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FOXO4-DRI- A New Tool To Remove Aged Cells
Nov 16, 2018

Aging and many diseases are mostly caused by the accumulation of damaged cells that no longer divide. Scientists have found that inhibitors of FOXO4 protein activity can clear aging cells in mice.

If the cell is severely damaged, it may enter a process of self-clearing called apoptosis, or a process of self-disability called aging. Since senescent cells can survive for a long time, they accumulate in aging and damaged organs. A series of evidence suggests that elimination of senescent cells prolongs the healthy lifespan of mice and reduces the severity of age-related diseases. The paper published by Baar et al. on Cell has deepened our understanding of this phenomenon. They point out that the survival of senescent cells depends on the transcription factor FOXO4. At the same time, mouse models show that tissue dysfunction and age-related diseases caused by chemotherapy can be reversed by pharmacological interference with the function of FOXO4.

Senescent cells inhibit their own proliferative capacity during reprogramming, while secreting signaling molecules, a phenomenon known as senescence-associated secretory phenotype (SASP).Scientists believe that the normal function of SASP is to restore tissue function in two ways: first, to stimulate tissue damage by stimulating adjacent cells with less damage; second, to eliminate senescent cells by attracting inflammatory cells, and to turn off SASP-mediated signal. However, this repair process may fail when the extent, duration or frequency of the damage exceeds the repair capacity, or when the SASP is no longer able to stimulate repair and attract inflammatory cells. The end result is an abnormal accumulation of senescent cells, which aggravates tissue dysfunction.

In the past two years, a number of studies have shown that because aging cells have significant molecular vulnerabilities, they can be targeted by compounds – these drugs preferentially kill senescent cells. Senescent cells express high levels of pro-apoptotic and anti-apoptotic factors and therefore remain on the verge of cell death. This is the theoretical basis for the preparation of typical anti-aging drugs. These drugs can inhibit the action of the BCL-2 protein family, a class of proteins that promote cell survival, and direct cells into the process of apoptosis. The scientists also proposed an anti-aging formula based on a combination of two drugs, but the molecular basis remains to be elucidated.

Baar et al. began to understand the mechanism by which senescent cells inhibit apoptosis. Gene expression data showed that the transcription factor FOXO4 was up-regulated in senescent cells compared to normal cells. Baar further pointed out that down-regulation of FOXO4 using inhibitory RNA molecules can trigger apoptosis in senescent cells, but not normal cells, whereas down-regulation of other FOXO family members does not.

To some extent, FOXO4 and some of its family members promote cell survival through interaction with multiple protein partners. According to Baar et al., FOXO4 is an important molecule that promotes the survival of senescent cells. Interestingly, FOXO4 can interact with the protein p53, a known aging-inducing protein. Therefore, the researchers concluded that this FOXO4-p53 interaction may be critical for the survival of senescent cells, and disrupting this interaction will drive apoptosis (Figure 1). To test this, they synthesized a modified peptide fragment called FOXO4-D reverse transcription (FOXO4-DRI). This peptide fragment lacks the normal transcriptional activity of FOXO4, but is more stable to bind to p53, and thus can competitively inhibit the FOXO4-p53 interaction.

Figure 1 Targets a population of aging cells. Aging cells do not proliferate, but they release inflammatory signals, which occur in mice after chemotherapy and in older mice, causing a range of diseases. Baar et al. reported that a complex of FOXO4 and p53 helps maintain cell senescence. They developed a pharmacological peptide called FOXO4-DRI and injected it into these mice. FOXO4-DRI competitively binds to p53, pushing senescent cells into the process of apoptosis, thereby greatly improving the side effects of aging and chemotherapy.

Within a certain concentration range, FOXO4-DRI can effectively kill senescent cells and does not affect non-senescent cells. Baar et al. pointed out that this specific killing is directly achieved by the action of p53. In addition, FOXO4-DRI may disrupt the activity of other ligands that bind to FOXO4 and participate in the survival of senescent cells. Because the academic community knows little about FOXO4, especially its role in aging, it is difficult to determine other potential mechanisms of action of FOXO4-DRI—more research is needed in this area.

It is worth noting that under the same killing effect, the concentration window of FOXO4-DRI selectively killing senescent cells is wider than the concentration range of BCL-2 inhibitors. In addition, it is well known that FOXO4 is expressed at a low level in most tissues, and mice lacking the Foxo4 gene also show no significant defects, suggesting that if FOXO4-DRI is used in mammals, it is likely that it is not obvious to healthy tissues. side effect. Therefore, FOXO4-DRI is a very promising anti-aging drug.

Baar et al. studied the role of FOXO-DRI in mice that fluoresce when expressing the p16 Ink4agene, a aging biomarker. Baar treated mice with doxorubicin, a widely used chemotherapy drug.Doxorubicin causes aging and often has toxic side effects in mice and humans, including liver damage and weight loss. After doxorubicin administration, continuous FOXO4-DRI treatment can reduce luminescence, reduce the number of senescent cells, and neutralize the toxic effects of the drug.

Next, the researchers studied the effects of FOXO-DRI on aging by using two-year-old mice and mice with premature aging caused by genetic mutations. In both mice, the fluorescent signal of p16 Ink4a was strong, that is, there were more senescent cells. After treatment with FOXO4-DRI, the luminescence in the mice was reduced, and the appearance became younger, such as hair was more vigorous, more active, and impaired renal function.

The results of Baar et al. strongly support the theory that can artificially interfere with, prevent and reverse the severity of aging-related defects and the side effects of chemotherapy. At the same time, anti-aging strategies are also conducive to cancer treatment. Chemotherapy drugs can induce senescence in sensitive cancer cells, including cells that function normally, such as p53 or p16Ink4a, which are frequently mutated in cancer, so only a few cells are more sensitive.Subsequently, the researchers used anti-aging drugs for research, which may help kill aging tumor cells. These anti-aging drugs not only weaken the role of SASP - SASP may promote tumor development, but also prevent these cells from returning to harmful cancer states. However, given the mechanism of action of FOXO4-DRI (affecting the effects of p53), FOXO4-DRI may only be effective against tumors with normal p53 function.

A study by Baar et al. proposed a new anti-aging drug. The next challenge will be human clinical trials - if human trials are successful, then Baar and others will open a new chapter in medicine.