The analysis of the extreme limits of human life span can provide a better understanding of how human beings can escape, delay, or survive the most frequent age-related diseases. For this purpose the study of extremely long-lived individuals can provide hints of considerable interest. Longevity is a particularly complex trait, with genetic, environmental, and lifestyle factors all contributing to the individual’s likelihood of reaching an advanced age.
Because it is conditional on both metabolism and the immune system, the population of microbes in the intestine (known as the intestinal microbiota) has been proposed as a possible factor in healthy aging. Indeed, the preservation of homeostasis in the intestinal flora can counteract inflammation, intestinal permeability, bone loss, and cognitive decline.
In recent years, the scientific community has focused on the study of the intestinal microbiota and its genetic makeup (known as the microbiome, or MB). The MB is nothing but a complex microbial community consisting of thousands of different species and essentially composed of bacteria, viruses, fungi and in some cases protozoa that live in symbiosis within the digestive tract, in the genitourinary apparatus, in the respiratory system and on the skin.
Our body offers an extraordinary food supply for these communities, which have adapted over the millennia to the oxygen-free environment of the gastrointestinal tract of mammals and have developed a symbiotic relationship with us. With our nutrition, we provide energy and protection to these colonies, while they promote the production of various substances useful for our metabolism. Their number is particularly high in the small intestine and colon. It is estimated that their total combined weight can reach one kilogram, and that their cells are ten times more numerous than the human ones in a given person’s body. (Each individual bacterial cell is far smaller than a human cell.) This complex and varied living system is endowed with its own genomic outfit that potentially interacts with the host and conditions its metabolism. Humans have about 60,000 genes; of these, only about 35,000 are active. If we consider only the bacteria of the intestinal MB, the total number of their genes exceeds three million. By virtue of this impressive figure, we are increasingly talking about the intestinal metabolome, consisting of billions of microorganisms and thousands of different species with millions of genes.
If you raise a mouse in the laboratory in conditions of complete sterility (free of all microorganisms), normal development will not occur. The mouse will remain very thin, and if it is later introduced into a non-sterile environment, will quickly die of infection. Without a healthy population of intestinal bacteria, the mouse does not develop an immune system capable of protecting it from environmental microbial contamination. One of the core activities of the gut microbiome (GM) is to stimulate and educate the immune system. Another important role concerns the control of metabolism. Non-digestible dietary fiber is degraded by intestinal bacteria and is transformed into a variety of metabolic products, such as short-chain fatty acids, some of which are useful to the human host. Overall, the GM is responsible for 40% of our metabolism.
It has also been found that people with obesity have an MB that differs from that of thin people. Some studies in the laboratory have shown that if you isolate the MB of a fat mouse and transplant it into the intestine of a lean mouse, the new host will also become fat, and vice versa. The interactions that the MB has with the central nervous system and other body systems are radical and complex. The brain, digestive tract, liver, pancreas, adipose tissue, and MB are constantly in communication with each other through a route known as the Nutrient Sensor Pathway. Studies have shown that, through this system, the intestinal MB is able to regulate the absorption of nutrients at the intestinal level. Depending on the characteristics of foods, such as carbohydrate composition and the presence of dietary fiber, the MB modulates the central nervous system, allowing the absorption of more or fewer nutrients. (This is known as the second meal effect.) It is clear that the concept of calories in food must be re-evaluated in virtue of these new discoveries. Any discussion of energy balance in the body must consider the fact that the energy absorbed from food, as well as the production of insulin by the pancreas (which affects the use of that energy within the body), is regulated by the Nutrient Sensor Pathway.
The characteristics of the environment and diet in the first years of life are crucial for the characterization of intestinal GM. This process, known as imprinting, determines the metabolic characteristics of the individual for life. Especially during the first 7 years of life, the environment, diet, and overall lifestyle have a influence on the balance of species constituting the MB. Beginning during childbirth, microbes pass from the mother into the intestine of the newborn, so that there is a transmission of environmental data even in the first moments of life. This set of bacterial flora, which in the adult contains about 600 genera and over 40,000 species of bacteria, can contain tens of billions of units. In a sense, it constitutes a true multicellular organism, which continuously receives and transmits information to its human host.
In obesity, the mother of all so-called non-communicable diseases (such as tumors, diabetes, and ischemic heart disease), the microbiota may be the cause of weight gain, or may affect the response to therapy. In 2013, a major study on obesity and diabetes was published in the New England Journal of Medicine. The research was carried out on a pair of homozygous (genetically identical) twins raised in different environmental contexts, resulting in one twin developing obesity while the other did not. It was discovered that by transplanting a sample of MB from the obese subject to a mouse, the latter began to gain weight. There were two experiment showed two particularly interesting aspects of these results. One was that the condition of obesity is not exclusively dependent on genetic characteristics; although the subjects were genetically identical, only one twin was obese. The second interesting finding was that fecal transplantation only from the obese twin was sufficient to alter metabolism in the normal weight mouse.
Recent data have identified a sort of extreme longevity signature in the tested Sardinian centenarians: the high frequency of the genus Eubacterium limosum in their microbiota. It is well established that Sardinia is one of the areas of the planet with the highest prevalence of centenarians, who are characteristically and unusually male. These findings make the microbiome an ideal candidate for further studies on aging markers and age-related disease, disability, and mortality.