Senescent cells serve many purposes in the body, such as aiding in wound healing and suppression of cancer, but they become harmful when present in significant numbers for an extended period of time. This occurs with age, as the immune system becomes less effective at its task of clearing those senescent cells that fail to undergo programmed cell death. As senescent cells are created constantly, when somatic cells hit the Hayflick limit on replication, and to a lesser degree in response to molecular damage, a slowing of clearance leads to an accumulation of these errant cells. Senescent cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that, when present over the long term, provokes harmful inflammation, restructuring of the extracellular matrix, and detrimental changes in cell behavior.
Atherosclerosis is an inflammatory condition, in which fatty deposits form in artery walls due to the dysfunction of the macrophage cells responsible for removing that damage. More inflammatory signaling makes matters worse, by both changing the behavior of macrophages, and calling in more macrophages to swell the mass of the atherosclerotic plaque. That is enough on its own to consider targeting senescent cells for destruction, to remove their inflammatory signaling as a way to slow the growth of plaque. Today’s open access paper adds a few other concerns, such as the way in which senescent cells may be disruptive of the protective fibrosis that helps stabilize soft plaques.
There is good reason to think that senolytic therapies to selectively destroy senescent cells may be beneficial in the context of atherosclerosis, or indeed in any age-related condition with a strong connection to chronic inflammation, but not all senolytics may effectively target the relevant senescent populations, or localize sufficiently to the arteries, as noted in the paper here. The question of whether senescent cells provide a major contribution or a minor contribution to the progression of atherosclerosis remains open, though the early attempts to produce benefits in animal models have not been promising. If that state of affairs continue, then attention must return to other pathological mechanisms.
Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Cellular senescence is not a static cellular state, but a dynamic process during which cells undergo quiescence (initial transient senescence), early senescence (stable growth arrest), complete senescence (chromatin changes associated with senescence and SASP), and late/deep senescence (phenotypic diversification). Similar to other cell types, senescent VSMCs have impaired proliferative potential coupled with increased propensity for expression of cellular senescence markers and cell death.
VSMCs aging is characterized by a shift from a contractile phenotype to a synthetic phenotype, impaired response to contractile or diastolic mediators secreted by endothelial cells, and changes in ion channel expression and abundance in the cell membrane. In atherosclerosis, senescent VSMCs may be present only in the intima rather than the mesenchyme, and VSMCs senescence is associated primarily with plaque size rather than plaque formation. Advanced atherosclerotic plaques are covered by fibrous caps containing VSMCs and extracellular matrix (ECM) molecules. Given that VSMCs can secrete and deposit ECM proteins, they are generally considered to be protective against atherosclerotic plaque instability. However, senescent VSMCs promote plaque vulnerability by secreting matrix-degrading proteases. Compared with normal VSMCs, collagen secretion from senescent VSMCs is reduced which further impairs plaque stability. Thus, senescent VSMCs not only accumulate in the atherosclerotic setting, but their properties exacerbate the development of atherosclerosis and increase the risk of atherosclerosis-related complications.
It is unclear whether senolytic drugs prevent atherosclerosis through multiple mechanisms or whether they do so only by clearing senescent cells. Not all anti-aging drugs are effective against atherosclerosis; long-term oral administration of dasatinib + quercetin (D + Q) significantly reduced aortic medial senescent cell markers in chronic hypercholesterolemic mice and naturally aging mice, as well as improving vasomotor function, but the mice still developed atherosclerosis. Further, the size of atherosclerotic plaques did not decrease following these treatments.