Today I noticed a set of interesting research materials in which researchers report on their investigation of links between chronic inflammation and intestinal dysfunction in aging. Growing inflammation is characteristic of aging in an age in which near everyone puts on a great deal of weight as they get older. Visceral fat tissue produces excessive inflammation through a number of mechanisms, which is one of the ways in which its presence accelerates the onset of all of the common age-related diseases. But even putting fat tissue to one side, aging is still accompanied by ever greater levels of chronic inflammation, a consequence of the progressive failure of the immune system, hampered by the fundamental cell and tissue damage of aging on the one hand, and on the other by limits to capacity that are inherent in the way in which it is structured. Unregulated inflammation due to immune system malfunction, either in the innate or adaptive components, is called inflammaging and considered by some to be a distinct process from immunosenescence, the inability of the immune system to effectively combat pathogens and destroy unwanted cells.
Intestinal dysfunction is a central feature of aging in lower species such as flies, and measures of aging in the intestines can predict mortality in this species. Further, a number of the methods shown to slow aging in flies appear to work through improved stem cell activity in intestinal tissues. Flies are not people, however, and it isn’t at all clear that the intestines have anywhere near the same degree of prominence in mammalian aging. If anything, that position should probably go to the cardiovascular system in our own species, given our mortality breakdown, and the way in which cardiovascular aging correlates well with many other forms of ultimately fatal age-related disease. Still, there is an increasing interest these days among aging researchers in the microbiome that dwells within the gut, and the roles that this microbial ecosystem might play in aging, especially as tissue function begins to break down, and as the immune system becomes more easily aggravated and less effective. Considered in the bigger picture, the open access paper here makes for interesting reading; you might just skip the publicity materials.
Researchers have identified the aging mechanisms of animals resulting from intestinal inflammation accumulation. So far, numerous hypotheses explaining animal aging have been published and one of them is inflammation-induced aging which proposes that accumulation of inflammation is the cause of animal aging. While inflammation-induced aging theory has been one of many hypotheses explaining the aging of animals, its substance has not been clearly proven. The research team has discovered that the pericytes surrounding the endothelial cells in the intestinal tissues decrease as an animal’s biological age increases and thus the blood vessel function deteriorated, including the progress of vascular leakage. Through the experiment, this study has shown that this phenomenon is due to the increase of gut-resident inflammatory cells (macrophages) and the increase of TNF-α, cytokine secreted by these cells, as well as the entailed changes in the surrounding environment of blood vessel.
“This study is significant as we have newly identified the mechanisms of aging associated with inflammation increase and opened possibilities of applied researches on aging delay through inflammation control as well as anti-aging. We will conduct follow-up studies to find ways to extend human health life by controlling inflammatory cells and vascular leakage to delay aging.” This study will open a new chapter in anti-aging, a long standing challenge for mankind. It is expected that the follow-up studies on intestinal inflammation control will make a great contribution to the development of various technologies that can practically delay aging. For these purposes, it is required to explore a variety of candidate substances that are able to control gut-resident inflammation and conduct clinical researches on them.
Of many proposed mechanisms underlying aging, inflammaging theory proposes that chronic low-grade inflammatory status caused by life-time exposure of animals to a variety of antigens contributes to age-associated morbidity and mortality. An hallmark of age-associated chronic inflammation would be macrophage infiltration. In intestine, the epithelial lining separates internal organs from the enteric environment loaded with various foreign substances including microbiota and its metabolic products as well as nutrients and wastes. The lamina propria (LP) lying beneath the enterocytes in the intestinal villi especially that in the lower part, houses a largest pool of macrophages for maintaining mucosal homeostasis against the gut microbiota and for the constant need of epithelial renewal. Age-associated deterioration of gastrointestinal function could be ascribed to inflammaging, although substantial evidence is yet to emerge.
In this study, we propose that the antigenic burden encountered in the intestine causes macrophage infiltration during the first few months after birth and that is sustained throughout life. Under the condition of chronic inflammation, it stands to reason to polarize macrophage toward the M2-like subtype to avoid tissue injury and eventual chaotic consequences caused by activated M1 macrophage. Consistently, it has been reported that total macrophages and myeloid derived suppressor cells cumulated in the spleens and bone marrow of aged mice were mostly anti-inflammatory M2 cells in aged mice. Macrophages are the sources of both pro-angiogenic and anti-angiogenic factors, which can differentially guide vascular network formation under many pathological conditions. We therefore propose that TNF-α derived from the macrophages in aged animals skews the angiopoetin-TIE-2 signaling in vascular endothelial cells to inflammatory settings that would facilitate recruitment of immune cells through endothelial cells. Such increase in vasculature permeability entails modulation of the endothelial cell network such as loss of VE-cadherin and pericyte, as demonstrated in this study. Together, our study demonstrates for the first time, to the best of our knowledge, that sustained aggravation of inflammation leads to age-related structural changes in organ.
Another item to consider here is a possible role for cellular senescence in these interactions, though this is not mentioned by the researchers. Senescent macrophages have been proposed to play a significant role in other inflammatory conditions, such as the development of atherosclerosis. Senescent cells produce inflammation in and of themselves, and so this might form the basis for a feedback loop of accelerated dysfunction in any situation in which macrophages accumulate over course of aging. Senescent macrophages have been identified in other tissues, so this doesn’t seem like a great leap, and possibly worth further investigation in the context of this research.