Senescent cells accumulate in tissues throughout the body with age. Cells constantly become senescent as a result of wound healing, cancer suppression, the Hayflick limit on cellular replication, or damage and a toxic local environment. Near all are destroyed quite quickly, either via programmed cell death or by the immune system. It remains to be rigorously determined as to whether the growth in numbers of senescent cells with age is an imbalance of slowed clearance and increased production, or whether a tiny fraction of all senescent cells manage to evade destruction and linger for the long term.
What is certain is that the burden of senescent cells is very damaging to health. Senescent cells generate the senescence-associated secretory phenotype, a secreted mix of molecules that causes chronic inflammation, destructive remodeling of surrounding tissue, and dysfunction of nearby cells. A comparatively small number of senescent cells can cause meaningful loss of organ function and the onset of age-related disease. This is thus one of the important contributing causes of aging.
The research community is exploring the consequences of cellular senescence tissue by tissue, starting with those most important to age-related mortality. In the heart, cellular senescence produces fibrosis, a disarray of normal tissue maintenance processes that manifests as inappropriate deposition of scar-like collagen structures. It is also connected to the ventricular hypertrophy that leads to heart failure. Targeted removal of senescent cells has been shown to reverse these pathologies in mice, and as a consequence there is considerable interest in further exploration of the biochemistry of senescence in the aging heart.
The heart is an organ with high energy demand: mitochondria content in cardiomyocytes is up to 70%. During aging and stress conditions, the metabolic pattern changes in cardiomyocytes, which is critically involved in the regulation of cardiomyocyte dysfunction and senescence. The non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment also contribute to the (dys)function/senescence of cardiomyocytes. In turn, the senescent cardiomyocytes modulate the microenvironment to contribute to functional compensatory response or decompensatory remodeling and cardiac dysfunction.
Although cell senescence plays essential roles in wound healing, limiting atherosclerotic plaque size, and preventing infections, the effects of cell senescence can be detrimental or beneficial. The exact roles of senescent cells that contribute to aging and age-related diseases can be named “senescaging”. Further studies are still needed to explore the physiological and pathological functions of senescent cardiomyocyte during cardiac development, regeneration, and pathological remodeling, and to elucidate how senescaging contributes to cardiac aging and disease. Specifically, more studies are needed to answer whether cardiomyocyte senescence critically contributes to cardiac aging and the related heart failure with preserved ejection fraction (HFpEF).
Microenvironmental non-myocytes function as central regulators of cardiomyocyte senescence, and metabolism switch is important for the homeostasis and senescence of cardiomyocytes. As thus, an interesting point is whether these non-myocytes affect the metabolic pattern of cardiomyocyte undergoing senescence. Also, studies are needed to explore how metabolism alternations in non-myocytes contribute to cardiomyocyte senescence and cardiac aging. Many studies have been carried out to study the effects of non-myocytes on cardiomyocyte senescence. Some studies also explored the paracrine effects of cardiomyocytes on non-myocytes. However, our knowledge about the effects of senescent cardiomyocytes on microenvironmental non-myocytes is few and further efforts are needed.
An interesting question is whether cardiomyocyte senescence and the myocardial microenvironment could serve as targets for anti-aging drugs such as the popular senolytics. Senolytics were recently reported to repress senescence and inhibit cardiac disease such as myocardial infarction and repress age-related vasomotor dysfunction and atherosclerosis. Further studies are still needed to elucidate how senolytics target cardiomyocyte senescence and local microenvironment, and that whether other anti-aging drugs could repress the senescaging of myocardial microenvironment.