Fight Aging!

Senescent cells accumulate with age in tissues throughout the body, most likely in large part because the aging immune system becomes less efficient in removing these cell in a timely fashion. Senescent cells do perform useful functions when present in the short term, drawing the attention of the immune system to potentially cancerous or injured tissues, but when present for the long term they are increasingly disruptive to tissue structure and function. Their presence contributes to the dysfunctions of degenerative aging. Thus researchers are engaged in the development of senolytic drugs capable of selectively destroying senescent cells, and the first such drugs have been demonstrated to product rejuvenation and reversal of age-related conditions in mice.

In principle, many flavonoid compounds have the ability to put stress on senescent cells that their peculiar biochemistry is ill-equipped to handle. In practice near all of those flavonoid compounds are likely senolytic to a small, uninteresting degree, producing trivial degrees of cell death that make no real difference to health outcomes. Quercetin, for example, doesn't do much on its own, even though it combines with dasatinib to produce one of the first proven senolytic treatments. Fisetin, on the other hand, is meaningfully senolytic in mice on its own. It is interesting to ask whether we should expect many more flavonoids to be as senolytic as fisetin.

On this topic, today's open access paper assesses the senolytic ability of 4,4′-dimethoxychalcone (DMC), finding it worthy of note, though the animal data isn't as extensive as one would like. It is worth noting that the degree to which fisetin is senolytic in humans remains to be determined, as data from human trials has yet to be published. Further, while it is established to clear senescent cells in mice, the Interventions Testing Program found that fisetin treatment did not extend mouse life span, unlike the dasatinib and quercetin combination in other non-ITP studies. Whether flavonoids are a useful place to look for senolytic treatments remains under assessment.

Flavonoid 4,4′-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy

4,4′-dimethoxychalcone (DMC) is a flavonoid previously reported as a small molecule promoting longevity and health. Our previous studies have shown that DMC functions as a ferroptosis inducer in cancer cells. However, there were no report on the function of DMC in senescent cells. Senotherapeutics consist of senolytics and senomorphics, which selectively eliminate senescent cells and reduce the senescence-associated secretory phenotype (SASP), respectively. Many flavonoids are senotherapeutics, and dasatinib + quercetin is so far the most commonly used senolytics. Dasatinib is a tyrosine kinase inhibitor, which inhibits cell proliferation and migration and induces apoptosis. Quercetin is a flavonoid that interacts with Bcl-2 family members to induce apoptosis. In the present study, we found that DMC, DMC + dasatinib, DMC + quercetin have a characteristic of senolytics. To investigate the senolytics effects, we employed replicative senescent cells and a DNA damage-induced senescent cells model. We found that DMC and its combination with dasatinib or quercetin selectively eliminated senescent cells, more effectively than using dasatinib + quercertin alone.

Senescent cells secrete a series of pro-inflammatory cytokines, chemokines, and growth factors, which is called SASP, to cause chronic inflammation and tissue dysfunction. In this study, we found that DMC reduced the SASP level in senescent cells. Furthermore, senescent cells enter irreversible cell cycle arrest, which involves the activation of p53/p21 and Rb/p16. In this study we found that the expression levels of p21 and p16 were decreased after DMC treatment. The downregulation of p21 may be attributed to the decrease of p53. In this study, we found that the mRNA level of p53 was reduced after DMC treatment.

Ferroptosis is an iron-dependent cell death process, which is accompanied by iron accumulation. Our previous study reported an important role of FECH, an enzyme inserts ferrous ion into PPIX, in ferroptosis, and showed that the inhibition of FECH by DMC led to iron accumulation in cancer cells. In this study, we found that the expression level of FECH increased in senescent cells, which may explain the sensitivity of DMC-induced ferroptosis in senescent cells. Senescent cells are associated with impaired ferritinophagy and ferroptosis. Interestingly, in our present study, we found that DMC could induce ferritinophagy, which may underlie DMC-induced ferroptosis in senescent cells.