MDS Labs® – ©2024

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Introduction

Senescence is thought to play an important role in aging and age-related diseases. Recent studies have highlighted the importance of developing senotherapeutic drugs to selectively kill senescent cells or to suppress the senescence-associated secretory phenotype (SASP) that drives sterile inflammation associated with aging (senomorphics), in order to extend healthspan and potentially lifespan. (Niedernhofer, 2018)

We know that many natural compounds can exhibit similar senolytic and senomorphic effects, acting as potent protein kinase inhibitors. Many of these natural compounds have been used in traditional Chinese medicine for thousands of years. Only now are we discovering their method of action and the unique synergy these compounds can provide. In the last few years, the D+Q senolytic therapy, a combination of the anti-cancer drug Dasatinib, and the natural flavonoid Quercetin, has entered the realm of human studies, and is showing potential eliminating senescent cells, providing substantial benefits in treating age-related diseases such as dementia.  

In a relatively novel approach, MDS Labs® has developed a phytochemical counterpart to Dasatinib by identifying the precise kinase enzymes it targets, and matching them with a combination of natural compounds thought to inhibit these same pathways. By utilizing Western blot assay in vitro to compare the activity of the selected isolates to Dasatinib, a natural formulation was eventually developed that targets these adverse signaling pathways. This combination also includes Quercetin to complete the alignment with the D+Q senolytic treatment. All of the ingredients in this formulation are fully FDA-approved and have been extensively studied in previous trials for both safety and efficacy.

MDS Labs’® unique development process resulted in a supplement that promotes a broad spectrum of senolytic and senomorphic action. It is believed that this blend provides enhanced targeting of senescent cells, while avoiding certain side effects of Dasatinib, such as Arterial Hypertension (Circulation: 125-17, 2012). Natural compounds can provide a clear advantage in safety, given the lower number of side effects in comparison to most synthetic substances. (Baier, Szyszka, 2020).

Niedernhofer, Robbins, Senotherapeutics for healthy ageing (2018)
https://www.nature.com/articles/nrd.2018.44#MOESM11

Montani, Bergot, Pulmonary Arterial Hypertension in Patients Treated by Dasatinib (2012)
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.079921

Baier, Szyszka, Compounds from Natural Sources as Protein Kinase Inhibitors (2020)
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.079921

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What is Senescence / Senotherapeutics  

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent the proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged.

Source:
Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School ; Robert and Arlene Kogod Center on Aging, Mayo Clinic Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2020) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790861

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Notable D+Q Studies:

• Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD) – Outcomes from the first clinical trial of senolytic therapy for Alzheimer’s disease
(2023)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10168460

• Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease 
https://pubmed.ncbi.nlm.nih.gov/31542391/

• D+Q Shows Potential in Treating Down Syndrome, and Eliminate Radiation Damage in Cells

Relevant Excerpt:

A recent study implicated cellular senescence and the beneficial effects of senolytics for Down syndrome (trisomy 21). A third copy of chromosome 21 in neural progenitor cells leads to transcriptional and nuclear organizational changes similar to those in senescent cells. Interestingly, D + Q alleviated transcriptional changes and cellular dysfunction in an in vitro human neural cell Down syndrome model. An accelerated aging-like phenotype has been observed in astronauts who are exposed to radiation, high G-forces, zero gravity and cabin air quality. Thus, senolytics might support long-distance space exploration by eliminating the senescent cells caused by cosmic and solar radiation, especially outside the van Allen radiation belts. In April 2022, effects of space travel on senescence biomarkers in astronauts and cultured human fat cell progenitors were tested during the Axiom-1 mission to the International Space Station; data are pending

Chaib, S., Tchkonia, T. & Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nat Med 28, 1556–1568 (2022). https://doi.org/10.1038/s41591-022-01923-y

• Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Relevant Excerpt:

In the present study we first document the efficacy of multiple senolytic interventions in clearing senescent cells in physiologically aged human pluripotent stem cell (hPSC)-derived brain organoids (BOs). Transcriptomic analysis across individual senolytic treatments revealed a differential effect in modulating the senescence-associated secretory phenotype (SASP), with a distinctive impact of D + Q administration in rejuvenation of the BO transcriptomic aging clock. Importantly, we report an enrichment of senescent cells in postmortem brain tissue of patients with COVID-19 and further show a direct role for SARS-CoV-2 and highly neurotropic viruses such as Zika (ZIKV) and Japanese encephalitis (JEV) in evoking cellular senescence in human BOs.

https://www.nature.com/articles/s43587-023-00519-6

• Critical Pathways Inhibited by Dasatinib

Relevant Excerpt:

Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors.

Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumor, Atanasio Pandiella, Instituto de Biología Molecular y Celular del Cáncer-CIC (2011) https://aacrjournals.org/clincancerres/article/17/17/5546/76509/Inhibition-of-Src-Family-Kinases-and-Receptor#

• Mechanisms of Neuroprotection by Quercetin

Relevant Excerpt:

Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress.

Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More Costa, Garrick, Roque, Pellacani (2016) https://pubmed.ncbi.nlm.nih.gov/26904161/

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Protein Kinase Signaling Pathways Explained

BCR-Abl Pathway: The BCR-Abl pathway involves a fusion protein called BCR-Abl, formed by parts of two different chromosomes, the BCR and ABL genes. This fusion creates an abnormal protein with increased tyrosine kinase activity, which causes cells to grow and divide uncontrollably. This pathway is notorious for its role in chronic myeloid leukemia (CML), where it leads to the excessive growth of white blood cells. This abnormal signaling disrupts normal cell functions, contributing to leukemia development. Using specific inhibitors like imatinib has been a significant advancement in CML treatment, turning it into a manageable chronic condition for many patients. 

• What it does: This pathway involves a protein that stimulates cell growth and division. In healthy cells, it helps regulate the growth of blood cells. However, when mutated, it leads to uncontrolled cell growth. 

• Benefit of Inhibition: By blocking the BCR-Abl pathway, treatments can stop the excessive growth of leukemic cells. This not only helps in treating leukemia. Short-term use can lower the risk of other cancers, promoting overall health and longevity.

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SRC Family Pathway: The SRC Family Pathway involves a group of proteins called SRC family kinases (SFKs), including SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK. These proteins play crucial roles in controlling various cell activities like growth, differentiation, and survival. They work by adding phosphate groups to specific tyrosine residues on target proteins, which changes their behavior and activates downstream signaling processes. These kinases get activated by signals from outside the cell, such as growth factors and cytokines. When these proteins aren’t properly regulated, they can become overactive, leading to cancerous growths and metastasis. Inhibiting the SRC family kinases can be a useful strategy in treating cancers and other diseases linked to abnormal cell signaling. By targeting these pathways, it’s possible to regulate unhealthy cell behaviors, which can improve patient outcomes.

• What it does: SRC family proteins control various cell processes like growth and survival. When they’re too active, they can cause cancerous growths.
• Example: Increased SRC activity is seen in colon, breast, and lung cancers.
• Benefit of Decreasing: Lowering SRC family protein activity can help prevent cancers and other diseases. This inhibition maintains normal cell functions and may support a longer, healthier life by reducing age-related diseases.

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c-KIT Pathway: The c-KIT pathway involves a receptor called c-KIT receptor tyrosine kinase, which is important for regulating cell growth, survival, and differentiation. When the c-KIT receptor binds to its partner molecule, stem cell factor (SCF), it triggers several downstream signaling pathways, including PI3K/AKT, JAK2/STAT3, and MAPK. The PI3K/AKT pathway helps cells survive and grow by blocking processes that lead to cell death. The JAK2/STAT3 pathway controls gene expression, supporting cell growth and differentiation. The MAPK pathway facilitates cell division and differentiation by relaying signals from the cell surface to the DNA in the nucleus. When the c-KIT pathway is disrupted, such as through mutations or excessive activity, it’s linked to various cancers like gastrointestinal stromal tumors (GIST) and certain types of leukemia. By targeting and inhibiting the c-KIT pathway, abnormal cell growth can be suppressed, promoting cell death in cancer cells, which can lead to better treatment outcomes and support longer, healthier lives.

• What it does: This pathway is crucial for the growth and survival of different cell types, especially stem cells and blood cells. It controls cell growth, differentiation, and cell death.
• Example: Mutations in the c-KIT gene are often found in gastrointestinal stromal tumors (GIST).
• Benefit of Inhibition: Blocking the c-KIT pathway can prevent abnormal cell growth, reducing the risk of cancers like GIST. This supports healthy cell renewal and tissue repair, essential for anti-aging and overall longevity.

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CSF1R Pathway: The CSF1R (Colony Stimulating Factor 1 Receptor) pathway is a key regulator of the immune system, particularly involved in the development, survival, and function of macrophages and monocytes. When CSF1R binds to its ligands, CSF1 or IL-34, it triggers a series of signaling pathways that promote the survival, growth, and specialization of macrophages. These cells are essential for innate immunity, maintaining tissue balance, and responding to inflammation. However, when CSF1R is overly activated, it can lead to chronic inflammation, contributing to diseases like rheumatoid arthritis and certain cancers. By targeting and controlling CSF1R activity, it’s possible to reduce excessive inflammatory responses and prevent tissue damage associated with age-related inflammatory diseases.

• What it does: The CSF1R pathway controls the production and function of macrophages, crucial white blood cells involved in immune responses. CSF1R signaling is vital for the survival and growth of macrophages.
• Example: Overactivity of CSF1R can cause chronic inflammation, which is linked to conditions such as rheumatoid arthritis and some cancers.
• Benefit of Inhibition: The short-term inhibition of CSF1R can decrease chronic inflammation and prevent tissue damage. This promotes a balanced immune response, supporting healthier aging and potentially extending lifespan.

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BCL-2 Pathway: BCL-2 (B-cell lymphoma 2) is a vital protein that controls apoptosis, the process of programmed cell death. Its role is to prevent apoptosis, ensuring cell survival. BCL-2 is part of a larger protein family that regulates the delicate balance between cell death and survival, crucial for normal cellular function and tissue stability. While BCL-2 is essential for the immune system and blood cell development, too much of it, seen in conditions like lymphomas and leukemias, allows cancer cells to evade death, leading to uncontrolled growth.

• What it does: BCL-2 helps cells evade programmed cell death, known as apoptosis. While this protects cell survival, it can also lead to the persistence of damaged cells that should be eliminated.
• Example: Elevated BCL-2 levels are found in various cancers, including lymphomas, aiding cancer cells in avoiding death.
• Benefit of Decreasing: Temporarily Lowering BCL-2 activity can facilitate the removal of damaged or potentially cancerous cells, promoting tissue health and reducing cancer risk. This supports longevity by preserving tissue integrity and preventing age-related diseases.

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CDK1 Pathway: The CDK1 (Cyclin-Dependent Kinase 1) pathway regulates the cell cycle, especially controlling the shift from the G2 phase to the M phase (mitosis) during cell division. CDK1, when paired with cyclin B, forms Mitosis Promoting Factor (MPF), which kickstarts processes like chromatin condensation and spindle formation necessary for proper cell division. When this pathway malfunctions, it can cause uncontrolled cell growth, leading to various cancers. By targeting and managing CDK1 activity, we can control cell division, preventing cancer cell proliferation. Proper CDK1 regulation ensures healthy cell cycles, maintaining tissue health and reducing the risk of genetic damage accumulation, crucial for longevity and warding off age-related diseases.

• What it does: CDK1 regulates the cell cycle, ensuring cells divide appropriately, especially during the transition from G2 to M phase.
• Example: Overactive CDK1 can cause uncontrolled cell division and cancer.
• Benefit of Inhibition: Short-term inhibition of CDK1 can curb excessive cell growth, lowering cancer risk and supporting proper cell cycle regulation for healthy tissues and a longer life.

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CDK2 Pathway: The CDK2 (Cyclin-Dependent Kinase 2) pathway is vital for managing the cell cycle, especially during the shift from the G1 phase to the S phase, where DNA replication occurs. CDK2 teams up with cyclins E and A to form complexes that push the cell cycle forward by modifying key proteins involved in DNA replication and cell cycle progression. This ensures cells accurately copy their DNA before splitting, maintaining genetic stability. When the CDK2 pathway goes awry, it can cause abnormal cell growth, linked to cancers like melanoma and breast cancer. Inhibiting CDK2 can help rein in cell growth and division, making it a potential target for cancer therapy. Proper CDK2 regulation is crucial for keeping the cell cycle on track, preventing genetic chaos, and lowering cancer risk, which promotes healthier aging and longer life spans.

• What it does: CDK2 oversees the transition from G1 to S phase, ensuring accurate DNA replication.
• Example: Overactive CDK2 can spur uncontrolled cell growth, fueling cancers such as melanoma.
• Benefit of Inhibition: By short-term inhibition of CDK2, abnormal cell growth can be managed, reducing the risk of cancer. Proper cell division regulation supports tissue health and renewal, essential for extending longevity.

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CDK3 Pathway: The CDK3 (Cyclin-Dependent Kinase 3) pathway is a significant controller of the cell cycle, mainly involved in shifting cells from the resting state (G0 phase) to the phase where DNA synthesis begins (G1 phase). CDK3 pairs up with cyclins like cyclin C to activate proteins that push quiet cells back into the cell cycle. This activation is vital for cell multiplication and tissue renewal. Although CDK3 isn’t as well understood as other CDKs, ongoing studies suggest that when the CDK3 pathway goes off track, it could contribute to unchecked cell growth and cancer. By adjusting CDK3 activity, we might manage abnormal cell multiplication and assist the body in repairing and renewing tissues. A well-working CDK3 pathway is crucial for balancing cell growth and rest, ensuring tissues function healthily, and warding off age-related diseases, thus promoting longevity and healthy aging.

• What it does: CDK3 helps shift cells from the resting (G0) phase to the cell division (G1) phase, kickstarting cell multiplication.
• Example: When CDK3 activity is abnormal, it can disrupt the cell cycle and contribute to cancer.
• Benefit of Inhibition: Short-term inhibition of CDK3 can maintain proper cell cycle management, preventing uncontrolled cell multiplication and lowering cancer risk, which fosters healthy aging and longevity.

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CDK5 Pathway: The CDK5 pathway, short for Cyclin-Dependent Kinase 5 pathway, is a crucial series of signals primarily linked to the growth of neurons, the function of synapses, and the brain’s adaptability in the central nervous system. Unlike some other kinases, CDK5 doesn’t need cyclins to activate. Instead, it relies on special helpers called p35 or p39. Once it’s turned on, CDK5 tags various proteins for action, like those in the cell’s skeleton, genes, and the connections between neurons. This controls processes like how neurons move, grow their branches, talk to each other, and change connections over time. When the CDK5 pathway gets out of whack, it’s linked to brain diseases like Alzheimer’s and Parkinson’s, and mental health issues like schizophrenia and bipolar disorder. Studying the CDK5 pathway offers hope for treatments for these brain conditions.

• What it does: CDK5 is unique among kinases because it’s mostly about the brain, not the cell cycle. It helps with how neurons communicate and how the brain grows.
• Example: When CDK5 isn’t working right, it’s tied to brain diseases such as Alzheimer’s.
• Benefit of Inhibition: Keeping CDK5 in check can protect neurons from damage and decline, supporting brain health and clear thinking as we age, which is crucial for living longer.

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CDK6 Pathway: The CDK6 pathway, also known as the Cyclin-Dependent Kinase 6 pathway, is a critical process that controls how cells progress through their cycle, especially during a stage called G1. CDK6, a member of the cyclin-dependent kinase family, teams up with cyclin D to form an active pair. Together, they trigger a series of events that allow cells to move from G1 to S phase, where they replicate their DNA. This pathway is carefully managed by different factors like cyclins, cyclin-dependent kinase inhibitors (CKIs), and signals from other parts of the cell. When CDK6 gets out of control, it can fuel the growth of tumors by making cells divide too much. Scientists are exploring ways to stop this by targeting CDK6, hoping to slow down or stop the growth of cancer cells.

• What it does: CDK6, along with CDK4, helps cells move from the G1 phase to the S phase of the cell cycle. It’s especially crucial for making blood cells.
• Example: Too much CDK6 is seen in various cancers, like lymphoma and leukemia.
• Benefit of Inhibition: Short-term inhibition of CDK6 can help keep blood cell growth in check, lowering the chances of cancer and keeping the cell cycle balanced, which is crucial for staying healthy and living longer.

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PDGFR Pathway (α and β): The PDGFR pathway, made up of PDGFR-α (platelet-derived growth factor receptor alpha) and PDGFR-β (platelet-derived growth factor receptor beta), is a vital signaling system involved in many cell activities like growth, healing, and movement. PDGFRs are like switches on the cell surface that get turned on when they connect with their partners, the platelet-derived growth factors (PDGFs). Once switched on, PDGFRs start a series of actions inside the cell through pathways like PI3K-AKT, MAPK-ERK, and PLC-γ. These actions control which genes get turned on and how the cell structure changes, affecting how the cell behaves. The PDGFR pathway is crucial for the body’s development, fixing tissues, and keeping things balanced. When the PDGFR system goes out of control, it can lead to diseases like cancer, fibrosis, and blood vessel problems. Scientists are looking into drugs that can target PDGFRs to treat these diseases.

• What it does: PDGFR proteins help cells grow and repair, especially in blood vessels and tissues. They’re important for healing wounds and growing properly.
• Example: Too much activity in PDGFR is linked to some cancers and diseases where tissues grow too much, causing problems.
• Benefit of Inhibition: Temporarily inhibiting PDGFR can stop abnormal tissue growth and fibrosis, helping keep blood vessels and tissues healthy. This is crucial for good blood flow and providing nutrients, which can slow down aging and increase lifespan.

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MAPK Pathway: The MAPK (Mitogen-Activated Protein Kinase) pathway is a vital communication system in cells that controls many activities like growth, differentiation, and how cells respond to stress. It gets turned on by signals like growth factors, cytokines, and stress.

• Example: When the MAPK pathway is too active, it’s often seen in different cancers and inflammatory diseases.
• Benefit of Activation: Turning on the MAPK pathway in the right way helps cells fix themselves and stay alive when they’re stressed, which is good for keeping cells healthy and living longer. It helps cells handle stress and fix damage, which is important for staying healthy as we age. But if it’s too active, it can cause long-term inflammation and cancer, so it needs to be balanced for anti-aging benefits.

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AMPK Pathway: AMPK (AMP-activated protein kinase) is like a cellular energy gauge. It wakes up when the cell’s energy is low, like when we’re working out, fasting, or eating less. It helps keep the cell’s energy balanced by controlling different ways the cell uses energy.

• What it does: When AMPK wakes up, it sets off a chain reaction that makes more energy and uses less. It helps the cell take in glucose, burn fat for energy, and stop making things the cell doesn’t need, like fats, cholesterol, and proteins. AMPK basically helps cells use energy wisely.
• Example: When we work out, AMPK gets activated in our muscles, making them use more glucose for energy. And when we fast, AMPK helps use up stored fat for energy, helping us go without food.
• Benefits of AMPK Activation for Longevity:
  • Better Metabolic Health: AMPK activation helps the body use energy better, reducing the risk of health problems like obesity, type 2 diabetes, and fatty liver disease. By making the body use glucose and fat for energy, AMPK keeps blood sugar and fat levels healthy.
  • Healthier Cells: AMPK activation supports autophagy, a process where cells clean up damaged parts and recycle them. This keeps cells healthy and stops the buildup of damaged stuff like proteins and cell parts, which is important for preventing diseases linked to aging.
  • Less Inflammation: AMPK helps fight inflammation by stopping pathways that cause long-term inflammation. This can lower the chance of getting diseases caused by inflammation, which are common as we age.
  • Protection Against Age-Related Illnesses: By making metabolism better and lowering inflammation, AMPK can lower the risk of diseases like heart disease, Alzheimer’s, and certain cancers linked to aging.
  • Longer Life: In studies with animals like mice and worms, activating AMPK has made them live longer. This is likely because it helps metabolism, supports autophagy, and reduces inflammation – all important for staying healthy and living longer. Overall, AMPK is a big player in balancing cell energy, and turning it on can have lots of good effects for health and living longer. It helps metabolism work better, fixes cells, and fights inflammation, all of which are key for staying healthy longer.

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Cyclin D1 Pathway: Cyclin D1 is a regulatory protein involved in the control of the cell cycle, specifically in the G1 phase. It functions by forming complexes with cyclin-dependent kinases (CDKs), particularly CDK4 and CDK6, to promote progression through the G1 checkpoint. This activation of CDK4/6 by cyclin D1 leads to the phosphorylation of the retinoblastoma protein (Rb), allowing cells to transition from G1 to S phase and initiate DNA replication.

An example of cyclin D1’s role in cellular regulation can be observed in cancer. In many cancer types, cyclin D1 is overexpressed or dysregulated, leading to increased cell proliferation and tumor growth. This overactivity of cyclin D1 promotes uncontrolled cell cycle progression, a hallmark of cancer.

In terms of longevity, inhibition of cyclin D1 activity could offer potential benefits. Aging is associated with cellular senescence, where cells cease to divide but remain metabolically active. Dysregulated cyclin D1 activity has been linked to the promotion of cellular senescence, particularly in age-related diseases such as cancer. By inhibiting cyclin D1, it may be possible to delay the onset of cellular senescence and slow down the aging process. Additionally, since cyclin D1 is implicated in cancer progression, inhibition of its activity could also reduce the risk of cancer development, potentially extending lifespan. However, further research is needed to fully understand the impact of cyclin D1 inhibition on longevity and its potential therapeutic applications.

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Compounds from Natural Sources as Protein Kinase Inhibitors

Quercetin

Quercetin is a naturally occurring flavonoid found in many fruits, vegetables, grains, and leaves, with a notable presence in onions, apples, berries, and tea. It’s celebrated for its potent antioxidant properties, which combat oxidative stress and inflammation, key contributors to aging and chronic diseases.

Quercetin has been linked to a plethora of health benefits, including enhancing immune function, reducing the risk of certain cancers, supporting heart health, and potentially offering anti-aging effects by protecting against cell damage. Its ability to modulate signaling pathways involved in cellular aging and inflammation makes Quercetin a promising compound in the quest for longevity and disease prevention, highlighting the importance of incorporating a Quercetin supplement into your routine.

Sophora japonica, also known as the Japanese pagoda tree, is a species of tree in the Fabaceae family, native to China and Korea, but widely cultivated in Japan and other parts of the world. Traditionally, it has been used in Chinese medicine to treat hemorrhages and vascular diseases.

Quercetin is known to support the inhibition of the SRC family kinase (SRC, FYN, LYN) as well as BCL-2, and AKT kinase enzymes. (Baier, Szyszka, 2020) AKT signaling pathways play an important part in aging and anti-aging, and studies have shown that treatment with an AKT inhibitor can contribute greatly to healthy aging. Studies have also shown that BCL-2 inhibitors can be beneficial in supporting the elimination of senescent cells. Quercetin, along with Dasatinib, are the fundamental components in the ground-breaking D+Q Senylotic treatment.

Baier, Szyszka, Compounds from Natural Sources as Protein Kinase Inhibitors (2020)
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.079921

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Senna (Sennocide B)

Senna, derived from the leaves and fruit of the Senna plant, is primarily known for its laxative properties, attributed to the presence of compounds called sennosides. These compounds stimulate the lining of the bowel, which aids in alleviating constipation, an issue that can become more prevalent with age. Maintaining a healthy digestive system is crucial for the overall health and well-being of the body.

Our Senna supplement is a unique 50:1 extract, standardized to 40% Sennocide B, which is believed to be one of the few natural ingredients that can act as an inhibitor of PDGF, and PDGFR-β pathways. PDGF and PDGFR-β are known as platelet-derived growth factors. These tyrosine kinases have important functions in the development of connective tissue. The detailed structural understanding of PDGF-PDGFR signaling has provided a template that can aid therapeutic intervention to counteract the aberrant signaling of this normally silent pathway, especially in proliferative diseases such as cancer.

Enhanced PDGF-PDGRF signaling is considered abnormal, except when happening briefly during wound repair. Inhibiting this pathway on a temporary basis is thought to be beneficial in the treatment of many diseases, and is one of the key enzymes targeted by both Imatinib and Dasatinib. This is thought to be an important component of the ground-breaking D+Q treatment.

The use of Senna dates back to 3150 BCE, where its residue has been found in Egyptian pottery jars. While generally consumed as a tea, these artifacts suggest it was preserved and used as a medicated wine, and taken as powders, decoctions and syrups.

Chen, Chang, Hsu, Chiou, Lee, Hseu; Sennoside B inhibits PDGF receptor signaling and cell proliferation induced by PDGF-BB in human osteosarcoma cells (2009) https://pubmed.ncbi.nlm.nih.gov/19393247/

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Fisetin

Fisetin, a flavonoid naturally found in many fruits and vegetables like strawberries, apples, persimmons, and onions, has garnered attention for its potential anti-aging properties. This compound has been studied for its ability to influence various biological pathways that contribute to the aging process.

Research suggests that Fisetin has strong senolytic activity, which means it can selectively induce the death of senescent cells. Senescent cells are damaged cells that cease to divide but do not die as they should. They release inflammatory factors that lead to tissue dysfunction and age-related diseases. By clearing these cells, Fisetin helps reduce inflammation and enhance tissue function, potentially extending lifespan and improving the quality of life in aging populations.

Additionally, Fisetin is known for its antioxidant properties. It combats oxidative stress, a key contributor to aging and chronic disease, by neutralizing free radicals and reducing oxidative damage. This activity not only helps in slowing down the aging process but also supports cognitive functions, protecting against age-related decline in brain health.

It has been demonstrated that Fisetin supports senescence by activating and regulating AMPK, MAPK, and mTOR pathways while inhibiting CDK1, and CDK4 kinase enzymes. (Baier, Szyszka, 2020) A 2015 study indicated that AMPK activation can delay aging.

Stancu, AMPK Activation Can Delay Aging, (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941559/

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Spermidine

Spermidine, a naturally occurring polyamine found in various foods like aged cheese, mushrooms, soy products, and whole grains, has emerged as a promising compound in the realm of anti-aging research. Its potential to extend lifespan and improve health as organisms age is supported by various studies, particularly those examining its role in autophagy.

Autophagy is a critical cellular process where cells degrade and recycle their internal components. This process declines with age but is essential for removing damaged cells and reducing the accumulation of cellular waste, which can lead to age-related diseases. Spermidine has been shown to enhance autophagy, thereby potentially improving cellular function and longevity.

Moreover, research indicates that Spermidine may also support cardiovascular health, which is a common concern as populations age. Studies have shown that regular intake of Spermidine can lead to reduced blood pressure and a lower incidence of cardiovascular disease, likely through its role in promoting healthier blood vessel function and improving metabolic parameters.

Spermidine has been shown to support the inhibition of SRC family kinase (SRC, FYN, and LYN), as well as BCL-2 enzymes. Some studies have shown that BCL-2 inhibitors can be beneficial for eliminating senescent cells.

Rossini, Gargaro, Scalis, Bianconi, Ambrosino; eLife 12: e85872; A Back-Door Insight into the Modulation of Src Kinase Activity by the Polyamine Spermidine (2023) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10328509/

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Pterostilbene

Pterostilbene, a compound chemically related to Resveratrol and found predominantly in blueberries, has garnered attention for its potential anti-aging benefits. It is prized for its high bioavailability compared to Resveratrol, which means it may be more effective at reaching and benefitting various parts of the body.

Pterostilbene demonstrates significant antioxidant activity, which is crucial in combating oxidative stress, a major factor in the aging process and associated diseases. Oxidative stress results from an imbalance between free radicals and antioxidants in the body, leading to cellular damage. Pterostilbene helps mitigate this damage by scavenging harmful free radicals, thus protecting cellular integrity over time.

Additionally, pterostilbene has been found to exhibit anti-inflammatory properties. Chronic inflammation is another pathway through which aging accelerates, contributing to various age-related diseases such as cardiovascular disease, diabetes, and Alzheimer’s disease. By reducing inflammation, pterostilbene could potentially delay the onset of these conditions and extend lifespan.

Furthermore, some studies suggest that pterostilbene may improve cognitive function and brain health. It appears to enhance pathways involved in brain cell repair and maintenance, which could counteract age-related declines in mental functioning and protect against neurodegenerative diseases.

It has been demonstrated that Pterostilbene supports activation of the AMPK pathway. A 2015 study indicated that AMPK activation can successfully delay aging. It has also been shown that Pterostilbene downregulates BRC/ABL pathways, similar to the D+Q Treatment.

Sci Rep, 12: 702, Pterostilbene downregulates BCR/ABL and induces apoptosis of T315I-mutated BCR/ABL-positive leukemic cells (2022) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758722/

Biochem Biophys Res Community, 498(3):640-645, AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells (2018) https://pubmed.ncbi.nlm.nih.gov/29524400/

Young Min Park, Soo Nam Park, Inhibitory Effect of Lupeol on MMPs Expression using Aged Fibroblast through Repeated UVA Irradiation, (2018) https://pubmed.ncbi.nlm.nih.gov/30257039/

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Berberine

Berberine, a bioactive compound extracted from several plants such as Coptis chinensis, has garnered attention for its anti-aging potential.One of the key mechanisms of Berberine is its activation of AMP-activated protein kinase (AMPK), often referred to as a “metabolic master switch”. Activation of AMPK improves metabolic efficiency and energy homeostasis, which are crucial for slowing down the aging process. Enhanced AMPK activity is associated with reducing mitochondrial dysfunction and promotes the removal of damaged cells through autophagy, thus preventing the accumulation of cellular debris and supporting cellular rejuvenation.

Additionally, Berberine has shown promise in managing metabolic disorders such as diabetes and obesity, which are closely linked with accelerated aging. By improving insulin sensitivity and reducing glucose production in the liver, Berberine helps manage blood sugar levels and lipid metabolism, potentially reducing the risk of metabolic diseases.

A unique quality of Berberine is its suspected ability to inhibit ROCK2, PIK3CD, KCNMA1, CSF1R, and KIT Kinase enzymes, and in a 2023 study, was suggested that Berberine is similar to nature’s own version of Imatinib or Dasatinib, the powerful anti-cancer drug used in the groundbreaking D + Q senolytic treatment.

Qin Z, Han Y, Du Y, Zhang Y, Bian Y, Wang R, Wang H, Guo F, Yuan H, Pan Y, Jin J, Zhou Q, Wang Y, Han F, Xu Y, Jiang J. Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization. Sci China Life Sci. 2024 May;67(5):1010-1026. doi: 10.1007/s11427-023-2454-9. Epub 2024 Mar 12. PMID: 38489007.https://pubmed.ncbi.nlm.nih.gov/38489007/

Choi YJ, Lee KY, Jung SH, Kim HS, Shim G, Kim MG, Oh YK, Oh SH, Jun DW, Lee BH. Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice.Toxicol Appl Pharmacol. 2017 Feb 1;316:74-82. doi: 10.1016/j.taap.2016.12.019. Epub 2016 Dec 28. Erratum in: Toxicol Appl Pharmacol. 2017 Apr 1;320:73. doi: 10.1016/j.taap.2017.02.005. PMID: 28038998.

Yun S. Lee; Woo S. Kim; Kang H. Kim; Myung J. Yoon; Hye J. Cho; Yun Shen; Ji-Ming Ye; Chul H. Lee; Won K. Oh; Chul T. Kim; Cordula Hohnen-Behrens; Alison Gosby; Edward W. Kraegen; David E. James; Jae B. Kim Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States, (2006), https://diabetesjournals.org/diabetes/article/55/8/2256/12348/Berberine-a-Natural-Plant-Product-Activates-AMP

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Rutin

Rutin is a bioflavonoid compound found in various plants such as buckwheat, apples, and citrus fruits. It has been extensively studied for its potential in anti-aging treatment. Rutin is known for its antiprotozoal, antibacterial, anti-inflammatory and antiviral properties.

Chronic inflammation is a significant factor in aging and can contribute to the development of disease. By modulating inflammatory pathways, Rutin is believed to reduce the risk of these conditions, thereby promoting healthier aging.

Rutin is also thought to support blood vessel health, which is vital for preventing age-related vascular diseases. Its believed to have the ability to strengthen blood vessels, improve circulation, and treat both varicose veins, which are more common as people age.

Interestingly, recent studies have indicated that Rutin has potential against SARS-CoV-2 due to its inhibition of Mpro, RdRp, PIpro, and spike (S)-protein.

Studies have shown that Rutinocide can cause the inhibition of c-Met Kinase enzymes. These proteins have recently been found to serve as an early marker of cellular senescence and might contribute to resistance to apoptosis and senescence-associated secretory phenotype, making it an important component in senotherapeutic and anti-aging applications.

Rahman F, Tabrez S, Ali R, Alqahtani AS, Ahmed MZ, Rub A. Molecular docking analysis of rutin reveals possible inhibition of SARS-CoV-2 vital proteins. J Tradit Complement Med. 2021 Mar;11(2):173-179. doi: 10.1016/j.jtcme.2021.01.006. Epub 2021 Jan 22. PMID: 33520682; PMCID: PMC7825826.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825826/

Elsayed HE, Ebrahim HY, Mohyeldin MM, Siddique AB, Kamal AM, Haggag EG, El Sayed KA. Rutin as A Novel c-Met Inhibitory Lead for The Control of Triple Negative Breast Malignancies. Nutr Cancer. 2017 Nov-Dec;69(8):1256-1271. doi: 10.1080/01635581.2017.1367936. Epub 2017 Oct 30. PMID: 29083228; PMCID: PMC6193555. https://pubmed.ncbi.nlm.nih.gov/29083228/

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