Wang Zhao's team at Tsinghua University revealed that a high-fat diet rescued the premature aging-related phenotype of SIRT6 knockout mice by improving the intestinal flora

Recently, Professor Wang Zhao's research group of Tsinghua University School of Pharmacy published a research paper in the journal Aging Cell entitled: Decreased Enterobacteriaceae translocation due to gut microbiota remodeling mediates the alleviation of premature aging by a high-fat diet
。

This study reported that high-fat diet rescued the premature aging related phenotype of SIRT6 knockout mice by improving intestinal flora, which provided a theoretical basis
for the importance and rationality of the formulation of a diet based on microbiota regulation.

With the aging of the population worldwide, aging and aging-related diseases bring serious burdens to individuals, families and society, and slowing down aging and preventing aging-related diseases have become hot issues
in scientific research.
Previously, Wang Zhao's group has reported that high-fat diet alleviates the characterization of aging-related excessive body consumption such as metabolic abnormalities and multi-tissue organ atrophy in SIRT6 knockout mice, and extends the life span of mice from 4 weeks to 26 weeks old (males) or 38 weeks old (females).

Building on this, the new study looks at the gut microbiota, focusing on the important functions
that the gut microbiota plays in improving Progeria in a high-fat diet.

There is growing evidence that the gut microbiota plays a key leading role in the development of aging and aging-related diseases, and dietary interventions can reshape the microbiota and significantly affect the body's metabolism, nutritional balance and even immune system function
.
In recent years, researchers have found that increasing the proportion of fat energy supply in the diet (such as high-fat diet, ketogenic diet) can enhance the motor and memory function of naturally aging mice or progeria mice, reduce mortality and prolong healthy life
.
However, little is known about the role that the gut microbiota plays in this
.
Therefore, this study revolves around the hypothesis that "high-fat diets remodel the intestinal microbiota of SIRT6 knockout mice to improve aging-related phenotypes" and try to explain the mechanism
.

Schematic cover diagram

Research results

1.
After transplanting the intestinal flora of SIRT6 knockout mice to young wild mice, it can induce the emergence of accelerated premature aging related phenotypes in wild mice

SIRT6 knockout mice showed typical indications of intestinal dysbacteriosis, including decreased microbiota diversity, decreased levels of short-chain fatty acids in feces, decreased abundance of probiotic Bacteroidetes and increased abundance of pathogenic bacteria Enterobacteriaceae, Verrucomicrobiaceae, Proteobacteria, and Prevotellaceae
。 The intestinal flora of SIRT6 KO mice was transplanted to young wild mice, and the wild mice exhibited accelerated aging-related phenotypes, which were manifested as increased white coarse hair, decreased blood glucose levels, decreased fat accumulation, and increased expression levels of inflammatory factors (TNFα, IL-1β, IL-6) and aging markers (P16, P21) in multi-tissue organs
.

Fig.
1: Transplantation of SIRT6 knockout mice intestinal flora to young wild mice induced the emergence of accelerated Progeria-related phenotypes in wild mice

2.
The intestinal flora of young wild mice transplanted to SIRT6 KO mice can improve the aging-related phenotype of KO mice

Through microbiota transplantation, wild mouse flora can extend the life span of SIRT6 KO mice, and improve the dysbacteriosis of KO mice to a certain extent, including increasing the diversity of flora, reducing the abundance of pathogenic bacteria such as Enterobacteriaceae, Verrucomicrobiaceae, Proteobacteria, Prevotellaceae, and SIRT6 receiving microbiota transplantation The levels of inflammation and aging of multi-tissue organs of KO mice were significantly reduced
.
This result further supports the important role
of dysbacteriosis in the process of premature aging in SIRT6 KO mice.

Fig.
2: Transplantation of intestinal flora of young wild mice to SIRT6 KO mice improved the aging-related phenotype of KO mice

3.
The overgrowth of Escherichia coli in the intestine is a key trigger for accelerated aging

By comparing the microbiota structure of different groups of mice, such as wild mice, SIRT6 KO mice, wild mice transplanted by SIRT6 KO microbiota, and SIRT6 KO mice transplanted by wild mouse microbiota, the results pointed to Escherichia coli as a key strain
to induce aging 。 It has been reported that the overgrowth of Escherichia coli will lead to the displacement of bacteria in the intestine to other internal organs and further accelerate tissue damage, and this study found that the shift of Enterobacteriaceae in the spleen, liver and kidney of mice was consistent
with the change of Escherichia coli abundance.
Escherichia coli in the feces of SIRT6 KO mice was isolated and cultured and gavaged to wild mice, and the expression level of aging markers in the tissues and organs of the mice was significantly increased
.

Figure 3: Overgrowth of Escherichia coli in the gut is a key trigger for accelerated aging

4.
High-fat diet significantly reduces the abundance of Escherichia coli in the intestine and the displacement of Enterobacteriaceae in internal organs

The high-fat diet not only improved the survival rate of SIRT6 KO mice and improved hypoglycemia, but also reshaped their microbiota, especially significantly reducing Escherichia coli levels and internal organ Enterobacteriaceae shift
.
The transplantation of SIRT6 KO mouse microbiota after dietary intervention to KO mice can still effectively reduce the expression levels
of inflammatory factors and aging markers in tissues and organs of KO mice.

Figure 4: High-fat diet significantly reduced the abundance of Escherichia coli in the intestine and the displacement of the internal organ Enterobacteriaceae

Conclusion of the study

In summary, this study systematically elucidates the important role of dysbacteriosis in the aging process of SIRT6 knockout mice, and the ability of high-fat diet to slow down premature aging
in SIRT6 knockout mice by remodeling the intestinal flora.
The findings further highlight the potential for microbiota-based dietary regimens to prevent aging or treat
aging-related diseases.

Aging and longevity are eternal topics for human beings, and many people are not afraid of the advent of death, but they are very afraid of the arrival of aging
.
In the future, Professor Wang Zhao's research group will continue to carry out related research work on aging and its intervention
.
Intervention in aging itself is not a treatment for a specific disease, but a huge change in the health care model: making us healthier, away from aging-related diseases, compressing the time of related diseases or disability/dementia, extending the healthy life expectancy of individuals and even groups, and thereby reducing personal suffering, family pressure, and social burden
.
Perhaps just lifestyle changes, such as food intake, can change the rate and process
of human aging.
It is believed that with the development of life science and medicine, the realization of "healthy aging" is just around the corner
.