Life Extension Magazine®

Issue: Winter Edition 2019

Combat Aging by Reducing the Senescent Cell Burden

New studies confirm how senescent cells accelerate old-age decline. Prestigious journals reveal marked regenerative improvements when senolytics are used to reduce the senescent cell burden.

By Sean Field

Published research conducted at the Mayo Clinic and other prestigious institutions is revolutionizing medicine.

The impact of these findings is the potential to delay and reverse the adverse effects of aging.

A major factor in old-age decline is the accumulation of senescent cells that:

  • Impede Organ Function
  • Create Chronic Inflammation
  • Emit Protein-Destroying Enzymes
  • Shorten Healthy Lifespan

Compounds that circumvent this aging mechanism are called senolytics.

“Seno” refers to old cells that secrete toxic chemicals.

“Lytic” refers to their destruction.

Senolytic compounds selectively destroy these old (senescent) cells.

Several landmark studies on senolytic therapy have recently been published.

They demonstrate that senolytics not only contribute to healthy longevity, but also show promise as treatment for heart failure, Alzheimer’s and lung disease.1-3

These studies, many published in 2019, corroborate the potential of senolytics to revitalize aging bodies by removing senescent cells.

This article provides updates to research we reported on last year. It also describes methods by which you can start purging your body of worn out, yet highly metabolic and very toxic senescent cells.

Senolytics Eliminate Senescent Cells

Strand of DNA

Scientists set out to find a way to get rid of the problematic senescent cells, while preserving healthy, functional cells.

They found the solution in senolytics.11 These compounds have the ability to selectively trigger cell death in abnormal, senescent cells.

A number of these substances have already been discovered, including naturally occurring compounds and synthetic drugs.

The most widely studied senolytic regimen originated at the Mayo Clinic. It consists of two senolytic compounds in combination, quercetin and dasatinib.

Quercetin is a natural compound found in many fruits and vegetables, while dasatinib is a drug used to treat leukemia. Together, they deliver a senolytic punch that has been shown to kill senescent cells and reverse age-related changes in cell culture and animal models.12

The dose schedule of dasatinib used in these studies is usually a fraction of what leukemia patients take.

The Problem of Cellular Senescence

The body normally gets rid of damaged, abnormal cells as part of its daily functioning. These damaged cells are programmed to die off, through a process called apoptosis, preventing the buildup of dysfunctional cells in tissues.

As we get older, that process changes. Elderly cells cease functioning properly, fail to accomplish their normal tasks, and lose their ability to divide. But instead of dying off, these cells linger and accumulate in various tissues.

This is known as cellular senescence. Scientists have discovered that these dysfunctional, older cells are a major contributor to many of the ailments that come with advancing age.

In fact, cellular senescence is believed to be one of the major causes of aging, loss of function with age, and risk for many age-related diseases, including diabetes, obesity, cardiovascular disorders, vision loss, dementia, arthritis, and cancer.4-8

Senescent cells create these problems in two major ways.

First, because they do not function normally, they prevent surrounding cells and tissues from functioning at peak capacity.

Second, they spread this dysfunction to surrounding healthy cells and throughout the whole body by secreting harmful compounds that, as a group, are known as the senescence-associated secretory phenotype.9,10

These compounds encourage other cells to enter the same senescent state, so this destructive process continues.

They also activate chronic inflammation, which has long been recognized as a major cause of premature aging and age-related diseases.

The First Human Senolytics Study

Testing the impact of senolytic therapy on human longevity is difficult, given the long timeframe needed to observe a significant change. But a proof-of-concept trial, to test whether senolytics have practical, clinical potential, has already been completed and its findings were published this year.2

Researchers at the Mayo Clinic and partner hospitals conducted a trial of quercetin and dasatinib senolytic therapy in patients with a lung disease known as idiopathic pulmonary fibrosis.

This condition leads to progressive changes in the lung tissue that make it difficult for the lungs to take in enough oxygen. That, in turn, causes breathing problems and deterioration in physical functioning until the patient dies. Although the underlying cause of the disease is not well understood, cellular senescence has been identified as a major contributing factor.

After baseline testing, subjects were placed on a senolytic regimen that included 1,250 mg/day of quercetin and 100 mg/day of dasatinib, given for three consecutive days each week for three weeks.

Despite the short duration of the trial, researchers observed some improvements in patients’ physical functioning after the senolytic treatment.

Timed six-minute walking distance improved by 5%, four-meter gait speed increased by 9%, and timed chair-stands were completed 15% faster.

Although this trial was relatively small, it is a major step in senolytic research. It demonstrates that senolytic therapy is feasible in humans and may have an impact on physical health related to chronic disease.

What you need to know

Senolytic Therapy

  • As the body ages, some cells become senescent, losing the ability to divide, while at the same time becoming dysfunctional and contributing to dangerous, chronic inflammation.
  • Cellular senescence is a major contributor to the aging of bodily tissues and the rapid deterioration of function.
  • Senolytics are compounds that interfere with cellular senescence pathways, helping to eliminate these abnormal cells.
  • Exciting, new studies published this year have shown that senolytics can have beneficial effects in both animal and human models.
  • Two plant-based compounds, quercetin and theaflavins, provide senolytic mechanisms without relying on pharmaceuticals.

Senolytics and Age-Related Heart Disease

Scientist looking at pietri dish

Another study published this year set out to explore the impact of cellular senescence on the heart and whether senolytic interventions could alleviate age-related heart damage.1

First, researchers found that senescent cell accumulation impacts the aging heart.

Senescence is involved in hypertrophy (enlargement) of heart muscle cells, and fibrosis (fibrous stiffening) of heart muscle tissue. These disturbances contribute to declining heart function and play a role in many cases of heart failure.

Next, the researchers tested whether senolytics could reduce this damage to the heart.

Using a senolytic compound called navitoclax (a synthetic anti-cancer drug) in a mouse model of heart disease, scientists were able to demonstrate two important findings:

1) Senolytic therapy reduced the number of senescent heart muscle cells, on average, by approximately 80%.

2) This reduction in senescence significantly reduced the hypertrophy and fibrosis present in the hearts of aged mice. A marker of hypertrophy was reduced by about 25%, while the area of fibrosis was reduced by more than 40%.

Combined with previous research showing that cellular senescence is a major contributor to blood vessel disease and to atherosclerotic plaque development, these findings have tremendous implications for cardiovascular disease, the most common cause of death worldwide.13,14

Anti-Cancer Mechanisms of Theaflavins

Theaflavins share many of the mechanistic senolytic effects of dasatinib (such as inhibiting a regulatory protein called BCL-2).

BCL-2 stands for “B-cell lymphoma-2.” An undesirable function of BCL-2 is that it prevents lymphoma cells from undergoing apoptosis.

Encouraging abnormal cells to undergo apoptosis (programmed cell death) is a function sought by those seeking to prevent or treat cancers, as well as induce senescent cells to self-destruct.

So, compounds that inhibit BCL-2, be they dasatinib or theaflavins, appear to be something helpful to have in your body.

In the May 17, 2019, issue of the journal Science, a major article was published revealing more deleterious effects of senescent cells, including inhibiting stem cell function.

This Science article went on to show senescent cell secretions can contribute to cancer development. Here is a quote about how senescent cell secretions promote cancer:

“[They] can stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting development of late-life cancers.”

The Science article suggested senolytic compounds may have further anti-cancer properties by concluding:

“Indeed, elimination of senescent cells with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.”

These studies indicate that mechanisms by which theaflavins or dasatinib remove senescent cells may also have anti-cancer effects. 


Senolytics as Treatment for Alzheimer’s

Studies of cellular senescence have also led to revelations in the search for effective treatments for Alzheimer’s disease, the most common cause of dementia, characterized by progressive cognitive decline.

With Alzheimer’s disease, abnormal accumulations of proteins, particularly beta-amyloid and tau, build up in the brain, impairing the function of surrounding nerve cells.

To date, conventional treatments attempting to reduce the burden of amyloid plaques in the brain have failed to produce clinical improvements in the cognitive symptoms of the disease.

However, researchers at the National Institutes of Health recently discovered that important helper cells in the brain exhibit signs of senescence when exposed to amyloid plaques.3 They hypothesized that this senescence plays an important role in the progression of Alzheimer’s disease and set out to test that theory.

Utilizing a mouse model of Alzheimer’s, these scientists used a senolytic treatment (dasatinib and quercetin) to rid the brain of these senescent cells. The results they found were remarkable. In the treated areas, inflammation was reduced, the amount of amyloid decreased, and most importantly, cognitive deficits in these mice were significantly improved.

This novel research opens the door to exploring senolytic therapy in humans to reverse the cognitive decline plaguing many older adults.

Plant-Based Senolytics

Imaging of cellular

As promising as these studies are, both rely on synthetic pharmaceutical drugs, navitoclax and dasatinib, whose side-effect profiles cause many people today to not want to take them yet.

But scientists have found another way to remove senescent cells using plant-based compounds found in commonly consumed food and beverages.

Quercetin, one of the senolytic compounds discussed previously in this magazine,15 is a plant pigment found in small amounts in many fruits and vegetables, including onions, apples and berries. Theaflavins, natural compounds found in black tea, have also demonstrated senolytic effects in an animal study.16

In fact, theaflavins act by mechanisms that mimic those of both navitoclax and dasatinib. Like navitoclax, theaflavins inhibit the Bcl-2 family of proteins, helping to push senescent cells into programmed cell death.17 They also decrease the activity of tyrosine kinase receptors, one of the mechanisms dasatinib uses to help stop the spread of cancer cells.18

Theaflavins also modulate cellular pathways that are implicated in cellular senescence.16

By combining quercetin and theaflavins, scientists created a plant-based compound, available without a prescription, that provides senolytic action without resorting to pharmaceutical drugs.

Cellular Senescence and Abnormal Blood Clotting

One of the ways senescent cells contribute to chronic disease is by spewing out hundreds of toxic proteins that degrade healthy tissues.

In addition to this effect, a newly published study has discovered that many of these secreted proteins also play roles in the control of blood clotting.19 The study showed that these secretions promote clotting, potentially contributing to dangerous clots that block normal blood vessels and can lead to deep venous thrombosis, heart attack, stroke, and other clotting-related conditions.

Many factors can increase one’s risk for abnormal clotting, including older age, cancer, sedentary lifestyle, and others. This clotting effect of senescent cells has important implications for individuals who are at high risk of clotting.

For example, the same study found that a common chemotherapy drug used to treat some forms of cancer, called doxorubicin, increases risk of clotting-related complications. However, removing senescent cells helped prevent this side-effect of doxorubicin.

These findings suggest that senolytic therapies may be potentially lifesaving in clinical situations where dangerous clotting is likely to occur.

Summary

The field of senolytics is evolving rapidly. New research demonstrates the ability of these compounds to eliminate senescent cells that accelerate the aging process and contribute to degenerative disorders and dysfunction.

As we age, senescent cells accumulate in tissues, causing harmful, chronic inflammation.

Senolytic compounds hold great promise for clearing the body of these aged, toxic cells.

A new animal study of senolytics has demonstrated their ability to clear the aging heart of senescent cells and reduce disease-related heart enlargement and fibrosis.

A first-ever human study of senolytics was also recently published and showed that they can lead to functional improvements in pulmonary fibrosis patients.

As this field continues to show promise, scientists have combined two natural, plant-based senolytics, quercetin and theaflavins, into one supplement aimed at targeting and reducing the senescent cell burden.

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

References

  1. Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5).
  2. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-63.
  3. Zhang P, Kishimoto Y, Grammatikakis I, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019 May;22(5):719-28.
  4. 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.
  5. Kirkland JL. Inflammation and cellular senescence: potential contribution to chronic diseases and disabilities with aging. Public Policy and Aging Report. 2013;23:12-5.
  6. Kirkland JL, Tchkonia T. Clinical strategies and animal models for developing senolytic agents. Exp Gerontol. 2015 Aug;68:19-25.
  7. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013 Mar;123(3):966-72.
  8. Zhu Y, Armstrong JL, Tchkonia T, et al. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):324-8.
  9. Borodkina AV, Deryabin PI, Giukova AA, et al. “Social Life” of Senescent Cells: What Is SASP and Why Study It? Acta Naturae. 2018 Jan-Mar;10(1):4-14.
  10. Coppe JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
  11. Soto-Gamez A, Demaria M. Therapeutic interventions for aging: the case of cellular senescence. Drug Discov Today. 2017 May;22(5):786-95.
  12. 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.
  13. Childs BG, Baker DJ, Wijshake T, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016 Oct 28;354(6311):472-7.
  14. Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002 Apr 2;105(13):1541-4.
  15. Available at: https://www.lifeextension.com/Magazine/2018/SS/Major-Advance-in-Healthy-Longevity/Page-01. Accessed June 11, 2019.
  16. Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017 Dec;113:59-70.
  17. Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21.
  18. Mizuno H, Cho YY, Zhu F, et al. Theaflavin-3, 3’-digallate induces epidermal growth factor receptor downregulation. Mol Carcinog. 2006 Mar;45(3):204-12.
  19. Wiley CD, Liu S, Limbad C, et al. SILAC analysis reveals increased secretion of hemostasis-related factors by senescent cells. Cell Reports. 2019;28(13):3329-3337.

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