a cell matures and ages, it is expected to die through apoptosis or programmed cell death [3]. Apoptosis is necessary for removing old cells and paving the way for the birth of new and healthier cells. Old cell materials are recycled and used as building blocks of new cells. However, some cells enter a state called senescence, where cell growth is arrested, and they no longer perform their functions. These senescent cells likewise do not die but continue to accumulate. Cellular senescence occurs as a response to various stressors that, include the following:
•  Hyperglycaemia 
• Saturated lipids 
• Increased reactive oxygen species (ROS) 
• Oncogene activation 
• Telomere shortening 
Typically, senescent cells are removed by macrophages of the immune system. However, an imbalance in the destruction and production of these cells could increase the aging of nearby cells and tissues. Senescent cells release chemicals called senescence-associated secretory phenotype or SASP. When senescent cells release SASP, which includes toxic chemicals and compounds, to the external environment, they would then inflict localised damage to healthy cells. The accumulation of senescent cells is associated with aging. As one gets older, the ability of the cells to remove toxic byproducts or to scavenge senescent cells is reduced. This explains why the accumulation of senescent cells becomes a vicious cycle. 
Studies conducted in recent years [5] revealed a strong association between the buildup of senescent cells and several age-related diseases and neurodegenerative diseases. Here are some conditions associated with senescence: 
•  Cancer 
• Vision loss 
• Stroke 
• Diabetes
• Obesity 
• Neurodegenerative disorders 
• Emphysema 
• Osteoarthritis 
Continuous accumulation of senescent cells can initiate early aging and increase the risk of developing chronic conditions. Removing the senescent cells could delay aging and promote overall health. In recent years, interest in senolytics has grown due to their ability to remove senescent cells. 
https://longevity.technology/lifestyle/what-are-senolytics-benefits-side-effects-and-research/

[ExomatrixTV]

Bioharmonizing Longevity With Ancient Ayurveda & Modern Science | Dr Nick Bitz @Neurohacker:

https://sp.rmbl.ws/s8/2/1/r/O/b/1rObh.caa.mp4

00:00 Introduction
01:25 Ashwagandha and its benefits
03:20 The downside of standardized herbal extracts
05:30 Advantages of ancient health sciences like Ayurveda & TCM
07:39 Ayurveda explained
12:10 Senolytic Therapy and its connection to Ayurveda
12:55 What is “Panchakarma”?
13:45 Link between emotions and bodily organs
16:10 Senolytic therapy and aging
18:36 Hallmarks and main mechanisms of aging
20:05 Cellular senescence and “Zombie Cells”
22:20 Damage caused by accumulation of senescent cells
23:45 SASP factors (Senescence Associated Secretory Phenotype)
25:23 Risk factors (if any) that increases senolytic support needs
27:35 Inflammatory proxies
28:29 Age to start using Senolytics
29:00 Side effects of senolytics
30:14 Usage of senolytics and the “hit and run" protocol
32:20 Qualia Senolytic Complex and its ingredients
36:18 Tests and trials done for Qualia products
39:02 Phytochemicals doses dependent on bioavailability
40:27 Considerations, contradictions, and other benefits of senolytics
41:13 Anabolic resistance and connection to senolytics
42:40 Tips for using senolytic products properly
43:26 Ayurveda, nootropics, cognitive enhancement
47:11 Dr. Bitz's favorite nootropics and adaptogens
53:23 Link between yoga and Ayurveda
55:30 Importance of getting a mentor when doing practices
57:00 Dr. Bitz's top teachers and books
60:10 Connect with Dr. Bitz and Neurohacker
60:49 Use Neurohacker code URBAN to save on Qualia supplements

Dr. Nick Bitz is a Naturopathic Physician that specializes in Ayurvedic medicine. He is a leading voice in the natural products industry and currently serves as Senior VP of Product Development at Neurohacker Collective. His areas of expertise include nootropics, anti-aging medicine, biohacking, herbology, nutrition, and dietary supplements.


source (https://rumble.com/v1y6b91-bioharmonizing-longevity-with-ancient-ayurveda-and-modern-science-dr-nick-b.html)

[Sue (Ayt)]

Many things cause senescent cells (also known as "zombie cells") besides general aging.
Toxins, radiation, and viruses are know inducers of cell senescence.

Here is an article about covid senescence and how senolytics can be used for damage treatment:

Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease
As alluded to already, therapeutic invention via senolytics is paving the way forward in the field of aging research. Indeed, we draw upon the potential of utilizing senolytics as viable therapeutic interventions or targets in COVID-19 to prevent severe infection in patients and specifically aged patients. Strong evidence has been reported recently in old mice where senescent cells became hyperinflammatory upon exposure to the SARS-CoV-2 virus. This resulted in enhanced SASP production of pre-existing senescent cells, increased senescence, inflammation, and high mortality rates in these aged mice. Furthermore, this study went on to show that the pharmacological removal of senescent cells via senolytic (Fisetin or Dasatinib + Quercetin) treatment, in these aged mice, was shown to significantly reduce senescence, inflammatory markers and mortality associated with COVID-19 [271]. These findings demonstrate the hypothetical rationale behind the therapeutic potential of senolytics, particularly in aged patients who have a higher burden of senescence, to interrupt the initial triggered immune cascade, cytokine storm and hyperinflammation evident in severe cases of SARS-CoV-2 infection. Indeed, Quercetin and Fisetin, which have excellent safety profiles thus serve as attractive candidates, are currently being investigated in COVID-19 trials as potential senolytic compounds for early intervention [272,273,274]. Moreover, it will be intriguing to explore if such strategies of early senolytic intervention could help alleviate the chronic post-COVID-19 syndrome, Long COVID [275]. Interestingly, findings from a recent study have shown that SARS-CoV-2 viral infection and subsequent virus induced senescence (VIS) is a pathogenic driver of dysregulated cytokine storm and tissue damage. This study found that patients infected with SARS-CoV-2 had markers of senescence present in their airway mucosa and also had increased levels of SASP factors within their serum. Excitingly, they showed that treatment with senolytics eradicated VIS cells, alleviated COVID-19 lung disease and reduced inflammation in two COVID-19 driven animal models [276]. This study highlights the potential clinical promise of senolytics as a novel treatment against COVID-19, of which could also be translated to treating other viral infections and ultimately enhance healthspan. This study along with a recently published review [277], affirms our hypothesis that the senescence-aging-COVID-19 axis along with the aging immune system has a paramount role in COVID-19 and a full understanding of the mechanistic networks underpinning this axis will be vital in the future.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699414/

and another article. (there are many)
COVID-19 and cellular senescence
Abstract
The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a ‘cytokine storm’, tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.
https://www.nature.com/articles/s41577-022-00785-2

[Sue (Ayt)]

So, many viruses can cause senescence, and the body can usually clear this senescence unless one already has a lot of senescent cell usually due to old age. Pretty easy to figure.
But then I searched "mrna vaccine induced senescence", and bingo.

Potential health risks of mRNA-based vaccine therapy: A hypothesis
Abstract
Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.
https://www.sciencedirect.com/science/article/pii/S0306987723000117

[Sue (Ayt)]

Here is a PDF I found about the mrna vaccines in general, and how the lipid nanoparticles may permanently fuse the virus components into the cellular material so that they continue their senescence causing properties, possibly permanently, reeking all kinds of damage on the bodies.

https://greatgameindia.com/wp-content/uploads/2022/12/Is-This-Ingredient-Inside-mRNA-Vaccines-Triggering-Long-COVID.pdf
https://greatgameindia.com/wp-content/uploads/2022/12/Is-This-Ingredient-Inside-mRNA-Vaccines-Triggering-Long-COVID.pdf

[Sue (Ayt)]

And another pdf, about Polyethylene glycol (PEG)in particular permanently fusing the vaccine mrna into the cells:

https://www.ilgiornaleditalia.it/userUpload/potentialmechanismsforhumangenomeintegrationofgeneticcodefromsarscov2mrnavaccinationimplicationsford iseas.pdf
https://www.ilgiornaleditalia.it/userUpload/potentialmechanismsforhumangenomeintegrationofgeneticcodefromsarscov2mrnavaccinationimplicationsford iseas.pdf

[Sue (Ayt)]

For more understanding and research on senescense and senolytics, the chart below taken from This Link (https://www.worldofmolecules.com/anti-aging-and-senolytics/piperlongumine-molecule.html) is helpful.
Each item in the chart is clickable. I have found that most of these substances are either available as supplements or can be found in natural foods that we can incorporate into our diets.

SENOLYTIC AND ANTI-AGING MOLECULES
RAPAMYCIN ---The mechanistic target of rapamycin (mTOR) pathway has a central role in cell activation...
METFORMIN -- The diabetes drug metformin used by some for anti-aging may diminish benefits of aerobic exercise...
QUERCETIN-- AND WITH DASATINIB--The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells...
FISETIN--Of the 10 flavonoids tested, fisetin was the most potent senolytic...
EGCG- The most active component of green tea....
NAD BOOSTERS --'...The cells of the old mice were indistinguishable from the young mice, after just one week of treatment...
SULFORAPHANE-- An isothiocyanate present in cruciferous vegetables activates antioxidant and anti-inflammatory responses by ...
UROLITHIN --Metabolite of Pomegranate compound with anti-aging effects passes human trial...
MITO-Q -- A water soluble fomr of CoQ10 that has excellent absorption and high bioavailability...
HONOKIOL - A bioactive natural product derived from Magnolia Bark have demonstrated ...
CURCUMIN AND ANALOGS -Recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents...
BERBERINE --berberine has recently been reported to expand life span in Drosophila melanogaster, and attenuate premature cellular senescence
N-ACETYL-CYSTINE (NAC)--"...pretreatment with NAC increased glutathione levels in the older cells and largely helped offset that level of cell death..."
PIPERLONGUMINE - A natural product from the Long pepper with high bioavailability...
RESVERATROL AND PTEROTSILBINE -- Pterostilben chemically similar to resveratrol bute differs from resveratrol by exhibiting increased bioavailability (80% compared to 20% in resveratrol)
SPERMIDINE--Spermidine delays aging in humans ...
ALLICIN -- Allicin is a compound produced when garlic is crushed or chopped. ...
VITAMIN D3 -- Production of the active forms of Vitamin D are reduced by 50% as a result of an age-related decline
VITAMIN K-- evidence suggests vitamin K has an anti-inflammatory action
TOCOTRIENOL(AND WITH QUERCETIN) --Tocotrieniols have been found to exert a synergistic antitumor effect on cancer cells when given in combination....
HSP-90 INHIBITORS --As a novel class of senolytics

https://www.worldofmolecules.com/anti-aging-and-senolytics/piperlongumine-molecule.html

-------------
Another good article for understanding these "zombie cells" and how to remove them is found at this link:
https://www.lifeextension.com/magazine/2019/2/jama-reports-on-senescent-cell-removal

[Feritciva]

This is what i've been working on for a couple of years - giving lectures to health professionals on cellular senescence.

At the moment there seems two scientifically confirmed natural senolytics: quercetin & fisetin (both can be found especially in red - purple - green leafy veggies & fruits).

Others are seen as "senolytic-like" or potential senolytics. Astragalus has a specific compound which protects telomers - so protects against one of the main reasons for aging.

Above links are excellent on the subject, thanks for this thread Sue!

By the way, one of the problems is we cant take enough dosages of these senolytics from foods - they normally are produced very small amounts in plants & herbs. So supplementation seems a good choice. But as I have written in some other thread, no two dietary supplements have the same quality. We can read on the label as 500 mg quercetin - but one may have %20 and other may have %90 quercetin in it. When it comes to supplements the saying "i'm not rich enough to buy a cheap product" may literally be right!

[Sue (Ayt)]

This is what i've been working on for a couple of years - giving lectures to health professionals on cellular senescence.

At the moment there seems two scientifically confirmed natural senolytics: quercetin & fisetin (both can be found especially in red - purple - green leafy veggies & fruits).

Others are seen as "senolytic-like" or potential senolytics. Astragalus has a specific compound which protects telomers - so protects against one of the main reasons for aging.

Above links are excellent on the subject, thanks for this thread Sue!

By the way, one of the problems is we cant take enough dosages of these senolytics from foods - they normally are produced very small amounts in plants & herbs. So supplementation seems a good choice. But as I have written in some other thread, no two dietary supplements have the same quality. We can read on the label as 500 mg quercetin - but one may have %20 and other may have %90 quercetin in it. When it comes to supplements the saying "i'm not rich enough to buy a cheap product" may literally be right!

Thanks so much for your input on this, Feritciva! Any info we can find out about this subject might be very helpful for folks dealing with chronic illnesses. (All input is welcome!)

I am NOT a medical professional at all, but just a layperson who stumbled upon the info and find it intriguing. Apparently, the pharma companies do too, considering the amount of studies and extraction methods they are working on. So many of these healing "discoveries" appear to have been made long ago, in ancient cultures. The fancy names that are revealed often translate into some very commonly known remedies, just with a fancy scientific name for a particular component.

For example, Zingiber officinale Rosc. which contains the molecule Gingerinone A had some recent publicity:

Ginger Extract Shows Strong Senolytic Effect
This compound could be superior to dasatinib and quercetin. (https://www.lifespan.io/news/ginger-extract-shows-strong-senolytic-effect/)
and
Identification of gingerenone A as a novel senolytic compound (https://pubmed.ncbi.nlm.nih.gov/35349590/)

haha - good old Ginger! Sounds like a good idea to add often to our cooking as a preventative, even when we aren't suffering. That is what I like to do with these substances, once I became aware of some of their great properties.

[Sue (Ayt)]

Found another fairly resent research paper, but it is quite complex and takes some time to digest. The chart below is taken from this article, and shows the various substances that appear to have these age slowing/reversal properties.

Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice

"Aging is a natural physiological process, but one that poses major challenges in an increasingly aging society prone to greater health risks such as diabetes, cardiovascular disease, cancer, frailty, increased susceptibility to infection, and reduced response to vaccine regimens. The loss of capacity for cell regeneration and the surrounding tissue microenvironment itself is conditioned by genetic, metabolic, and even environmental factors, such as nutrition. The senescence of the immune system (immunosenescence) represents a challenge, especially when associated with the presence of age-related chronic inflammation (inflammaging) and affecting the metabolic programming of immune cells (immunometabolism). These aspects are linked to poorer health outcomes and therefore present an opportunity for host-directed interventions aimed at both eliminating senescent cells and curbing the underlying inflammation. Senotherapeutics are a class of drugs and natural products that delay, prevent, or reverse the senescence process – senolytics; or inhibit senescence-associated secretory phenotype – senomorphics. Natural senotherapeutics from food sources – nutritional senotherapeutics – may constitute an interesting way to achieve better age-associated outcomes through personalized nutrition. In this sense, the authors present herein a framework of nutritional senotherapeutics as an intervention targeting immunosenescence and immunometabolism, identifying research gaps in this area, and gathering information on concluded and ongoing clinical trials on this subject. Also, we present future directions and ideation for future clinical possibilities in this field.

(Intro above, with much more at link)
https://www.frontiersin.org/articles/10.3389/fnut.2022.958563/full#:~:text=Nutritional%20senolytics%20that%20selectively%20eliminate,in%20vitro%20and%20in%20vivo.

This is the chart that accompanies the article above:
51447
https://www.frontiersin.org/files/Articles/958563/fnut-09-958563-HTML/image_m/fnut-09-958563-t002.jpg

[Sue (Ayt)]

New Senolytics from Artificial Intelligence
Researchers identified three new compounds with senolytic properties.
Aug. 9, 2023

Searching for new senolytics
Senolytics are molecules that destroy senescent cells. Only a small number of such molecules have been identified, and only two have shown efficacy in clinical trials: dasatinib and quercetin in combination [2]. One of the biggest challenges is that senolytics often only work against specific types of cells. Additionally, some senolytics may work well for one cell type while being toxic to other, non-senescent cell types [3].

There is also a group of senolytics that are used in cancer therapies. However, most of them target pathways that are mutated in cancer. Therefore, they cannot be used as therapeutic agents in different contexts.

These limitations highlight the need to identify new senolytics that can be safely applied in therapies. Sometimes, this search involves panel screens [4]. Other times, it involves targeting the proteins upregulated in senescence. The authors of this paper used a different approach: AI-based computational screens that detect hidden patterns in chemical data.

From big datasets to a few hits
First, the authors assembled an extensive dataset for training the algorithms. Based on published data, they identified 58 senolytics. They also added 19 senolytics reported in commercial patents.

The authors then combined their list of senolytic compounds with a wide variety of compounds that were never described in the literature as having senolytic properties, with the final list consisting of 2,523 compounds. They used this list to train machine learning models to predict whether or not a compound may be a senolytic.

First, researchers focused on two models that both showed poor performance, but the errors they displayed were different. The first model, while returning a few false positives, gave a high number of false negatives. The second model returned the opposite. Other models showed even worse performance.

These researchers then decided to choose a model that turns fewer false positives, with the reason being that false positives are worse than false negatives for early-stage drug discovery, as higher number of false positives will increase the number of predicted hits. More predicted hits result in more compounds that need to be experimentally validated, thus increasing the cost and time.

After choosing their initial model, the researchers used different tools to optimize its performance. Following optimization, they screened a 4,340-compound library and identified 21 hits, then experimentally validated them, first in cells with oncogene-induced senescence.

Three natural products found
The initial experiment identified three compounds with senolytic properties: the natural products ginkgetin, oleandrin, and periplocin, which can be found in traditional herbal medicines. Ginkgetin is a product of Ginkgo biloba, commonly known as ginkgo or maidenhair tree. Oleandrin is a product of Nerium oleander, known as oleander or nerium, and periplocin is a product of Periploca sepium, a Chinese silk vine.

These identified compounds, when added in proper concentrations, have minimal effect on normal cells but decrease the number of senescent cells.

This paper’s authors further validated their hits using a second cell line. This time, they induced senescence in human cancerous cell lines by adding etoposide, a cancer treatment medication, and treated them with the 21 candidates. Again, the same three compounds showed senolytic activity toward the senescent cells but not the normal cells.

Utilizing artificial intelligence in the screens for new compounds
These researchers have shown how machine learning can utilize published screening data and find new therapeutic molecules. This approach reduced the number of potential hits by 200-fold. That efficiency resulted in fewer compounds that proceeded to experimental testing, thus reducing time and cost.

More of this article HERE (https://www.lifespan.io/news/new-senolytics-from-artificial-intelligence/) along with reference citations.

[Sue (Ayt)]

Quercetin again...

Phase I trial of senolytic therapy shows promise in Alzheimer's disease

Sep 8 2023
Alzheimer's disease is the most common cause of dementia that affects more than 6.5 million Americans, according to the Alzheimer's Association. To find effective treatments and slow the progression of this debilitating disease, researchers have made much progress in developing new drugs that target beta-amyloid plaques, one of the hallmarks of Alzheimer's disease.

Beta-amyloid plaques are accumulations of brain protein fragments, which can impact cognition. However, these recent drugs have only yielded modest results.

Now, scientists at Wake Forest University School of Medicine are reporting results from a Phase I trial in another area of promising research-;cellular senescence.

The findings appear online today in Nature Medicine.

<snip>

"Dr. Orr's research is a critical part of this pivotal moment in Alzheimer's research as the focus shifts from amyloid and tau, the classic disease hallmarks, toward how the biology of aging underlies the disease," said Howard Fillit, M.D., co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation (ADDF). "Aging is the leading risk factor for Alzheimer's, and it is important that the field explores new approaches for developing therapeutics, like senolytics, that target biological aging.

Journal reference:
Gonzales, M. M., et al. (2023). Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature Medicine. doi.org/10.1038/s41591-023-02543-w.

https://www.news-medical.net/news/20230908/Phase-I-trial-of-senolytic-therapy-shows-promise-in-Alzheimers-disease.aspx