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.
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.
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.