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Senolytics Offer New Hope

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Senolytics Offer New Hope
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Heart failure occurs when the heart is unable to pump enough blood to fully oxygenate the body. As it progresses, heart failure patients may lose the ability to walk, speak, or carry out basic activities without pausing for breath or stopping to rest.

In advanced stages, vital organs stop functioning. Unless the clinical course of chronic heart failure is reversed, death ensues. Heart failure is associated with a cumulative burden of senescent cells that don’t function normally. Instead, senescent cells emit pro-inflammatory and protein-degrading factors that damage healthy heart cells.

In a compelling study, researchers found that the senolytic cocktail of dasatinib + quercetin cleared senescent cells effectively in lab cultures of human senescent heart tissue and promoted survival of crucial cardiac progenitor cells.2

Senolytics are a promising therapy that may allow the heart to heal itself.

Senescent Cells Damage the Heart

Old, dysfunctional senescent cells contribute to heart failure and prevent damaged heart tissue from healing.2,3 Among people older than 70 with cardiovascular disease, more than half of cardiac progenitor cells—cells capable of producing fresh, new heart muscle tissue—are senescent.2 In recent years, anti-aging research has increasingly focused on compounds called senolytics that remove senescent cells while leaving healthy cells to flourish.

Senolytics Slow Aging and Fight Disease

Many age-related diseases are associated with an accruing senescent cell burden.4-6 These aged, damaged cells accumulate in our tissues, refusing to die off. They instead secrete inflammatory molecules that damage surrounding healthy cells.

Within the last few years, scientists have discovered that compounds called senolytics have the power to selectively trigger senescent cells to self-destruct, while leaving most normal cells unharmed. Using senolytics to eliminate those “zombie” cells improves health and extends life in animals.7

Decreasing the senescent cell burden has been shown to:

  • Reduce glucose levels, raise insulin sensitivity, lower inflammation, and improve kidney and heart function in obese mice,8
  • Restore memory loss in a mouse model of Alzheimer’s disease and decrease the toxic proteins that make up the amyloid plaques found in the brains of Alzheimer’s patients,9
  • Increase lifespan, promote youthful body type, and reduce age-related diseases in mice, and10
  • Reverse age-related damage to heart muscle, including stiffening and over-growth of tissue, in aged mice.11

Senolytics were initially studied in animals or lab cultures.Recent human studies on the experimental senolytic cocktail—dasatinib and quercetin—have shown some early promise as an effective clinical therapy.

The First Human Study

Dasatinib is a prescription drug developed to treat certain forms of leukemia.12 It is on the latest report of the World Health Organization’s Model List of Essential Medicines.13

Quercetin is a bioflavonoid found in apples, honey, berries, onions, red grapes, cherries, citrus fruits, green leafy vegetables, tea, and other food sources.14 The combination of these two compounds has been used as senolytic therapy to eliminate senescent cells in multiple animal and lab studies.15 Scientists at the Mayo Clinic expanded this research into patients with idiopathic pulmonary fibrosis. This progressive lung disease, once diagnosed, carries a median survival of 3.8 years in adults aged 65 and over.16 Cellular senescence has been identified as a major contributing factor to this disease.

In a three-week study, 100 mg/day dasatinib and 1,250 mg/day quercetin, taken three consecutive days per week for three weeks, improved:15

  • Distance walked in six minutes,
  • Speed of gait in a four-meter walk, and
  • Time to complete five consecutive stand-up/sit-down cycles on a chair.

None of the subjects experienced adverse effects requiring discontinuation of treatment.15 Though it was a preliminary study, it showed that the dasatinib-quercetin cocktail may have a positive impact on health.

Dasatinib and Quercetin in Heart Failure

Intriguing evidence that senescent cells are involved in cardiovascular disease has led scientists to look for ways to use senolytics to clear out those cells from heart muscle and restore youthful heart function. In a compelling study, researchers from Kings College London and the Mayo Clinic tested the dasatinib-quercetin combination in lab cultures of human senescent heart tissue.2 The combination not only cleared senescent cells effectively, but also promoted survival of crucial cardiac progenitor cells, those that produce fresh, new heart muscle tissue.2

Summary

At this point, the dasatinib-quercetin combination is still experimental. Anyone who uses it should report results to Life Extension® so we can include them in future issues. Those concerned about taking a chemotherapy drug like dasatinib, even on the limited basis used in experimental research, have been using a black tea extract called theaflavins combined with high-dose quercetin on a once-weekly basis.Theaflavins function via some similar mechanisms as does dasatinib.17,18 Even more exciting, anticipated later this year is the introduction of bioavailable fisetin, a plant extract that some scientists believe may be the most effective senolytic compound.19 •

References

  1. Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020 Mar 3;141(9):e139-e596..
  2. Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019 Jun;18(3):e12931.
  3. Shimizu I, Minamino T. Cellular senescence in cardiac diseases. J Cardiol. 2019 Oct;74(4):313-9.
  4. Childs BG, Durik M, Baker DJ, et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015 Dec;21(12):1424-35.
  5. He S, Sharpless NE. Senescence in Health and Disease. Cell. 2017 Jun 1;169(6): 1000-11.
  6. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013 11/08;75:685-705.
  7. 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.
  8. Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun;18(3):e12950.
  9. 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.
  10. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-9.
  11. Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5).
  12. Available at: https://www.drugs.com/monograph/dasatinib.html. Accessed 6 December, 2019.
  13. World Health Organization (WHO). WHO Model List of Essential Medications. 2019.
  14. Available at: https://www.sciencedirect.com/topics/neuroscience/.... Accessed July 24, 2020.
  15. 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.
  16. Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014 Jul;2(7):566-72.
  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. Available at: https://www.worldhealth.net/news/fisetin-may-be-ef.... Accessed July 27, 2020.
Posted in: Heart health