Chronic inflammation is an important aspect of aging, a process that stems from low-level biochemical damage and cellular dysfunction, and that then contributes to the progression of age-related disease and tissue dysfunction. Chronic inflammation sustained over years accelerates all of the common fatal age-related conditions: it disrupts tissue maintenance, and leads to fibrosis, immune dysfunction, and many more issues. The chronic inflammation of aging is important enough that beneficial therapies have been built on the basis of suppressing inflammation directly, without addressing its causes. Treatments that actually address the causes should be very much better at the end of the day, of course.
Interventions that have been demonstrated to slow aging in laboratory species tend to act to suppress the age-related increase in inflammation - they would have to, in order to achieve the outcome of a longer, healthier life in these animals. Calorie restriction is the best studied of these interventions, and a wide range of calorie restriction mimetic drugs have arisen from this field of research, compounds that mimic a fraction of the overall metabolic response to a lower intake of calories. Today's open access paper reviews what is known of the way in which mechanisms of the calorie restriction response act to reduce chronic inflammation and its impact on age-related disease.
A sizable fraction of the inflammation of aging arises from the presence of senescent cells. These cells grow in number with age, and their signaling produces a range of detrimental effects on surrounding tissue, of which chronic inflammation is just one - though, as noted here, an important one. Calorie restriction adopted in later life doesn't impact the burden of cellular senescence to anywhere near as great a degree as the use of senolytic drugs can achieve by selectively destroying senescent cells. That point is worth keeping in mind while looking over the paper noted here.
Under certain circumstances such as aging, there is a failure in the resolution mechanisms leading to the chronic activation of immune cells and persistent inflammation. This state of low-grade but chronic inflammation is known as inflammaging, and is characterized by increased levels of pro-inflammatory cytokines in the circulation. Notably, inflammaging is considered a risk factor for many age-related diseases. Even in certain tissues like the brain, that possesses a privilege protection against inflammation, certain signs of inflammation appear gradually with age, and this neuroinflammation can anticipate the appearance of some neurodegenerative diseases. In addition, the integrity of the intestinal barrier is compromised due to inflammatory stress during aging and contributes to the development of several diseases. Finding drugs that protect against inflammaging, the disruption of the intestinal barrier, and neuroinflammation should be a priority for geroscience in the next years.
Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. It is well known that an intense crosstalk exists between mitochondria and autophagosomes, and the activity or stress status of either one of these organelles may affect the other. A mitochondrial or autophagy decline compromises cellular homeostasis and induces inflammation. Furthermore, mitochondrial function and autophagy are key pathways controlling the activation of both the innate and the adaptive immune system. In the last decade, it has become evident that mitochondria are essential organelles that direct the fate of immune cells, giving rise to a new scientific discipline that is called immunometabolism. Moreover, the outcome of the inflammatory response can be controlled by modulating the metabolism of immune cells.
Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.