With the growing interest in the accumulation of senescent cells as an important cause of aging, and more funding flowing into this part of the field, researchers are uncovering numerous direct links between cellular senescence and age-related conditions. Senescent cells cause harm to tissues via their inflammatory secretions, the senescence-associated secretory phenotype (SASP). The SASP is damaging, but there are usually too few senescent cells, even in later life, to have a significant effect on tissue dysfunction through their localized actions. There may be exceptions to that rule, but the evidence to date strongly suggests that the SASP is the dominant mechanism in the contribution of cellular senescence to degenerative aging.
One of the many conditions in which cellular senescence is implicated is vascular calcification, the inappropriate deposition of calcium that stiffens blood vessels and heart tissue. Senescence causes some cells, senescent cells and others, triggered by the SASP, to behave as though they are maintaining bone. Stiffening of blood vessels causes the chronic raised blood pressure of hypertension and consequent pressure damage to fragile tissues throughout the body and brain. This downstream harm is so important that forcing a lower blood pressure can significantly reduce age-related mortality, even without addressing the deeper causes.
The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification
The deterioration of arterial anatomy and physiology that occurs during chronological aging is a risk factor for cardiovascular morbidity and all-cause mortality. Aged arteries are characterized by functional changes of vascular smooth muscle cells (VSMCs) from a contractile and quiescent status to a senescent phenotype. VSMCs approaching senescence acquire the senescence-associated secretory phenotype (SASP) that consists of the secretion of a variety of soluble molecules, mostly pro-inflammatory cytokines and chemokines, growth factors, and matrix-remodeling enzymes. SASP factors are released in the blood circulation and act locally in a paracrine manner to spread senescence to neighboring cells; in this way, they contribute to the development of a sterile, low-grade, chronic age-associated systemic and tissues inflammation known as “inflammaging” considered the main risk factor for the most common age related diseases, included cardiovascular diseases.
Senescent VSMCs express bone-related genes, like Runt-related transcription factor 2 (Runx2), alkaline phosphatase, and osteocalcin that favor their maladaptive switching to an osteoblastic phenotype and eventually, the onset of vascular calcification (VC), a cardiovascular complication characterized by hydroxyapatite crystals deposition and mineralization of the arterial wall. Accordingly, during aging or in pathological conditions including chronic kidney disease (CKD), atherosclerosis, or type 2 diabetes (T2D), the molecular mechanisms that promote VSMCs senescence support their osteogenic transdifferentiation and VC.
MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors, and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a-/- mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.