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JAMA Reports on Senescent Cell Removal

February 2019

By Richard Basillico

Researchers at the Mayo Clinic have identified a major cause of aging—and a way to reverse it.1

The scientists showed for the first time that harmful "zombie cells" lurk in all of our tissues.

Also known as senescent cells, they accumulate over time and clog up the efficient function of our bodies. They also emit proinflammatory factors that accelerate degenerative aging.2

The good news: Researchers have identified a class of compounds called senolytics, which can selectively remove senescent cells.

By getting rid of these harmful cells, senolytics increased the median post-treatment lifespan of aged mice by 36%.

These senolytic compounds also decreased age-related physical deterioration and prevented cognitive decline in rodent models.1,3

These findings have been hailed as potential breakthroughs by major scientific journals such as the Journal of the American Medical Association (JAMA) as well as research institutions for good reason: Doctors may soon prescribe drugs that safely remove this cause of systemic aging and restore youthful functionality. Numerous clinical trials of senolytic agents are underway.

But aging people can't wait for new senolytic drugs to be approved. They want to start purging their bodies of senescent cells today.

Senescent Cells: A Root of Aging

Scientist looking through Microscope

Senescent cells have been found in virtually every human tissue. These cells have reached the end of their natural lifespans. But instead of dying off in the normal process called apoptosis, they accumulate within tissues, where they secrete protein-degrading enzymes that damage healthy cells.1,3,4

These secreted substances also produce chronic, low-grade inflammation associated with most age-related disorders.

As senescent cells accumulate, they damage cellular DNA and mitochondria, while causing telomere dysfunction. Telomeres are nucleotide sequences at the ends of chromosomes. Loss of telomere structure accelerates degenerative aging processes.1,3,4

Senescent cells also inflict damage to our body's pool of stem cells, limiting normal tissue's capacity for repair and replacement.5

Once researchers clearly identified senescent cells as an underlying cause of age-associated diseases, they wanted to answer an urgent question: Can these cells be removed from the body, and will doing so improve health and slow aging?

Thanks to senolytics, the answer is "yes."

Senolytics: A Major Anti-Aging Advance

The term "seno" refers to senescence cells.

The term "lytic" refers to their destruction.

The new class of compounds called senolytics selectively destroys senescent cells in tissues.

Because they remove a root cause of aging, senolytics are expected to fight age-associated diseases and help people live longer. For the first time, scientists can target and remove old, damaged cells to make way for younger, thriving cells.

Researchers at the Mayo Clinic are at the forefront in uncovering the exciting potential of using senolytics to target senescent cells.

Targeting Senescent Cells

In the first of two Mayo Clinic studies, researchers made a series of startling discoveries about the impact of senescent cells on normal, healthy tissue.1,3

They found that transplanting just a small number of senescent cells into young mice triggered the accelerated aging processes.

Young mice implanted with just a few senescent cells quickly developed physical ailments typically seen in older animals, such as slower walking, reduced endurance, and weaker grip strength. The greater the number of senescent cells, the greater the deterioration.1

More alarming, the presence of just a few senescent cells produced a snowball effect, triggering senescence in a larger number of previously healthy cells. Senescent cells acted with an almost brutal efficiency to speed aging—and lead to the problems that come with it.

As bad as these aging cells are by themselves, a high-fat diet appears to amplify their negative impact. When the mice were fed such a diet for the month prior to transplant, it took even fewer senescent cells to produce age-related ailments. This finding is unsurprising since both a high-fat diet and obesity are known to induce cellular senescence in animal models.

The most dramatic finding of all: the discovery that the mice with the senescent cells had a 5-fold higher risk of death compared to control mice.1

The Senolytic Effect

Mayo Clinic researchers weren't only interested in the negative impact senescent cells have on healthy tissue. They also wanted a solution to the problem.

For the trial, they chose two well-known compounds with excellent potential to serve as senolytic compounds to remove these aged cells and decrease their negative impact on the body.

The compounds came from an unlikely partnership: a natural substance known as quercetin—a flavonoid found in abundance in apples, onions, and other plants—and an anti-cancer drug called dasatinib.

This combination had a remarkable senolytic effect by: 1

  • Reducing the number of senescent cells, and
  • Decreasing their secretion of proinflammatory signaling factors.

When the mice were given the quercetin/dasatinib combination immediately following senescent cell transplant, their tissues showed significantly fewer senescent cells.1 This indicates that the senolytic combination "swept away" these dangerous, age-accelerating cells.

Even when the supplement wasn't started until five weeks after senescent cell transplants—long after the negative impact of senescence was evident—the effects were comparable to those of immediate use.1

This is of vital importance to aging adults because it means that senolytic treatment doesn't need to be started at a young age to produce beneficial effects.

Overall, removing the senescent cells with senolytics had three key benefits:1

  • It reduced the severity of age-related physical deterioration. When elderly mice were given the senolytic combination for four months, it increased their walking speed, improved their endurance, and boosted grip strength. It also improved daily activity levels in these older animals.
  • It improved late-life survival. Giving the senolytics to elderly mice increased their median post-treatment lifespan by 36% and reduced their risk of dying by a stunning 65%, compared with control animals. The researchers flagged this result as "remarkable" for its implication that senolytics can reduce the risk of dying in old age.
  • It increased healthspan. This means that in addition to living longer, the animals lived healthier.

Taken together, these findings show that senolytics can improve survival and reduce overall disability.1

What You Need to Know
Woman in Kayak

Senolytics Extend Lifespan

  • Senescent cells are one of the root causes of aging and disease.
  • Senolytic compounds can selectively remove senescent cells by reactivating cells' normal ability to die off gracefully.
  • Senolytic compounds have extended the median post-treatment lifespans of mice by as much as 36% while also reducing their risk of dying by 65%.
  • Life Extension scientists have developed a combination of quercetin and theaflavins, two naturally derived, plant-based senolytics. Theaflavins have similar senolytic mechanisms as dasatinib.
  • By targeting a root cause of aging itself, senolytics have the potential to reverse aging and reduce the diseases of aging.

Senolytics and Dementia

The second Mayo Clinic study focused on one of the most-feared consequences of aging: dementia.3

The researchers used a strain of mice bred to produce tau, a protein that is believed to cause brain cell death in older adults. Tau protein buildup is a structural hallmark of Alzheimer's disease.

The rodents bred from this strain also have high levels of neurofibrillary tangles, neurodegeneration, and loss of cognitive function by early middle-age.3

The researchers found that the presence of senescent cells in the brain tissue increases neurodegeneration.

Brain tissue with large numbers of senescent cells had high levels of tau and neurofibrillary tangles. In addition, the overall brain size was smaller, and there was marked brain cell degeneration in the memory center of the brain (called the hippocampus).

Amazingly, the researchers discovered that a senolytic agent can sweep these senescent cells out of brain regions, including the hippocampus. Doing so reduced the deposits of neurofibrillary tangles and lessened tau aggregation.

Most importantly, removing the senescent cells lessened the short-term memory loss and prevented the neurodegeneration seen in untreated animals.3

Widespread Acclaim Greets News of Senolytic Successes

Studies demonstrating the effectiveness of senolytic compounds in animal models have met with unprecedented favorable press in the world's most prestigious journals, even from some of the most notorious skeptics of life extension:

"In animal models, both health and longevity have been extended by multiple genetic and dietary interventions…six candidate drugs have already been shown to extend life in at least one mouse sex."25
Journal of the American Medical Association

"Targeting senescent cells may arrest or reverse Alzheimer's and related neurodegenerative diseases."5
Journal of the American Medical Association

"Clearing even a small percentage of these cells improves healthspan and delays age-associated diseases."26
Aging Cell

"The time has come to recognize the achievement of life extension. Efforts should be focused on achieving the goals of extending and improving the healthspan."27
Journal of the American Medical Association

Systemic Reversal of Aging Pathologies

Doctor holding Xray

What generated a firestorm of interest in senolytics was a landmark study emanating from the Mayo Clinic in 2015. 6

Researchers observed that combining the plant compound quercetin with the drug dasatinib targeted and eliminated senescent cells. The result of this study was systemic restoration of youthful function and improved survival in old mice given the senolytic combination.6

Fascinated by these findings, Life Extension® scientists have studied the mechanisms of dasatinib and identified intriguing natural compounds (theaflavins) that function in a similar senolytic fashion.

Their search also led them to a highly absorbable form of quercetin.

Supercharged Quercetin

Aged cells are programmed to self-terminate through a natural process called apoptosis.

When cells suppress normal self-destruct mechanisms, they can turn into metabolically active senescent cells that inflict systemic damage. 6

Quercetin helps induce apoptosis in senescent cells, triggering their ability to die off.4

Both human and basic lab studies have shown that quercetin reduces chemical markers of aging. And animal studies reveal that quercetin therapy can extend lifespan.4,7-13

More recently, as shown in the Mayo Clinic studies discussed here, quercetin has been shown to have specific senolytic properties that enable it to sweep away senescent cells.1,4,6,14-17

The problem is that quercetin is not well-absorbed in its natural state. 18

By formulating the compound with a food-grade, plant-based carrier (a phytosome) quercetin's absorption from the bloodstream is sharply enhanced.19,20

Life Extension scientists selected quercetin phytosome for its improved bio-availability and its senolytic properties.

Black Tea Theaflavins

Black Tea

In the Mayo Clinic study, the chemotherapy agent dasatinib was shown to complement quercetin's senolytic activities.1,6 While the results of this combination are impressive, most people choose to use compounds without the side effect profile of dasatinib, even though the human equivalent dose of dasatinib for senolytic purposes is far lower than what leukemia patients take.

Life Extension scientists scoured hundreds of plant-based compounds to find those with mechanisms and effects similar to those of dasatinib, to pair with quercetin as an alternative to this anti-cancer drug.

Their search for a dasatinib alternative led to a group of natural polyphenols called theaflavins found in black tea.

Theaflavins have been shown to extend lifespan in animal studies and were recently confirmed to have specific senolytic properties.21-24

But unlike dasatinib, neither quercetin nor theaflavins have any known toxicity or harsh side effects.

That means that this dual plant-based combination can be used to target senescent cells.

Summary

Man and woman Kayaking

Senescent cells cause age-related dysfunction in every tissue. They are a fundamental cause of degenerative aging.

Senolytics selectively remove senescent cells.

Senolytic compounds have been shown to increase the median post-treatment lifespan in older animals up to 36% while reducing their risk of dying in that period by 65%.

These compounds also increased the animals' ability to sustain healthy aging.

Plant-based senolytics such as quercetin and black tea theaflavins have an impressive safety record to back them up.

Senolytics have the potential to reverse aging and reduce the diseases of aging by targeting one of the root causes of aging itself.

Look forward to updates about rapidly emerging regenerative medicine technologies.

We believe an important first step, however, may be the removal of senescent cells that block the restorative potential of other steps we take to regain youthful vitality.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

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References

  1. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018 Aug;24(8):1246-56.
  2. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40.
  3. Bussian TJ, Aziz A, Meyer CF, et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018 Oct;562(7728):578-82.
  4. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017 Jul;21:21-8.
  5. Tchkonia T, Kirkland JL. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. JAMA. 2018 Oct 2;320(13):1319-20.
  6. 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.
  7. Abharzanjani F, Afshar M, Hemmati M, et al. Short-term High Dose of Quercetin and Resveratrol Alters Aging Markers in Human Kidney Cells. Int J Prev Med. 2017;8:64.
  8. Chekalina NI, Shut SV, Trybrat TA, et al. Effect of quercetin on parameters of central hemodynamics and myocardial ischemia in patients with stable coronary heart disease. Wiad Lek. 2017;70(4):707-11.
  9. Chondrogianni N, Kapeta S, Chinou I, et al. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol. 2010 Oct;45(10):763-71.
  10. Duenas M, Surco-Laos F, Gonzalez-Manzano S, et al. Deglycosylation is a key step in biotransformation and lifespan effects of quercetin-3-O-glucoside in Caenorhabditis elegans. Pharmacol Res. 2013 Oct;76:41-8.
  11. Javadi F, Ahmadzadeh A, Eghtesadi S, et al. The Effect of Quercetin on Inflammatory Factors and Clinical Symptoms in Women with Rheumatoid Arthritis: A Double-Blind, Randomized Controlled Trial. J Am Coll Nutr. 2017 Jan;36(1):9-15.
  12. Pietsch K, Saul N, Menzel R, et al. Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43. Biogerontology. 2009 Oct;10(5):565-78.
  13. Surco-Laos F, Cabello J, Gomez-Orte E, et al. Effects of O-methylated metabolites of quercetin on oxidative stress, thermotolerance, lifespan and bioavailability on Caenorhabditis elegans. Food Funct. 2011 Aug;2(8):445-56.
  14. Ogrodnik M, Miwa S, Tchkonia T, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017 Jun 13;8:15691.
  15. Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532.
  16. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7.
  17. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016 Jun;15(3):428-35.
  18. Rich GT, Buchweitz M, Winterbone MS, et al. Towards an Understanding of the Low Bioavailability of Quercetin: A Study of Its Interaction with Intestinal Lipids. Nutrients. 2017 Feb 5;9(2).
  19. Abd El-Fattah AI, Fathy MM, Ali ZY, et al. Enhanced therapeutic benefit of quercetin-loaded phytosome nanoparticles in ovariectomized rats. Chem Biol Interact. 2017 Jun 1;271:30-8.
  20. Riva A, Ronchi M, Petrangolini G, et al. Improved Oral Absorption of Quercetin from Quercetin Phytosome(R), a New Delivery System Based on Food Grade Lecithin. Eur J Drug Metab Pharmacokinet. 2018 Oct 16.
  21. Cameron AR, Anton S, Melville L, et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell. 2008 Jan;7(1):69-77.
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  24. Peng C, Chan HY, Li YM, et al. Black tea theaflavins extend the lifespan of fruit flies. Exp Gerontol. 2009 Dec;44(12):773-83.
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