Long-Term Benefits of Senolytic Drugs on Vascular Health

Senolytic treatments are those that at least partially clear senescent cells, producing a narrow form of rejuvenation, enhanced longevity, and improvement in long-term health. One of the fortuitous discoveries of recent years was that a combination of the drugs dasatinib and quercetin can clear enough senescent cells in a single treatment in mice to demonstrate that doing so is beneficial. The research noted here extends that result to investigate some of the outcomes of a series of treatments over time.

It is unfortunately unlikely that the same degree of clearance will happen in humans via the use of these particular drugs, but people are certainly going to try anyway. The real value of this research lies in the ability to prove that getting rid of these cells is robustly beneficial in mammals. This will result in increased support for the clinical development of methods that will work in humans. Some of those methods already exist in prototype form and work is presently underway on these approaches at Oisin Biotechnology and Unity Biotechnology, for example.

Cells become senescent in response to stress or damage, irreversibly removing themselves from the cycle of division and replication. This most likely initially serves to reduce risk of cancer by suppressing the ability of the most vulnerable cells to become cancerous, but as the number of senescent cells rises, they have a growing detrimental effect on tissue function. Senescent cells secrete signals that produce chronic inflammation, haphazardly remodel surrounding tissue structures, and encourage bad behavior in neighboring cells. In short, senescent cells are one of the causes of aging, and therapies under development to remove them are the first practical rejuvenation biotechnologies after the SENS model.

Building on previous studies, researchers have demonstrated significant health improvements in the vascular system of mice following repeated treatments to remove senescent cells. They say this is the first study to show that regular and continual clearance of senescent cells improves age-related vascular conditions - and that the method may be a viable approach to reduce cardiovascular disease and death. "Cardiovascular disease remains the leading cause of death in our population today, and disability related to heart disease and stroke has a tremendous impact on our aging population. This is the first evidence that longer term use of senolytic drugs to clear these damaged cells from the body can have a preventative impact against vascular diseases."

Senescent cells are damaged cells that no longer function properly, but remain in the body and contribute to frailty and many of the other health conditions associated with aging. Prior studies showed chronic removal of the cells from genetically-altered mice can alter or delay many of these conditions, and short-term treatment with drugs that remove senescent cells can improve the function of the endothelial cells that line the blood vessels. This study, however, looked at the structural and functional impacts of cell clearance using a unique combination of drugs on blood vessels over time. Mice were 24 months old when the drugs - a cocktail of dasatinib and quercetin - were administered orally over a three-month period following those initial two years. A separate set of mice with high cholesterol was allowed to develop atherosclerotic plaques for 4 months and were then treated with the drug cocktail for two months.

The research showed that senescent cell clearance in either naturally-aged or atherosclerotic mice alleviated vascular dysfunction. Although it did not reduce the size of plaques in mice with high cholesterol, it did reduce calcification of existing plaques on the interior of vessel walls. "Our finding that senolytic drugs can reduce cardiovascular calcification is very exciting, since blood vessels with calcified plaques are notoriously difficult to reduce in size, and patients with heart valve calcification currently do not have any treatment options other than surgery. While more research is needed, our findings are encouraging that one day removal of senescent cells in humans may be used as a complementary therapy along with traditional management of risk factors to reduce surgery, disability, or death resulting from cardiovascular disease."

Link: http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-aging-researchers-show-long-term-benefits-of-senolytic-drugs-on-vascular-health-in-mice/

Comments

There is actual some data for Quercetin having benefits to the vascular system in humans. This 2007 study is an example of some benefits for hypertension:

http://jn.nutrition.org/content/137/11/2405.long

As you know the MMTP is due to test D&Q in aged mice though we are using an interesting testing system to explore variable dosages to generate maximum data.

I personally take Quercetin as well and I am aware of a Russian gerotrial launching in Georgia shortly to test D&Q in humans.

Posted by: Steve H at February 11th, 2016 9:20 AM

"It is unfortunately unlikely that the same degree of clearance will happen in humans via the use of these particular drugs"

I could speculate that humans have more efficient glucuronidation and sulfation pathways that would clear quercetin faster than in a mouse, and of course people aren't mice, so any number of other factors might be different as well, but do you have any particular insight regarding D+Q in humans, or is this more of an "on general principle" statement?

Humans are certainly taking D+Q already, with some anecdotal evidence that it's "working". I expect we'll see a lot more of this experimentation, among those of us who don't want to wait for the FDA.

Posted by: niner at February 11th, 2016 11:20 AM

@niner: More of a general principle. I wouldn't expect drug interactions to translate well. It still has to be tested, of course, but I think such tests will be overtaken by events.

Posted by: Reason at February 11th, 2016 11:57 AM

Reason I take Quercetin in mega doses and I have noticed some difference. I suspect you are right that such compounds will be replaced with better alternatives eg, Oisin's system.

But there are a number of interesting papers including the one I linked that show evidence of vascular improvement which considering Quercetin has an affinity for vascular cells is not really that surprising.

That said of course we need something a bit more systemic for general repair.

Posted by: Steve H at February 11th, 2016 1:05 PM

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