Ma Anqi, Wang Moye, Wang Hongjiang, Research Department of Characteristic Medical Center (formerly 306 Hospital).
Edited by Liu Yan/Cui Yan, Medical Science Popularization Center
Calorie restriction (CR), a dietary regimen that reduces calorie intake without causing malnutrition, is used for weight control, health improvement, and quality of life improvement, and is currently one of the most commonly used methods for healthy aging. Although CR has the function of prolonging the life of a person, it is difficult to implement long-term CR, so there is a need for a drug that can reproduce the CR effect in the absence of CR. There are more than 10 drugs classified as CR mimics (CRMs), some classified as upstream CRMs with glycolytic inhibitory effects, and some as downstream CRMs that regulate or genetically regulate cell-to-cell signaling proteins. Recent reports have revealed beneficial effects of CRM on the body, such as improving the host's body condition through gut bacteria and their metabolites, and this beneficial effect may lead to longer lifespan.
Some scholars have summarized and collectively discussed the cumulative evidence that CRM improves the intestinal environment to prolong healthy lifespan, filling the gap in our understanding of CRM and its physiological impact on the host.
Table 1. Characteristics and targets of CRMs
This article describes bioactive carbohydrates, such as D-glucosamine, D-allulose, and D-allose, as well as antidiabetic drugs such as metformin, acarbose, and glucose-sodium transporter 2 inhibitors (SGLT-2) (Table 1). In addition, the authors analyzed other promising anti-aging CRMs, such as rapamycin, resveratrol, and polyamines.
Effects of metformin, acarbose, and SGLT-2 inhibitors on gut microbes
Metformin is the most commonly prescribed medication for diabetes worldwide. The study found that metformin, as a CRM, transiently inhibits oxidized proteins, and its mitochondrial respiratory chain increases the pathway by which metformin transfers glucose to the intestine, so it affects the intestinal microbiota by altering the level of carbohydrates entering the cecum. Studies have shown that oral metformin may induce selective growth of E. coli, upregulate the secretion of SCFAs, and ultimately help improve insulin sensitivity.
Acarbose is a α-glycosidase inhibitor that reduces postprandial blood sugar spikes by delaying the digestion of carbohydrates into absorbable monosaccharides. This antidiabetic drug has been shown to increase the concentration of undigested carbohydrates in the feces, and an increase in the excretion of hydrogen from the breath has been observed, which is the result of the fermentation of the intestinal flora.
The mechanism of action of SGLT-2 inhibitors involves inhibition of proximal tubular SGLT-2, which promotes urinary glucose excretion by inhibiting glucose reabsorption, which not only lowers blood glucose, but also reduces body weight and blood pressure. SGLT-2-mediated inhibition of SGLT-1 enables intestinal absorption of glucose, and inhibition of SGLT-1 (which contributes to glucose absorption by the small intestinal epithelium) is effective in reducing blood levels of the urinary toxin phenyl sulfate, which is derived from intestinal bacteria. Therefore, inhibition of intestinal SGLT-1 affects the intestinal environment.
Effects of D glucosamine, D allulose, and D allulose on intestinal microbes
D-glucosamine is a dietary supplement used to treat osteoarthritis and other joint diseases, induce autophagy and prolong life in the body. In clinical trials, D-glucosamine can alter gut bacteria. The study examined the effect of five months of D-glucosamine administration on the fecal microbiota of mice. The α-diversity and species richness of gut microbes did not change, but the relative abundance of several beneficial bacteria was significantly higher than that of the high-fat diet control group, and the treatment inhibited the increase of some harmful bacteria.
Allulose is a low-calorie sugar substitute that is generally safe to consume by altering glucose homeostasis through glucokinase and prolonging life through AMPK (AMP-activated protein kinase). D-allulose (Dallulose) alters the relative abundance of gut bacteria by altering the diversity of gut microbes. It has also been shown to interact closely with candidate genes and microbes to reduce weight gain and inflammation. Studies have also shown that D-allulose increases the abundance of lactobacilli and faecococcus in the composition of the gut microbiota.
D-allulose (Dallose) is an isomer of D-allulose that has a variety of beneficial effects, such as antihypertensive, antitumor, and protective effects against ischemia-reperfusion. Recently, it has been reported that it can affect lifespan, however it is not absorbed by the small intestine and then flows into the large intestine and eventually reaches the feces, so it is expected to affect the gut microbiota. At present, there are no reports of D-allulose altering the intestinal microbiota in humans.
Effects of rapamycin, resveratrol, and polyamines on the gut microbiotamine
Rapamycin is widely used in biomedical science as a mammalian target inhibitor of the drug rapamycin, and it is a drug used to prevent organ rejection in organ transplantation or to treat lymphangioleiomyomatosis. But it can suppress the immune system, which makes it difficult to fight infections. Rapamycin substantially regulates protein homeostasis, cell proliferation, and inflammation. Rapamycin can increase the lifespan of adult mice by 30%, but no clinical studies have reported on the effects of rapamycin on the gut.
Resveratrol is a natural polyphenolic phytoanxin found mainly in red wine, and it is a compound found in certain plants that can be taken as a dietary supplement. This polyphenol has been intensively studied as a compound that activates sirtuin1 or invertebrate homologues, which protects organisms from ROS and exerts its antioxidant effects by activating SIRT2 to deacetylate peroxide-reducing protein 1. It improves the imbalance of intestinal flora caused by a high-fat diet. Mechanisms include increasing the abundance of Lactobacillus and Bifidobacteria and decreasing the Bacillus/Bacteroidetes ratio by inhibiting the growth of Enterococcus faecalis, and promoting the diversity of the gut microbiota. It attenuates trimethylamine-N-oxide-induced atherosclerosis by remodeling the intestinal flora.
Polyamines are organic compounds that contain more than two amino groups, such as putrescine, spermidine, and spermine. Polyamines are natural compounds found in a variety of foods that play a role in many physiological processes. Polyamines are involved in many cellular processes, including DNA maintenance, RNA processing, translation, and protein activation. Spermidine is present in many fermented foods and is well studied, and spermidine administration can prolong the lifespan of mice by inducing autophagy and improve cardiac dysfunction and metabolic syndrome. Gut bacteria-promoted polyamine production has been shown to prolong mouse lifespan. In one study, spermidine altered the composition of the gut microbiota in obese mice by increasing the abundance of organic bacteria.
A healthy gut environment means that the gut has a good balance of beneficial microbes and avoids harmful microbes. This can be manifested in several ways, such as regular bowel movements, no gastrointestinal diseases, no chronic inflammation, a strong immune system, and normal nutrient absorption. Basically, it's about having a well-functioning gut that keeps you healthy. In this study, CRM may prolong life in part through the gut microbiota, all of which alter the gut-like microbiota.
Table 2. Effect of CRMs on gut microbiome
In addition, CRM does not necessarily increase the diversity of gut microbes, it increases the abundance of one or more specific beneficial species. It appears to be beneficial in modifying the microbiota, especially in terms of diabetes and anti-obesity, and some CRMs have also reduced the number of harmful species. CRM can also be used as a next-generation prebiotic because it selectively promotes the growth of gut bacteria.
Recently, important papers have been published on the relationship between gut microbiota and longevity, suggesting that gut microbiota may play a role in promoting healthy aging and longevity, and that higher levels of SCFAs in stool samples are associated with longer lifespan, suggesting that gut microbial metabolism may be an important factor in promoting healthy aging. Another research team found that gut microbiota diversity is related to biological age, suggesting that gut microbiota may play a role in regulating the aging process.
(The picture comes from the Internet)