An Example of High Dose Fisetin Exhibiting Senolytic Effects in Mice
Fisetin is perhaps the most intriguing of the first generation senolytic compounds, those capable of selectively destroying senescent cells in old tissues and thus producing rejuvenation to a meaningful degree. Senolytics have been demonstrated in animal studies to reverse many age-related conditions to a greater degree than any other approaches. Why is fisetin intriguing? Because in mice, it appears to be about as effective as the dasatinib and quercetin combination, yet it is a widely used dietary supplement.
Supplement dosing of fisetin in humans is not that much lower than the lowest demonstrated senolytic dose in mice. Senolytics are highly effective as treatments for inflammatory age-related conditions in mice, and starting to show similar effects in human trials. Should we expect that no older individual ever took enough fisetin to notice that it has profound effects on common inflammatory age-related conditions at higher doses? Is it realistic to think that strong medicines can be hiding in plain sight in this way for years upon years? The alternative explanation is that fisetin, unlike datastinib and quercetin, only effectively destroys senescent cells in mice. Which seems equally implausible, given what is known of the biochemistry of cellular senescence.
Questions regarding fisetin will be resolved (hopefully) at some point in the near future, given that human clinical trials of fisetin as a senolytic drug are presently ongoing, targeting frailty, cartilage degeneration, kidney disease, and osteoporosis. It is also worth looking at the materials on fisetin put together by the Forever Healthy Foundation, an extensive review of the evidence to date.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease, which is characterized by the aberrant accumulation of extracellular matrix (ECM) in the lung parenchyma and deterioration of lung function. Both clinical observations and epidemiological investigations indicate that IPF is an aging-associated disease, since IPF occurs primarily in middle-aged and elderly people (median age at diagnosis is around 65 years), and the incidence rises remarkably with advancing age.
Cellular senescence is pivotal for phenotype of aging. The characteristics of senescent cells include growth arrest, enlarged cell morphology, elevated activity of SA-β-Gal as well as increased expression of cell cycle inhibitors, such as p16 and p21. Dysfunctional re-epithelialisation, following repetitive micro-injury, initiates the process of pulmonary fibrosis (PF). Increasing evidences have implicated that accelerated senescence of alveolar epithelial cells, a main cause of epithelial dysfunction, plays an important role in IPF pathogenesis. Senescent alveolar epithelial cells not only lose the ability of regeneration and repair, but also exert deleterious effects on neighboring cells by secreting a variety of proinflammatory cytokines, pro-fibrosis factors, growth factors, matrix metalloproteinases, and chemokines, described as senescence-associated secretory phenotype (SASP).
Fisetin (FIS), a natural non-toxic flavonoid, is present in various plants, fruits, and vegetables. Previous research has demonstrated that FIS has anti-inflammatory, anti-fibrosis, anti-oxidant, and anti-aging properties. Senolytic drugs, dasatinib and quercetin (D + Q), can attenuate experimental PF via selective depletion of senescent alveolar epithelial cells. More encouragingly, a recent first-in-human open-label clinical trial has suggested that short-term administration of D + Q could improve the physical dysfunction in IPF patients. Both FIS and quercetin belong to the flavonoid class, and FIS exhibits stronger senotherapeutic activity in cultured cells than quercetin, and can extend lifespan in mice. These traits remind us that FIS may have protective effect in PF. However, the role of FIS in PF has not been elucidated.
Bleomycin (BLM)-induced PF is the most frequently used animal model. Treatment with BLM can also induce alveolar epithelial cell senescence in vitro and in vivo. In this study, BLM was used to reproduce PF in mice and induce alveolar epithelial cell senescence to investigate the effect and mechanism of FIS in experimental PF. We found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype. FIS may be a promising candidate for patients with pulmonary fibrosis.