Senility and many diseases are largely caused by the accumulation of damaged cells that no longer divide. The scientists found that an inhibitor of FOXO4 activity cleared senescent cells from mice.
If the cell is severely damaged, it may enter a process of self-clearing called apoptosis, or a process of self-incapacitation called aging. As senescent cells can survive for long periods, they accumulate in aging and damaged organs. A range of evidence suggests that eliminating senescent cells can extend the healthy lifespan of mice and reduce the severity of age-related diseases. Baar et al. 's paper, published in Cell, deepens our understanding of this phenomenon. They note that the survival of senescent cells depends on the transcription factor FOXO4. Meanwhile, mouse models showed that tissue dysfunction and age-related diseases caused by chemotherapy could be reversed by pharmacologically interfering with FOXO4's function.
Sensory-associated secretory phenotype (SASP) is a phenomenon in which sensory-associated secretory phenotype (SASP) is secreted by sensory-associated secretory phenotype. The scientists believe that the normal function of SASP is restored in two ways. Second, the senescent cells were eliminated by attracting inflammatory cells and turning off the sasp-mediated signal. However, this repair process can fail when the extent, duration, or frequency of damage exceeds the ability to repair, or when SASP no longer stimulates repair and attracts inflammatory cells. The end result is abnormal accumulation of senescent cells, which aggravates tissue dysfunction.
Over the past two years, multiple studies have shown that because of the apparent molecular vulnerability of senescent cells, targeted therapies can be targeted through compounds - drugs that kill senescent cells in preference to other drugs. Senile cells express high levels of pro-apoptotic and anti-apoptotic factors, and therefore remain on the edge of cell death. This is the theoretical basis for the preparation of typical anti-aging drugs. These drugs inhibit the action of the bcl-2 protein family, a group of pro-cell proteins, and guide cells into apoptosis. The scientists also proposed an anti-aging formula based on a combination of two drugs, but the exact molecular basis remains to be clarified.
Baar et al. set out to further understand the mechanisms 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 downregulation of FOXO4 by an inhibitive RNA molecule could induce apoptosis in senescent cells rather than normal cells, whereas the downregulation of other FOXO family members had no such effect.
To some extent, FOXO4 and some of its family members promote cell survival by interacting with multiple protein partners. According to the findings of Baar et al., FOXO4 is an important molecule to promote the survival of senescent cells. Interestingly, FOXO4 can interact with the protein p53, a known senile induction protein. Therefore, the researchers concluded that this foxo4-p53 interaction may be essential for the survival of senescent cells, and that destruction of this interaction would promote 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 transcription activity of FOXO4, but its binding to p53 is more stable and thus can competitively inhibit foxo4-p53 interaction.
New anti-aging tools to remove aging cells in vivo figure 1 targeted senile cell population. Senescent cells do not proliferate but emit inflammatory signals that appear in mice after chemotherapy and in older mice, causing a range of diseases. Baar et al. reported that the combination of FOXO4 and p53 helps maintain cell aging. They developed a pharmacological peptide called foxo4-dri and injected it into the mice. Foxo4-dri competitively binds to p53, propelling senescent cells into the apoptosis process, thus greatly improving the side effects of aging and chemotherapy.
Within a certain concentration range, foxo4-dri can effectively kill senescent cells without affecting non-senescent cells. Baar et al. pointed out that this specific killing is directly achieved through the effect of p53. In addition, foxo4-dri may disrupt the activity of other binding ligands involved in the survival of senescent cells. Because little is known about FOXO4, especially its role in aging, it is difficult to identify other potential mechanisms for foxo4-dri - more research is needed.
It is worth noting that the concentration window of foxo4-dri selectively killing senescent cells was wider than the concentration range of bcl-2 inhibitor under the same killing effect. In addition, FOXO4 is known to have low levels of expression in most tissues, and mice lacking the FOXO4 gene showed no obvious defects, suggesting that when used in mammals, foxo4-dri would probably have no significant adverse effects on healthy tissue. Therefore, foxo4-dri is a potential anti-aging drug.
Baar et al. studied the effects of foxo-dri in mice that glowed when expressing the gene p16Ink4a, a biomarker for aging. Baar treated mice with doxorubicin, a widely used chemotherapy drug. Doxorubicin can cause aging and often has toxic side effects in mice and humans, including liver damage and weight loss. After doxorubicin administration, continuous foxo4-dri treatment reduced the number of glowing, senescent cells and neutralized the drug's toxic effects.
Next, the researchers studied the effects of foxo-dri on aging in two-year old mice and mice whose genetic mutations caused premature aging. In both types of mice, p16Ink4a showed strong fluorescence signal, i.e. more senescent cells. After treatment with foxo4-dri, the mice showed less light and younger appearance, such as more vigorous and active hair, and less kidney damage.
The results of Baar et al. strongly support the theory that the severity of age-related defects and the side effects of chemotherapy can be artificially interfered, prevented and reversed. At the same time, anti-aging strategies are also beneficial for cancer treatment. Chemotherapeutic drugs can induce senescence in sensitive cancer cells, including cells that function normally, such as p53 or p16Ink4a (two genes that often mutate in cancer and are therefore more sensitive to only a few cells). The researchers then used anti-aging drugs, which could help kill aging tumor cells. These anti-aging drugs not only attenuate the effects of SASP - which may boost tumor development - but also prevent these cells from returning to a harmful cancer state. However, given the mechanism of action of foxo4-dri (which affects the action of p53), foxo4-dri may only be effective for tumors with normal p53 function.
Research by Baar et al. has proposed a new anti-aging drug. The next challenge will be human clinical trials - and if human trials are successful, people like Baar will open a new chapter in medicine.
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