Kill Your Senescence Before It Kills You

Written by BLOCK, WILL

What Dasatinib and Quercetin can do for you

Care to wait ten years for commercially available all-body senolytics? Beware! When it arrives, it may be too late! As cells grow older and/or are damaged, they can enter into the state of senescence, from which toxins are spewed.

These toxins can drag other cells into the same dilemna. For those who study the scientific literature, the current clear option is to take a measured dose of the drug Dasatinib + the supplement Quercetin. According to recent research—when taken together—D + Q synergize their senolytic effects. Now is the time to get rid of your senescence!

Drugs and Plants Meeting

Dasatinib is a chemotherapeutic drug and is a plant flavonoid. Dasatinib is a senolytic that extends life by a notch. However, when taken together in clinical trials, the drug cocktail (D + Q) was shown to extend the life of lab mice by 36 percent. If human life could be extended proportionately as much, you could lengthen it long enough to arrive in the future!

It has been said that if we want to live a long time, we need something to help us now. Senolytics such as D + Q could prove necessary for that goal.

Senescent cells no longer divide or support the tissues and organs of which they are part. Senolytics target cellular senescence, a process in which damaged cells, rather than dying, persist and become toxic to cells around them. Instead, they secrete a range of harmful inflammatory chemical signals, which are collectively known as the senescence-associated secretory phenotype (SASP).

Correct Annual Dose

The Dasatinib + Quercetin treatment was new for 2018 with senolytic reviewers working out what they believe is the correct twice-a-year dosage based on how much you weigh. Furthermore, others who want to agressively adopt the latest antiaging treatment can pay up to several thousands of dollars to a compounding pharmacy to provide Dasatinib (more on this later).

Quercetin is found in Kale, Tomatoes, Broccoli, Raw asparagus, Capers, and Raw red onions; it’s cheap!

Senolytics Are as Good as Caloric Restriction

The effect of D + Q seems to have the same amount of antiaging benefits as calorie restriction. Supplementing with D + Q can promote the selective elimination of senescent cells. Before—when younger and healthier—these cells were the building blocks of life. But once senescence is stopped, there is a significant decrease in the secretion of frailty-related pro-inflammatory cytokines of human adipose tissue. This is highly desirable. D + Qare one example of a new class of drugs/supplements called senolytics, which can prevent cells from becoming senescent.

Senescence occurs when certain cells cease to divide, usually after 50 divisions. This phenomenon is known as “replicative senescence,” or the Hayflick limit.

Senolytics target cellular senescence, a process in which damaged cells, rather than dying, persist and become toxic to cells around them. These cells improve physical function and increase lifespan in old age.

High Dose Side Effects

Dasatinib, sold under the brand name Sprycel®, is a targeted therapy used to treat certain cases of chronic myelogenous leukemia and acute lymphoblastic leukemia. Common side effects include low white blood cells, low blood platelets, anemia, swelling, rash, and diarrhea, when taken orally and chronically on a daily or continuous basis. But generally, these are the consequence of unmanageably high amounts.

Cellular senescence is one phenomenon by which normal cells cease to divide. Also known as biological aging, this is represented by the gradual deterioration of functional characteristics. The word senescence can refer either to cellular senescence or to senescence of the whole organism.

The above diagram shows the difference between a normal cell and a cell which is in a senescent state. A senescent cell is a cell that has stopped replicating. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt a pattern of secreting pro-inflammatory cytokines. In general, these cells are trouble makers.

Cellular senescence is one of the aging processes that makes up the hallmarks of aging. As cells grow older or are damaged, they can enter a state of senescence. They then dispose of themselves with a self-destruct program called apoptosis.

This is a natural safety mechanism that fights cancer and promotes tissue repair. Senescent cells no longer fulfill their roles nor support the tissues which they are part. Instead they produce SASP (see above). The SASP promotes cellular inflammation, blocks cellular processes, and leads to age-related diseases. Additionally, SASP also encourage nearby cells to become senescent, compounding the problem.

Normally, Cells Are Destroyed by Apoptosis

Normally, cells are destroyed by apoptosis and are cleared away by the immune system. However, as some cells evade apoptosis and the immune system, and the immune system fails with age, they accumulate. Therapies that eliminate senescent cells are called senolytics. In mice, senolytics have been shown to increase lifespan and ameliorate symptoms of age-related diseases. It may also be possible to restore a more youthful immune system, thus deleting senescent cells.

Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism’s life cycle. But with senolytics, this is significantly reduced.

Longevity Escape Velocity

Only last July, the world awoke to news from the Mayo Clinic that many age-related afflictions can be reversed by eliminating senescent cells from old mice by using D + Q.[1] In addition to regaining aspects of youthful health, the old mice whose senescent cells were selectively removed lived 36% longer.

If this is translated to humans, it could provide just what is needed to reach the next breakthrough. One of these is called longevity escape velocity, this is when your longevity is expanded more than one year for each year you live. The scientists found that D + Q could prevent cell damage, delay physical dysfunction, and extend lifespan in naturally aging mice.

Scientists had previously demonstrated that the combination of the chemotherapeutic drug Dasatinib and the flavonoid Quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis, and cardiovascular disease.

The End of Life Can Be Delayed

Senescence is the inevitable fate of all multicellular organisms with germ-soma separation, but it can be delayed. The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats, and the existence of species having negligible senescence and potentially immortal organisms such as Hydra, have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Intermittent Oral Administration

Intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%.

The Xu M, et al, study (2018) provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice. 1 The simplest human trial involves the FDA-approved drug Dasatinib that demonstrated profound age-reversal effects in a mouse study published in 2015.

The Dangers of Using Dasatinib

Are there any dangers to senolytics? Once again, only when taken in large or continuous amounts. And for people with osteoarthritis; it works, and the concept has been proven![2] Taken once for three days, and then repeated for a total of three weeks (9 servings), along with Quercetin seems to work well.

How About Fisetin?

The Mayo group had previously tested Fisetin and found it effective in killing some kinds of human senescent cells but not others. In previous tests, Fisetin was found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), and that is where it was primarily tested in the new studies.[3] “It is exciting to see animal data arrive for some of the potentially senolytic compounds that may turn out to destroy enough senescent cells in mammals to be worth using as first generation rejuvenation therapies.”

Clearing Zombie Cells

A combination of Dasatinib and the common supplement Quercetin was found to be synergistic in removing senescence rogue cells with a tremendous impact on quality of life and the burden of age-related chronic diseases. Dasatinib + Quercetin clear senescent (“zombie”) cells, the accumulation of which are one of the key ways in which we age and eventually die …

In a first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in idiopathic pulmonary fibrosis (IPF), warranting evaluation of D + Q in larger randomized controlled trials for senescence-related diseases.

A New Therapeutic Avenue for Treating Neuropsychiatric Disorders

This study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.

The hypothesis-driven, bioinformatics-based approach we used to discover that Dasatinib + Quercetin are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type-specific senolytic agents.

Rodent study shows what senolytics D + Q can do:

  • Improve frailty symptoms (gait, grip strength)
  • Enhance hair color appearance
  • Improve cardiac/arterial function
  • Reduce tremors and urinary incontinence
  • Decrease osteoporosis
  • Increase exercise endurance
  • Improve kidney/liver age scores
  • Extend healthy lifespan

Taking Care of Zombie Cells

D + Q can clear senescent (aka “zombie”) cells, which are one of the key ways in which we age and eventually die. They are called zombie cells because they wander aimlessly, as if they have no self-directed.

By reenergizing cells using metformin and other AMPK activators to remove waste and suppress fat storage/excess cell proliferation and then NAD+ to repair broken DNA, the body may be more primed for senolytic therapy using D + Q.

Rejuvenated Protein GDF-11

Removal of accumulated senescent cells is critical for systemic rejuvenation. Senescent cells secrete protein-degrading enzymes and generate chronic inflammation, both of which can neutralize the beneficial effects of stem cell replacement and/or young plasma that contain a myriad of rejuvenating proteins like GDF-11.

Initially It Would Be: Fossel Disagrees

Not all observers agree with Dr. Michael Fossel, the telomerase expert, telling us in a recent interview, that the senolytic approach is to remove those ten percent of the cells that are causing damage.

However, the remaining 90 percent must divide to make up for the missing cells, which means that you’ve just accelerated senescence in the remaining cellsSo, the next year, you must kill another 10 percent, and every time you do that, you’re increasing the rate of senescence of the remaining percentage of cells.

If you look at graphs of the published data you find that, initially, there’s a little improvement in function, and then the vector goes down at a much steeper rate than when you don’t do anything at all. Does Fossel have a point here or do you think he’s being too pessimistic? Can stem cells fill in the gaps (literally) and replace the killed off zombie cells?

Fortunately, senolytics are tissue-specific and only kill some types of senescent cells, which may make them safer. The term “senolytics” refers to compounds that selectively induce cell death in senescent cells. 

Senescent cells are cells whose metabolism has gone awry for one reason or another, often due to DNA damage. The metabolism of these cells involves secretion of inflammatory molecules. These cells do not function and divide properly, and are considered by some researchers to contribute to age-related inflammation, increased cancer risk, and possibly a shortened lifespan.

One remarkable study published in 2015 reported that Dasatinib + Quercetin were effective senolytics, selectively eliminating different types of senescent cells in mice.[4]

The term “senolytics” refers to compounds that selectively induce cell death in senescent cells.

Senescent cells are cells’ whose metabolism has gone awry for one reason or another, often due to DNA damage. The metabolism of these cells involves secretion of inflammatory molecules. These cells do not function and divide properly and are considered by some researchers to contribute to age-related inflammation, increased cancer risk, and possibly a shortened lifespan.

One remarkable study published in 2015 reported that the chemotherapy agent dasatinib, and the plant flavonoid quercetin, were effective senolytics, selectively eliminating different types

of senescent cells in mice.

I became curious as to just how it was determined that the combination of Dasatinib + Quercetin in a 1:10 combination was an effective senolytic treatment.  There are very many compounds out there, and it was difficult for me to imagine how this combination could emerge from that vast range of possibilities. Therefore, I tracked down the original source of the idea as a reference in a Kirkland paper. The key paper was published in 2015 in the journal Aging, entitled “The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.” [5]

The authors noted that senolytic cells were somehow avoiding the natural process of apoptosis that should have cleared them.  When they were eliminated at all, it was done by the immune system rather than the processes of apoptosis or necrosis.  They hypothesized that senescent cells are using the same pathways employed by cancer cells to block the apoptosis process.  Therefore, they suggested that a drug that prevents apoptosis blockage should clear senescent cells.

The researchers determined that a 1:10 D + Q combination was more effective than either drug individually.

Scientists tested 46 different candidate compounds on cell cultures of human senescent cells and found that Dasatinib and Quercetin showed promise in clearing the senescent cell targets. 

Serving Size: 3 Days, 3 Weeks (Based on Weight)

Quercetin                                                                        Dasatinib

100 pounds = 1,125 mg 100 pounds 112 mg
165 pounds = 1,875 mg 165 pounds 187 mg
220 pounds = 2,500 mg 220 pounds 250 mg

Further, they found that the actions of the drugs were somewhat complementary, with Dasatinib being particularly effective on senescent pre-adipocyte cells (fat cells) and Quercetin being particularly effective on senescent endothelial cells (blood-vessel lining cells). Moreover, the researchers determined that a 1:10 D + Q combination was more effective than either drug individually. They then tested this combination on mice and found very positive results in extending health spans.

Again, those of us looking for an edge to step further into our future may find it in senolytics. If it increases our lives by 36% that my enable us to live long enough to live forever.

Rejuvenate Youth and Health Now

If you don’t treat aging you inevitably become frail, which is the hallmark of aging diseases. All the other aging diseases including those affecting your cardiovascular system and brain, eventually lead to death. Thus, we require rejuvenation biotechnology to reverse the aging processes and thereby restore youth and health.

Anti-aging products that purport to “rejuvenate” the body but do not actually address any of these hallmarks and therefore, cannot affect the root causes of age-related disease.

More Affordable

Looking more closely at senolytics, you and many other commentators are excited about the results in model animals and early human results, particularly for the D + Qcombo approach, which you describe as being much more affordable now than was the case before, when a single service could be thousands of dollars. But now it can be taken down considerably.

Advanced Medical Technology

Rejuvenation biotechnology is advanced medical technology that directly addresses any of the various aging processes in order to restore tissue and organ function to a more youthful state, thereby ameliorating, delaying, or preventing age-related diseases.

Ultimately, the goal of rejuvenation biotechnology is to change chronologically old and chronologically young people, at every physical level, indistinguishable from one another.

However, no single rejuvenation therapy will completely restore someone to a youthful state. That’s because the causes of aging are so broad and interlinked, rejuvenation biotechnology must be broad and comprehensive to match.

Eliminating Harmful Senescent Cells

For example, senolytics are rejuvenative because they eliminate harmful senescent cells, which accumulate with age and are one of the hallmarks of aging. However, because types of senescent cells differ from one another, a comprehensive suite of senolytic therapies is required to directly address this hallmark through destroying these cells.

Stem cell therapies are rejuvenative because they address stem cell exhaustion, restoring the body’s youthful ability to repair tissues. However, because the body requires many types of stem cells for long-term function, each stem cell niche must be replenished.

Changing Our View of Age-Related Diseases

There are potentially huge changes coming to medicine which will change how we regard age-related diseases in the next few decades. With these changes comes the potential for people to live longer and healthier lives thanks to the development of new therapies.

New therapies can directly target the various aging processes in order to delay, prevent, or even reverse age-related diseases.

[1] Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018 Aug;24(8):1246-56.

[2] McCulloch K, Litherland GJ, Rai TS. Cellular senescence in osteoarthritis pathology. Aging Cell. 2017 Apr; 16(2):210–8.

[3] Reason. Animal data shows fisetin to be a surprisingly effective senolytic. Fight Aging! 3 Oct. 2018.

[4] Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug; 14(4): 644–58.

Copyright: Will Block 2019