Fight Aging!

Senescent cells accumulate with age in tissues throughout the body. Cells enter a senescent state constantly throughout life, largely the result of cells reaching the Hayflick limit on replication, but also due to stress, injury, and damage. A senescent cell ceases replication and instead produces a potent mix of pro-growth, pro-inflammatory signals. The primary purpose of senescence in an adult is to signal to the immune system that a cell needs to be removed, and potentially that the surrounding region of tissue requires further attention, such as in the case of an injury or toxic environment that is damaging other cells. Unfortunately, the immune system becomes progressively incapable with advancing age, and clearance of senescent cells falters and slows. The burden of senescent cells grows, and their signaling turns from helpful to harmful when sustained constantly, disrupting tissue structure and function.

The heart is one of the least regenerative organs, and also one of the most vital. What limited capacity for regeneration that it does have is diminished with age, in part because of a growing burden of senescent cells. Thus among the many potential uses for senolytic therapies capable of selectively clearing senescent cells from tissues, we might consider treatment to improve outcomes following heart attack, or in a more preventative sense to reverse the harmful remodeling of heart muscle that occurs in response to hypertension, changes in the systemic environment, and narrowed blood vessels.

Targeting Cell Senescence to Improve Cardiac Regeneration

Aging impairs the heart's ability to repair and regenerate. As people age, their cardiac stem cells, i.e. cardiac progenitor cells (CPCs), become senescent, upregulating key markers of senescence, such as p16Ink4a and senescence-associated β-galactosidase, and markers of DNA damage, such phosphorylated histone 2AX. Senescent CPCs also possess critically short telomeres and a senescence-associated secretory phenotype (SASP). Indeed, by the time a person is 75 years old, approximately 50% of their CPCs are senescent. Cardiac progenitor cells from older patients are dysfunctional, showing impaired growth, clonogenicity, and cardiomyogenic differentiation potential. When senescent human CPCs were transplanted into a myocardial-infarcted mouse heart, there was decreased cardiac regeneration and cardiac function compared with when non-senescent CPCs were transplanted.

Next, the effects of senolytics and global senescent cell removal on the aged heart were determined. In this experiment, 24- to 32-month-old wild-type mice were randomly assigned to vehicle or senolytic dasatinib and quercetin (D+Q) treatment, administered in 4 cycles at 3 consecutive days per cycle, with the cycles occurring 12 days apart. P16Ink4a messenger RNA expression decreased in the heart following D+Q treatment in older mice. Morphometric analysis of heart sections showed that D+Q-treated mice had decreased fibrosis and hypertrophy and that senolytic treatment had induced compensatory cardiomyocyte renewal and replacement. An increased number of smaller ventricular 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes were found, suggesting that these mice had cardiomyocytes that were immature and newly formed compared with vehicle-treated mice, which exhibited only rare, small 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes but a greater proportion of hypertrophied myocytes. Finally, D+Q treatment rejuvenated the heart's regenerative potential, activating and increasing the number of CPCs.

The present findings support targeting senescence using senolytics to prevent, delay, and treat multiple age-related heart disorders as well as the toxic and senescence-inducing effects of cancer chemotherapy on the heart. Clinical trials on senolytics are already underway. The Translational Geroscience Network in the United States is conducting 15 clinical studies on senolytics for age-related conditions. They have developed assays for measuring biomarkers in the blood and tissues that can be used to test the efficacy of senolytics in the proposed trials and to identify people who are most likely to benefit from senolytic therapy. Research into understanding how senolytics act on the human heart, in clearing senescent cells, or whether they have any off-target side effects is greatly needed.