The presence of senescent cells is a contributing cause of aging; the number of such cells grows over time as a consequence of the normal operation of metabolism, and collectively they cause considerable harm to tissue and organ function. The most important lines of research on cellular senescence aim at the production of senolytic therapies capable of removing these unwanted cells, but a sizable fraction of the researchers involved in this part of the field are more interested in antisenescence treatments, those that minimize the bad behavior of these cells, or reduce the number of cells that become senescent.
It would perhaps be more accurate to say that there is an ongoing reassessment of protein and drug candidate libraries in order to categorize known effects in terms of their influence on cellular senescence; all too much of medical research involves repurposing of existing drugs where there is any small positive outcome rather than building better technologies from first principles. When it comes to looking at existing outcomes from the drug and protein libraries in search of modifications to the behavior of senescent cells, my impression is that this is a road to marginal therapies only, those that slightly reduce the impact of senescent cells rather than solving the problem completely. This is a widespread problem in the research community, in which too many people are devoting resources to projects that are unlikely to have a sizable impact on aging.
Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells (EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin (STZ)-induced diabetic mice, and Caenorhabditis elegans (C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and microRNA-21 (miR-21) and p16INK4a synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes.
Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 (SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a-SIRT1 pathway.