Inflammaging is not uniform in cardiovascular tissues, with the primary “hotspots” occurring in vascular niches. Also, various cell types can be affected by senescence; for example, endothelial cell senescence is associated with insulin resistance and endothelial dysfunction. Mature atherosclerotic plaques are rich in senescent cells, including endothelial cells, senescent “foamy” macrophages, and senescent vascular smooth muscle cells, with the associated SASP (including inflammatory signals such as IL‐1α, IL‐6, IL‐8, and CCL2) creating an inflammatory and pro-atherogenic environment.
This review also highlights the important physiological functions of certain forms of senescence, as seen during embryonic development and wound healing. It’s also speculated that senescence evolved alongside apoptosis as a protective mechanism that limits the propagation of dysfunctional cells, which either undergo programmed cell death or permanently stop dividing. Indeed, the SASP recruits immune cells that should clear senescent cells, which in physiological states have a short half-life. It is only in aging and age-related diseases that these cells persist, as does the inflammatory phenotype they create.
SASP also includes growth factors, some of which are now being used to help identify senescent cells (at least in the research setting). Among these are transforming growth factor beta (TGF‐β) and growth differentiation factor 15 (GDF‐15), with the latter emerging as a “key whole-body biomarker, consistently associated with mitochondrial dysfunction and inflammatory processes.” Indeed, mitochondrial stress specifically seems to be one of the main drivers of cellular senescence, producing mitokines (stress response molecules) such as GDF-15 in response to mitochondrial stress/dysfunction, suggesting that supporting healthy mitochondria could potentially mitigate this progression.
This latest review also briefly describes therapeutic approaches targeting senescence, broadly grouped into 2 categories: senolytics and senomorphics. Senolytics induce apoptosis in senescent cells, which normally evade this type of cell death via several mechanisms. A number of preclinical models suggest multiple natural compounds may act as senolytics, such as quercetin and fisetin, and are sometimes partnered with drugs like dasatinib, a tyrosine kinase inhibitor. Dasatinib and quercetin are used in combination, for example, with dasatinib targeting senescent preadipocytes and quercetin targeting senescent HUVECs (human umbilical vein endothelial cells). Senomorphics modulate SASP rather than target senescent cells, and include drugs such as rapamycin and metformin as well as natural compounds like resveratrol and kaempferol.
Many lifestyle interventions, including exercise and a Mediterranean diet, appear to target inflammaging and address hallmarks of the aging process, though the authors point out that their role in cardiovascular aging specifically needs more research. They also call for “selective, biomarker‐guided, and possibly intermittent therapeutic strategies” to target pathological aging, with a reduction in CVD being a substantial payoff of effective therapies.