A slow accumulation of long-lived senescent cells takes place throughout the body over the years, and is involved in the age-related decline of all tissues. Cells become senescent constantly, in response to damage, a toxic environment, participation in the wound healing response, or simply reaching the Hayflick limit on replication. Near all newly senescent cells either quickly self-destruct or are soon hunted down by the immune system, but a tiny fraction survive to linger. Senescent cells do not replicate, but are very active, secreting a potent mix of inflammatory and other signals that disrupt cell behavior and tissue structure. A sizable fraction of the chronic inflammation of aging is produced by the activities of senescent cells, and this inflammation drives the progression of all of the common age-related diseases.
Fortunately, senescent cells can be reduced in number, a fraction selectively destroyed, via strategies ranging from small molecule senolytic drugs to suicide gene therapies. A fair number of startup biotech companies are moving towards human trials for their approaches to therapy, while at least some of the presently available prototype senolytic compounds appear likely to be effective enough and safe enough to consider using. Given the continued intermittent arrival of new evidence showing the sizable contribution of senescent cells to conditions from type 2 diabetes to Alzheimer’s disease to lung disease to kidney disease and atherosclerosis, and that removing these cells reverses the progression of these age-related diseases, the future for this part of the field of rejuvenation biotechnology seems bright.
Cellular senescence in cardiac diseases
Aging and age-related disorders progress through an integration of complex biological processes, and do not allow a simple approach to understand the whole picture, however, evidence indicates the central roles of cellular senescence in the pathogenesis of these conditions. Prevalence of age-associated diseases, including atherosclerotic disorders or heart failure increases with chronological aging, and cells positive for senescent markers are now well recognized to have causal roles for the progression of pathologies in these age-related diseases. In vitro studies showed that exposure of young somatic cells to senescent cells promotes senescence of the young cells, and this is described as the “bystander effect”. Pharmacological or genetic depletion of senescent cells contributed to reverse aging phenotype, and suppressed pathologies in chronological as well as age-related disease models.
Adult cardiomyocytes were long thought to be terminally differentiated post-mitotic cells, however, accumulating evidence indicates these cells retain proliferative capacity. It was previously reported that in humans, cardiomyocyte turnover was at a rate of less than 1% per year, and this was demonstrated to decline with aging both in humans and mice. The underlying machinery of diminished cardiomyocyte turnover with aging is yet to be defined, and whether this is attributable to cardiomyocyte senescence is not clear due to the lack of specific senescence markers. In mice, it was reported that chronological aging links with an increase in cardiomyocyte size, together with reactive oxygen species (ROS) production, telomere attrition, and high level of p53 or p16Ink4a expression. In this study, compared to young mice (4 months of age), aged mice (20-22 months of age) exhibited increased left ventricular weight and cardiomyocyte volume, and showed reduction in cardiomyocyte number, together with reduced ventricular function, indicating the pathological roles of cardiomyocyte senescence in the aged heart.
Heart failure can be characterized into two types depending on the level of systolic function. One is described as heart failure with reduced ejection fraction (HFrEF), another is classified as heart failure with preserved ejection fraction (HFpEF), and both types of heart failure are prevalent among elderly persons. In the failing heart, chronic sterile inflammation develops, and this is well recognized to promote cardiac remodeling. Inflammation in coronary microvasculature is now thought to have central roles in the pathogenesis of HFpEF, and it was recently indicated that cellular senescence in endothelial cells may also be involved. When senescence-accelerated mice were fed a high-fat high-salt diet, endothelial cell senescence developed in cardiac tissues, and this coincided with the typical hemodynamic and structural changes of HFpEF. Given that aged and/or obese population has higher prevalence for HFpEF, inhibition of endothelial cell senescence pathway may become a next generation therapy for this untreatable disorder.