By getting rid of senescent cells …

Quercetin Prolongs Healthspan
And may very well improve lifespan too

By Will Block

Some ideas worth recollecting have their origin in the ancient past. In Greek mythology, Tithonus was a mortal who was in love with Eos, the goddess of the dawn. Eos didn’t want Tithonus to grow old and die, so she asked Zeus to give him eternal life, which the top god granted.

But she forgot to ask for eternal youth, so Tithonus just got older and older and more decrepit. Eventually he couldn’t move but babbled endlessly, with no strength at all, such as once he had in his supple limbs. The moral of the myth is that healthspan trumps lifespan.


The moral of the myth is that
healthspan trumps lifespan.


Senescence Accelerates Aging

In a recent “tour de force” scientific study, researchers at The Scripps Research Institute (TSRI), the Mayo Clinic, and other institutions began with the assumption that the accumulations of senescent cells have been associated with accelerated aging.1 Senescent cells have stopped dividing and secrete compounds that both harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. Scripps et al searched for ways to eliminate senescent cells in the body that have become destructive, hypothesizing that the outcome would be beneficial for overall health.

Their study, published online a few months ago in Aging Cell, documents the discovery of increased expression of pro-survival networks in senescent cells. The researchers found that senescent cells were similar to cancer cells in that they possessed an increased expression of so called pro-survival networks that help them resist apoptosis, aka programmed cell death.


Senescent cells were similar to
cancer cells in that they possessed
an increased expression of so called
pro-survival networks that help them
resist programmed cell death.


Inducing Senescent Cell Self-Destruction


Turning the page on cells that turn over rapidly such as skin and blood cells. Stem cells also renew our muscles and blood vessels.
The scientists conjectured that the pro-survival, protective mechanisms of senescent cells could be altered in ways to cause self-destruction. Based on their hypotheses, they identified two compounds, a nutrient and a drug—chosen from screening 46 agents—that could induce apoptosis (cell suicide) of senescent cells in vitro and in vivo, leading to improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan in mice developed to age rapidly. These mice age at six times the rate of normal mice, and in the study their healthy lifespans, or “healthspans” were greatly extended by 10 percent. They also had more than 15 percent greater bone density. Astonishingly, dramatic improvements were noticeable just days after treatment.


Senolytics can help delay,
prevent, improve, or even
reverse several chronic age-related
diseases and disabilities as a group,
rather than concentrating on
one at a time.


Senolytics: Anti-Aging Intervention in Humans?

Dubbed senolytics, these compounds consist of the nutrient quercetin and the drug dasatinib. Separately and together, the new research shows that they selectively kill senescent cells. What is amazing is that senolytics directly target the source of the majority of free radicals. This is the same source that Denham Harman observed 65 years ago.2

The researchers documented how senolytics can help delay, prevent, improve, or even reverse several chronic age-related diseases and disabilities as a group, rather than concentrating on one at a time.


If senolytics work in humans,
it could truly be
an “anti-aging” intervention.


Quercetin: Many Benefits and Few Side Effects

The nutrient quercetin—widely found as a flavonol in fruits and vegetables—is a nutritional supplement that acts as an antihistamine,3 anti-inflammatory,4 and anti-cancer agent5 among many other benefits, including:

• Quercetin’s natural metabolites of dietary quercetin target and protect macrophages from becoming foam cells6

• Quercetin extends lifespan in C. elegans7

• Quercetin decreases high-fat diet induced body weight gain8

• Quercetin is more effective anti-diabetic than anti-obesity biomolecule9

• Quercetin increases insulin sensitivity and improves glucose tolerance10

• Quercetin exhibits cardioprotective properties through an anti-atherogenic gene11


Throughout our lifetimes, stem cells
renew our muscles and blood vessels.
They also do the same for skin and
blood cells that turn over rapidly.


Dasatinib’s Adverse Effects

Dasatinib is a cancer drug, sold under the trade name Sprycel.® It is not at home in the human body and has many adverse effects. For example, it may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment. Aside from that, the cost of dasatinib is also outrageously high; a daily dose is $367 per day!

On the other hand, quercetin has been used as a supplement for a long time, is very low-cost, and has very few side effects compared to dasatinib.

In the study, quercetin showed a greater effect against both senescent human endothelial cells and senescent mouse bone marrow mesenchymal stem cells, while dasatinib was found to reduce senescent human fat cell progenitors.

Mesenchymal stem cells are multipotent stromal cells (connective tissue cells of any organ) that can differentiate into a variety of cell types. These include bone cells, cartilage cells, muscle cells, and fat cells (see Fig. 1). Throughout our lifetimes, stem cells renew our muscles and blood vessels. They also do the same for skin and blood cells that turn over rapidly.

Also, the combination of quercetin and dasatinib eliminate senescent mouse embryonic fibroblasts. Senolytics are now thought to combat some of the factors associated with aging as other research indicates (see Fig. 2). Scientists project that other anti-senescent senolytics are on the way.


Fat cells are arguably one of
the most abundant types of
senescent cells in humans.


What Is the Human Equivalent Dose of Quercetin?

The dose of quercetin used in the study was 50-mg per kg body weight in mice given weekly. Using the FDA’s “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (see http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf), that would be about 283 mg for a 70 kg (154 lb) person. This is considered to be a safe dose, and many supplement formulations already use this amount or more on a daily basis. The amount of dasatinib given weekly to the mice was 5-mg kg body weight or 28 mg for a 154 lb person. These are small amounts indeed. However, there are so many adverse effects reported that its use at any level might be a problem.

The Discovery of Senescent Cells

The human fibroblast cell line that Leonard Hayflick used in the discovery of the famous Hayflick limit, demonstrated that cells would replicate only a limited number of times before becoming terminally senescent.

Senescent cells don’t immediately die but they no longer replicate and they undergo many negative changes not found in non-senescent cells. Senescent cells are not generally beneficial to have around, other than the fact that their exit from the cell cycle acts as a protective mechanism against those cells becoming cancerous.


The Hayflick limit was one of the
earliest findings in which the
processes that impair the function
of aging cells started to
be discovered.


In fact, a growing population of senescent cells with age has been found to have a damaging effect on the functioning of non-senescent cells in their cellular neighborhood. This is because they sustain, for example, chronic inflammation and extracellular matrix remodeling. The Hayflick limit was one of the earliest findings in which the processes that impair the function of aging cells started to be discovered.

The Underlying Concept

The Senescent Transcriptome and Anti-Apoptotic Pathways

In the study, the scientific collaborators initially tested their hypotheses by comparing gene expression insenescent vs. nonsenescent cells using transcript array analysis. They focused on fat cell progenitors, or preadipocytes (fat cells), as they are arguably one of the most abundant types of senescent cells in humans.12 From the perspective of this study, this could lead one to conclude that our fat cells are killing us!

Figure 1 Mesenchymal stem cells effects on various tissues of the body.
LEM1509Fig1_274.gif
(click on thumbnail for full sized image)

Cultures were split and senescence induced in half of the cells. Twenty-five days later, gene expression was measured using gene chips. Overall patterns of gene expression differed substantially between senescent and nonsenescent preadipocytes isolated from the same subjects. Analyses of gene categories indeed revealed upregulation of negative regulators of apoptosis and antiapoptotic gene sets in senescent compared to nonsenescent cells.

While not mentioned in the Scripps et al study, the chromosomes in stem cells continually lose their telomeres and when they become too short to divide they are said to become “senescent.” Importantly, when these cells senesce they stop dividing, losing their functions, and becoming moribund. At this point, they eventually poison nearby tissue, thus creating more senescent cells.


In the mice that had their senescent
cells removed by employing the
trigger, a 20 to 25% increase in
lifespan followed and this was from a
single treatment, quite late in life.


Defunct stem cells poison the body with chemical inflammatory signals (cytokines) that spread the “fire” of what has been called inflam-aging. These age-associated changes involve the overexpression of inflammation and immune response genes and also genes associated with the lysosomal system (which breaks down cell garbage, as in autophagy).

Even though senescent cell abundance in aging or diseased tissues is low—achieving a maximum of 15 percent of nucleated cells in very old primates13—senescent cells can secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together constitute the senescence-associated secretory phenotype (SASP). Just a small number of senescent cells can cause a great deal of damage. That’s like saying that even if only 15% of the “apples” in your basket are “bad apples,” that is enough to kill you.

Removing Senescent Cells Increased Lifespan

Figure 2 Mice whose bodies were cleared of senescent cells didn’t live longer—but they did live better, which means that destroying senescent cells might also prolong our golden years, thus enhancing our healthspans. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
LEM1509Fig2_274.jpg
(click on thumbnail for full sized image)

In the earlier research conducted by many of the same scientists who worked on the Scripps Research Institute study (see Fig. 1), the question was asked about whether senescent cell removal could affect lifespan.14 Using genetically modified mice in such a way that senescent cells would self-detonate if a trigger was pulled, by feeding the mice a molecule that matched the trigger, the researchers could cause the senescent cells to terminate themselves while leaving normal cells intact. Comparing the same mice, not triggered and triggered into self-immolation, the results were amazing. In the mice that had their senescent cells removed by employing the trigger, a 20 to 25% increase in lifespan followed and this was from a single treatment, quite late in life.

Unlike the earlier study, the research group at Scripps et al started with gene expression profiles for senescent cells, comparing them to profiles for non-senescent cells. They determined that the target for the drug and nutrient agents that keeps senescent cells alive—when they really should be eliminating themselves—should be identified through RNA interference to silence these genes, one at a time. This they thought would help identify effective strategies for differentially targeting the senescent cells. As already mentioned, they screened 46 compounds to see which would best attack the targets they had identified.

Summarizing their findings: the nutrient quercetin seemed to work best for endothelial cells (in arteries), and dasatinib was best for fat stem cells. Quercetin is cheap and found in many herbs and berries; dasatinib is a patented chemotherapy agent, sold for a scandalously high price by Bristol Myers Squib, the maker of dasatinib.


Senescent cells are cells that
have stopped dividing,
which accumulate with age and
accelerate the aging process.


The Results Could Be Transformative

“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said TSRI Professor Paul Robbins, PhD, who with Associate Professor Laura Niedernhofer, MD, PhD, led the research efforts for the paper at TSRI in Florida. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”15

“The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time.”15


Dasatinib eliminated senescent
human fat cell progenitors, while
quercetin was more effective against
senescent human endothelial cells
and mouse bone marrow stem cells.
A combination of the two was most
effective overall.


Identifying the Target

To repeat, senescent cells are cells that have stopped dividing, which accumulate with age and accelerate the aging process. Since the “healthspan” (defined as the time in life free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that if they could accomplish this in humans, the results could open the doors to tremendous treatment potential.

How should they go about identifying and targeting senescent cells without damaging other cells? Their suspicion was that senescent cells’ resistance to death by stress and damage could provide a clue. By using transcript analysis, as described above, the researchers found that this common characteristic of cancer and senescent cells provided the clue. When they increased the expression of “pro-survival networks” both cancer and senescent cells were better able to resist apoptosis (programmed cell death) and this finding provided key criteria to search for potential drug candidates.

Using these criteria, the team honed in on two available compounds—the cancer drug dasatinib and quercetin, a natural supplement, as we already know.

Further cell culture testing showed that these compounds do indeed selectively induce death of senescent cells. As already outlined, each of the two agents had different strong points. To repeat, dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.

“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” said Niedernhofer, whose animal models of accelerated aging were used extensively in the study. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”15

“Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds,” Robbins said. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”15 However, if it turned out that most of the “drugs” were nutrients, without significant adverse effects, infrequent treatment would not be an issue.


Old mice given a single dose of
both senolytics exhibited improved
cardiovascular function within
five days.


Remarkable Results

Old mice given a single dose of both senolytics exhibited improved cardiovascular function within five days. After seven months mice weakened by radiation therapy used for cancer treatment showing improved exercise capacity. Healthspan was also extended in mice models with accelerated aging that were periodically administered the drugs, with age-related symptoms of spine degeneration and osteoporosis delayed.

Barking up the Wrong Tree

In the study’s conflict of interest section, runs the following: “Mayo Clinic, JK, TT, YZ, TP, NG, AP [initials of the authors] have a financial interest related to this research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. LJN and PDR are co-founders of, and have an equity interest in, Aldabra Bioscience.”


As passionate health seekers,
we need to make every effort
to avoid this at all reasonable costs
and that includes the use of our
minds to stay on top of the relevant
fields of rapidly growing knowledge.


The Point Is Not Only Living Longer…

The point is living healthier. If you look only at longevity, you may overlook the horror of outliving yourself. This means outliving your ability to have a healthy, meaningful, productive life. That makes healthspan a necessary and adjunctive aspect of research in the area.

While it is more and more likely that we will live into our eighties and nineties, for far too many of us, it may be more like a jail sentence, in which our life at those ages consists of debilitation and all that that entails. Slowly decaying away, physically and mentally, in assisted living facilities and nursing centers where we are treated like cattle. As passionate health seekers, we need to make every effort to avoid this at all reasonable costs and that includes the use of our minds to stay on top of the relevant fields of rapidly growing knowledge.

References

  1. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22.
  2. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;2:298–300.
  3. Sakai-Kashiwabara M, Abe S, Asano K. Suppressive activity of quercetin on the production of eosinophil chemoattractants from eosinophils in vitro. In Vivo. 2014 Jul-Aug;28(4):515-22. PubMed PMID: 24982217.
  4. Boots AW, Drent M, de Boer VC, Bast A, Haenen GR. Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin Nutr. 2011 Aug;30(4):506-12. doi: 10.1016/j.clnu.2011.01.010. Epub 2011 Feb 15. PubMed PMID:21324570.
  5. Brito AF, Ribeiro M, Abrantes AM, Pires AS, Teixo RJ, Tralhão JG, Botelho MF. Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem. 2015 Aug 12. [Epub ahead of print] PubMed PMID:26264923.
  6. Kawai Y, Nishikawa T, Shiba Y, et al. Macrophage as a target of quercetin glucuronidesin human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids. J Biol Chem. 2008 Apr 4;283(14):9424-34. doi:10.1074/jbc.M706571200. Epub 2008 Jan 16. PubMed PMID: 18199750.
  7. Pietsch K1, Saul N, Chakrabarti S, et al. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011 Aug;12(4):329–47.
  8. Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, et al. Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice. Genes Nutr. 2014 Sep;9(5):418. doi: 10.1007/s12263-014-0418-2. Epub 2014 Jul 22.
  9. Arias N1, Macarulla MT, Aguirre L, et al. Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation. Genes Nutr. 2014 Jan;9(1):361. doi: 10.1007/s12263-013-0361-7. Epub 2013 Dec 14.
  10. Henagan TM, Cefalu WT, Ribnicky DM, et al. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015 Jan;10(1):451–63.
  11. Lakshman R, Garige M, Gong M, et al. Is alcohol beneficial or harmful for cardioprotection? Genes Nutr. 2010 Jun;5(2):111-20. doi: 10.1007/s12263-009-0161-2.
  12. Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell. 2010 Oct;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x. Epub 2010 Aug 15. Review. PubMed PMID: 20701600; PubMed Central PMCID: PMC2941545.
  13. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007 Jan;128(1):36-44. Epub 2006 Nov 20. PubMed PMID: 17116315; PubMed Central PMCID: PMC3654105.
  14. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
  15. Scripps Research Institute. [Internet] Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan. March 9, 2015. Available from https://www.scripps.edu/news/press/2015/20150309agingcell.html Accessed August 18, 2015.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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