Targeting Senescent Cells to Reverse the Aging of the Heart

Almost a decade has passed since the first compelling demonstration that clearance of senescent cells in mice could produce rejuvenation. This validated decades of prior evidence, largely ignored in the research community, indicating that accumulation of senescent cells is a significant cause of degenerative aging. It was a wake-up call. Since then, numerous research groups have shown that targeted clearance of senescent cells reverses many age-related conditions and extends healthy life span in mice. It is easy to accomplish in the lab. Near any approach works, to the degree that it can destroy senescent cells without harming normal cells. As a consequence, a new biotech industry has come into being, a range of startups and programs working on clinical development of the first generation of senolytic drugs capable of safely removing senescent cells from aged tissues.

As a result of this field of research, it has been shown that accumulation of senescent cells is an important part of the development of cardiovascular disease. Senescent foam cells accelerate the progression of atherosclerosis, driving the growth of fatty lesions that narrow and weaken blood vessels, leading to stroke and heart attack. Senescent cells drive the calcification of blood vessels, and degrade the function of smooth muscle tissue in blood vessel walls. Senescent cells are a part of the dysfunction that leads to cardiac hypertrophy, the enlargement and weakening of heart muscle that causes heart failure, as well as fibrosis, a disruption of tissue structure by inappropriate collagen deposits. We now know all of this because it is possible to run animal studies in which senolytic treatments remove senescent cells, and then observe the result - a reversal of age-related cardiovascular disease.

Therapeutic Potential of Senolytics in Cardiovascular Disease

The most significant determining factor of cardiovascular health is a person's age, with cardiovascular disease (CVD) being the leading cause of death in 40% of individuals over 65 years. The ageing heart undergoes a process of myocardial remodelling, which is characterised by physiological and molecular alterations that result in endothelial stenosis, vasomotor dysfunction and stiffening, cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation which result in increased ventricular stiffness, impaired cardiac function and can ultimately lead to HF. In particular, HF with preserved ejection fraction (HFpEF), characterised by diastolic ventricular dysfunction with maintained systolic function, is clinically associated with ageing.

The association between senescence and myocardial ageing in humans has been reported for nearly 20 years. More recently it has been demonstrated that senescence contributes directly to age-related myocardial remodelling in mice, as pharmacogenetic elimination of senescent cells, using the p16-INKATTAC model, reduced myocardial fibrosis, and attenuated cardiomyocyte hypertrophy. Elimination of senescent cells from aged p16-INKATTAC mice also increased their survival and reduced the development of cardiac dysfunction following isoproterenol-induced myocardial stress. Following on from this data, we and others have hypothesised that an accumulation of senescence and the expression of a senescence-associated secretory phenotype (SASP) drive age-related myocardial remodelling and have begun to independently investigate if senolytics can eliminate senescent cell populations resident in the aged heart in order to improve myocardial function.

Pharmacological elimination of senescent cells from aged mice could improve myocardial function. Treatment of 24-month-old mice with a single dose of dasatinib and quercetin significantly improved left ventricular (LV) ejection fraction and fractional shortening. This observed change in function was suggested to be a result of a restoration in vascular endothelial function. We have shown in aged mice that senescence occurred primarily within the cardiomyocyte population and led to the expression of a cardiomyocyte-specific SASP with the potential to promote myofibroblast differentiation of fibroblasts and induce cardiomyocytes to hypertrophy in vitro. In vivo, cyclical oral administration of navitoclax reduced the number of senescent cardiomyocytes, attenuated components of the cardiomyocyte SASP and reduced myocardial remodelling as indicated by a reduction in both cardiomyocyte hypertrophy and interstitial fibrosis.

Given the limited regenerative capacity of the heart, there is considerable interest in the potential of regenerative cellular therapies for the treatment of CVD such as myocardial infarction (MI) and age-related HF. For cellular therapies to be effective, the grafted cells must survive, integrate, and function within the surviving myocardium. The data discussed above suggest that older age not only increases the potential for dysfunction in the very populations that are being used for cellular therapies but also increases the hostility of the recipient myocardial environment as a result of SASP mediated inflammation and the bystander effect. This may in part explain the failure of pre-clinical trials to translate clinically into regenerative therapies. Preclinical studies showing successful cell regenerative therapies use young healthy animals, whereas the prevalence of CVD increases linearly with age, and therefore, most patients undergoing cellular therapy are likely to display high levels of myocardial senescence which could create an unfavourable environment impeding incorporation and differentiation of the transplanted cell populations. Senolytic-mediated elimination of senescent cells from aged patients may, therefore, have the potential to improve the outcomes of such regenerative cellular therapies.


We've heard a lot about senolytics for a couple of years now. Is there any clarity yet forming on the best was to remove them? Fisetin, Z pack,chemo drug? I just feel like we don't know any more than we did last year at this time. Any updates from a year ago when we were all doing the Mayo Fisetin protocol and/or Q/D appreciated.

Posted by: august33 at October 6th, 2020 8:40 PM


It is ironic that we don't hear about new molecules with Senolytic properties. There's OISIN with their delivery platform (staying to quiet for the last couple of years)
A prodrug based on dasatinib with activation by beta galactoseass... cannot spell from the top of my head ... Why there are no new compounds?

There's a surprisingly low number of human studies to test d+q and probably fisetin.

What we are mssing are meta studies to statistically analyze the use of dasatinib and the expected effects.

Posted by: Cuberat at October 6th, 2020 9:48 PM

Thsnks for the comments Cuberat and August 33.

I was hoping we'd have sufficient information to self medicate within 5 years if there is not a formal treatment on the market by then. Some of us can't wait too long:( I wanted to start this year but disappointed there is not enough information yet.


Posted by: Robert at October 7th, 2020 2:49 AM the list almost doubled just within the year. There are also combinations not listed there like usage of F+D (Q+D but quercetin exchanged with fisetin). I managed to get tendon pains under control (sort of) with increasing doses of magnesium and adding calcium to suplementation and removing resveratrol and limiting sulforafane, and finally get rid of after I added fish collagen, so I resumed fisetin.

Posted by: SilverSeeker at October 7th, 2020 6:42 AM


The newer articles are about different delivery strategies (prodrug) or non-simple molecules

Posted by: Cuberat at October 7th, 2020 7:32 AM

Btw, I personally have added a couple of points to that wikipedia page; a small edit but large enough impact for our community.

Nevertheless, for the moment, we have just a handful of small molecule Senolytics available. Did the search stop ? It took only a few months to identify the first candidates and it has been several years since. I would expect by now to have dozens of small molecule candidates, even if inferior to the first line...

In the other hand the whole concept of SASP and senecent cells needs to percolate to the research and medical circles. I am hoping, without any proof, though, that the wheels of research are grinding slowly but surely and there are many studies currently ongoing outside of the spotlight and soon will emerge, and a couple of them will have good medical applications...

Posted by: Cuberat at October 7th, 2020 9:29 AM

This issue here is that many senolytics are to some extent cardio-toxic and prolong QT intervals

Not great for cardiac health (or staying alive for that matter)

So this is an area that needs to be proceeded with cautiously

Posted by: James Burnbrae at October 7th, 2020 9:55 AM


There's still not enough information for self medication. And self medication by definition is a risky undertaking, unless you have a medical degree, or even then.

Quercetin and fisetin seem to be harmless enough, unlike dasatinib and rapamycin, wich are more effective and as result are considered dangerous

Posted by: Cuberat at October 7th, 2020 10:13 AM


Where do you get sulfurafane ? Broccoli sprout ? Prostafane ? Broccomax ? Somewhere else ?

Posted by: Marco S at October 7th, 2020 11:07 AM

@Marco sulforafane? one usa based common supplement brand. I use it for psoriasis combined with arjuna, in higher doses (one bottle for 10-12 does, ie much less then a week ;/) it's as effective as other biological drags (>90% remission) but it handicaps immune system as hell too. So it's dead end, itss effective but then you get ill for 6 weeks in the middle of the summer with ordinary cold :< They have it spelled in usa english try google "Sulforaphane from Broccoli Sprout Extract"

Posted by: SilverSeeker at October 8th, 2020 2:01 AM

@Cuberat fisetin was identified long before as anti pulmonary cancer cure in combination with wogonin, where in a such combination they are much more effective than separately. So there are most probably many substances then will also enhance senolytic properties of fisetin, such as dasatinib does (dr Green's protocol). As usual, funding is the problem. They do not dig fisetin with other cheap supplements to enhance it efficiency (I guess it would put it close to SSK1 in efficiency), they tweak fisetin to make another molecule that can be patented and profitted from. What we lack badly is a cheap method to measure whether senescent cells were removed in vivo and how much of them, for effective cheap in-home testing. Then such combinations would be revealed very quickly.

Posted by: SilverSeeker at October 8th, 2020 2:24 AM

I have come to the conclusion that researchers are content to just "create" super mice. Moving on to human trials is just too hard.

Posted by: Trevor Bingley at October 11th, 2020 8:07 PM
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