Clearance of Senescent Cells Reverses Cardiac Fibrosis and Hypertrophy in Mice

Cells become senescent in response to a toxic environment, or during regeneration, or when damaged in ways that may increase cancer risk, but the vast majority are created when cells reach the end of their replicative life span, the Hayflick limit. Senescence is irreversible, and a senescent cell is blocked from further replication. In all these cases, near all newly senescent cells are soon destroyed, either by their own programmed cell death mechanisms, or by the immune system. A tiny fraction lingers, however. Senescent cells are very metabolically active, secreting a potent mix of molecules that disrupts tissue structure, produces chronic inflammation, and encourages nearby cells to also become senescent. This is just fine in the short-term context in which a cell becomes senescent: it assists regeneration, or helps protect against cancer, and so forth, and then it is gone when the senescent cells are destroyed. But when a small but growing number of senescent cells remain alive, and their secretions continue, day in and day out, their presence becomes very harmful. In fact, long-lasting senescent cells are one of the causes of aging and age-related disease.

Senolytic therapies are those that can selectively destroy senescent cells without impacting normal cells to the level of producing significant unwanted side-effects. A number of chemotherapeutics appear safely senolytic when taken as a single dose or in short dosing periods. Since the therapy destroys all of the problem cells it can reach immediately, and senescent cells accumulate only very slowly, treatment can be very intermittent. The research community has demonstrated senolytic therapies to extend life in mice, and to reverse measures of many age-related diseases.

The paper here is one example of many lines of work focused on understand exactly how senescent cells are harming tissues, and the degree to which senolytic therapies can reverse this process. The authors are focused on the aging of the heart, something that senescent cells appear to contribute to significantly. There are a number of very interesting observations in this data. Firstly, the evidence strongly suggests that senescent cells in the heart are larger than their normal peers. You might recall that a research group last year produced a method of counting senescent cells in a blood sample that worked via size-grading, as senescence immune cells are larger than normal immune cells. It is interesting to see this phenomenon in another senescent cell type, and makes me ponder how to build a decent clinical assay based on cell size for other tissues. Secondly, removing senescent cells from the heart reversed cardiac hypertrophy. I think that this is a big deal. The growth and weakening of heart muscle that occurs in response to the damage of aging was one of the line items that I suspected would be hard to repair once it had happened. If this problem to even some degree fixes itself, given a more youthful tissue environment, that is very pleasing to hear.

Scientists are killing zombie cells to reverse age-related damage in the heart

Ageing is one of the main risk-factors for heart failure, as older people are more likely to develop heart disease and don't recover as well following a heart attack. New research explores how senescent cells - also known as zombie cells - form in the heart during ageing and lead to heart failure. Zombie cells occur all over the body as it ages. They get their nickname from the fact that although they are not dead they do not function correctly and can cause other cells around them to become senescent (or zombiefied!) Elsewhere in the body, zombie cells are usually caused by the shortening of structures found at the end of chromosomes called telomeres, which happens progressively each time a cell divides. But as heart cells - cardiomyocytes - rarely divide it was not known if or how these cells could become senescent.

"Previously, it was believed that senescence occurs only as a result of a lifetime of cell division and the shortening of telomeres. Our data support the very exciting idea that heart cells can become senescent due to stress that damages their telomeres rather than the process of division. This mechanism could also explain how other non-dividing cells in our bodies age. We saw that removing senescent cardiomyocytes from the hearts of aged mice, both genetically and using drugs, was able to restore cardiac health - essentially removing the damage caused by ageing. This data provides critical support for the potential of using medicines to kill zombie cells. If this is validated through clinical trials it would provide us with a new way of treating cardiac diseases.

Length-independent telomere damage drives post-mitotic cardiomyocyte senescence

To investigate further the therapeutic impact of targeting senescent cells to counteract cardiac ageing, we treated aged wild-type mice with the previously described senolytic drug, ABT263 (navitoclax) intermittently for 2 weeks. We found that navitoclax reduced telomere dysfunction in cardiomyocytes without affecting telomere length. Similarly, to genetic clearance of p16Ink4a cells in INK-ATTAC mice, we found that navitoclax significantly reduced hypertrophy and fibrosis in aged wild-type mice. However, navitoclax had no significant impact on cardiac function, left ventricle mass and ventricle wall rigidity.

The decrease in mean cardiomyocyte size without significant changes in left ventricle mass suggested a compensatory increase in overall cardiomyocyte number. Supporting de novo cardiomyocyte proliferation, we observed that frequency distribution analyses of cardiomyocyte cross-sectional area suggested that the decrease in mean cardiomyocyte area following navitoclax treatment is a function of both an elimination of the largest cardiomyocytes, presumably as these are senescent, and the appearance of a "new" population of small cardiomyocytes.


Reason, do you know which senolytics trial will be the first to finish?

Posted by: Antonio at February 11th, 2019 4:31 PM

@Antonio: Not a clue, and publication of data is another uncertain delay.

Posted by: Reason at February 11th, 2019 4:40 PM

"However, navitoclax had no significant impact on cardiac function"
what this essentially means ?
as far as I know there are type of senescent cells and the drug required for clearing those should be various type of targets , and if we clear the zombie cells , we still need to clear the Plaque ? aging is complex and I am sure it will take tons of time and research to understand this disease .

Posted by: Salman at February 11th, 2019 10:58 PM

Heart failure is a huge market too. About 5 million people in America and 6 million or in Europe are in heart failure. Along with Japan, Korea, Canada, Australia and other countries.

Right now heart failure is treated with polypharmacy of beta-blockers, ace-inhibitors or Angiotensin II receptor blockers(ARBs), and aldosterone inhibitors. Each of these advances dramatically improved the prognosis for heart failure people, and these drugs are now generics, so relatively cheap.

Recently added has been Novartis' heart failure drug Entresto, which combines an ARB with a neprilysin inhibitor, which is shown in studies to be a big advance. Entresto was approved in 2015 I believe, and last year it had sales of $1 billion. Novartis thinks Entresto can become a $3-5 billion a year drug, and if things go perfectly, possibly a $10 billion a year drug.

Even with the incredible advances in heart failure, there is still a lot of mortality and especially morbidity. Like people who with the advances are not going to die soon of heart failure, but their heart is not full strength. So they have decreased energy, reduced activity levels, just generally don't feel as well as they did before heart failure.

Posted by: aa3 at February 12th, 2019 12:19 AM

Don't we need technically senolytics and STEM cells to repair the heart completely?

Posted by: Dokuganryu at February 12th, 2019 9:21 AM

Yes we do. The immediate answer is stem cells, now in late phase 111. They work. Better than anything else so far.

Posted by: JLH at February 12th, 2019 2:23 PM

I remain highly skeptical about how cadiotoxic / hematotoxic drugs like navitoclax are going to be useful human with heart damage - or prolonging life for that matter

Posted by: Ira S. Pastor at February 13th, 2019 4:13 AM

So you cleared the senescent cardiomyocytes, but still have nothing to replace them - as they are post mitotic. Maybe best to leave these alone for now.

Posted by: Mark at February 13th, 2019 5:43 AM

Also relevant is this recently reported paper (, which shows that telomere damage generates cytosolic telomeric DNA fragments that trigger arrest via autophagy. Failing autophagy, and the inflammatory STING reaction, is probably what is driving hypertrophy and senescence. This might provide a better method for addressing CM senescence, rather than clearance and (stem cell) replacement.

Posted by: Mark at February 13th, 2019 5:55 AM

I take it back - from the paper: 'Altogether, our data support that senescent CMs are involved in age-associated cardiac hypertrophy and fibrosis and that their clearance may induce a compensatory CM regeneration'. So in mice at least, removal of the senescent CM caused compensatory proliferation and replacement.

Posted by: Mark at February 13th, 2019 10:46 AM

Having the beneficial genetic variants of FOX1/3 suppresses fibrosis and hypertrophy according to Xin, et al, 2017 Potential Supression of Fibrosis. FOX1/3 are thought to suppress fibrosis in many human tissues, such as the lungs, etc.

Posted by: Biotechy Marcks at February 13th, 2019 2:30 PM

"Having the beneficial genetic variants of FOX1/3 suppresses fibrosis and hypertrophy according to Xin, et al, 2017 Potential Supression of Fibrosis. FOX1/3 are thought to suppress fibrosis in many human tissues, such as the lungs, etc."

Seems like this might well be similar to the senolytic activities of Azithromycin . . .

Posted by: Gavrick at April 14th, 2019 9:01 AM

So increasing foxo helps those with heart failure?
A friend of mine examined the gene expression for all existing drugs to see which ones activated Foxo whilst also deactivating the PI3K pathway. Tretinoin had the highest activation of Foxo3 with a concordance of 0.82 which is very high.
Is it possible that ultra low dose accurate would be helpful in eliminating fibrosis via foxo?

Posted by: August at September 18th, 2019 12:15 PM
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