Today's open access research is an interesting demonstration of the importance of chronic inflammation in aging. Researchers generate a mouse lineage in which the NLRP3 gene is deleted, and show that these mice live significantly longer, and in better health, as a result. The protein produced from the NLRP3 gene is important in the innate immune response; it is a component part of one of the inflammasomes, protein complexes with a central role in regulation of the inflammatory response. NLRP3 appears important in the inflammatory signaling generated by senescent cells as well.
Inflammation is a necessary part of wound healing and defense against pathogens, among other processes. It isn't plausible to build a better mouse by simply disabling large parts of the immune response, as is reported here. Such mice can live longer in ideal circumstances, but probably won't do very well in a natural environment. The utility of this sort of research is not as a blueprint for human therapy, but rather to provide some idea as to the size of benefits that might be realized through success in addressing the problem of chronic inflammation in aging.
Periodic removal of senescent cells via senolytic therapies is the first concrete step forward to an old age free from chronic inflammation. These errant cells grow in number with age, and their secretions drive a sizable fraction of age-related chronic inflammation. Then we might look to methods of restoring a youthful immune system: restoration of the thymus, replacement of the hematopoietic stem cell population, and clearing out the malfunctioning immune cells that accumulate over the years. There are other mechanisms beyond these that may also be significant in spurring inflammation in aged tissues. Given the means to address them, old age might be made far less terrible.
Markers of inflammation have been associated with cardiovascular diseases and proposed as other cardiovascular risk factors. Recently, the role of the NLR family pyrin domain containing 3 protein (NLRP3) inflammasome has been studied in cardiovascular diseases. NLRP3 inflammasome is upregulated after myocardial infarction, atherosclerosis, ischemic heart disease, diabetic cardiomyopathy, chronic heart failure, and hypertension, and recently, NLRP3 and IL-1β have also been proposed as new cardiovascular risk biomarkers.
Previous studies have suggested a role for NLRP3 inflammasome in several events associated with aging. Genetic deletion of NLRP3 in mice has been shown to improve healthspan by attenuation of multiple age-related degenerative changes, such as glycemic control, bone loss, cognitive function, and motor performance. Furthermore, the deletion of NLRP3 in old mice increased muscle strength and endurance and prevented from age-related increase in the number of myopathic fibers. However, the role of the NLRP3 inflammasome in lifespan and cardiac aging has not been studied. Hence, we sought to determine whether or not genetic deletion of NLRP3 may have effect on lifespan and potentially prevent cardiac aging.
To evaluate the impact of NLRP3 deletion on survival and metabolic changes during aging, we followed NLRP3 deficient (NLRP3 -/-) and NLRP3 +/+ littermate control wild type (WT) mice throughout the entire lifespan. The survival of NLRP3 -/- mice compared to littermate controls was augmented with an increase in mean lifespan of 34% and in maximum lifespan of 29%, while body weights and food intake did not differ between the two groups during the entire observation period. Fasting blood glucose and circulating IGF-1 levels were reduced in young and old NLRP3-/- mice, indicating that the insulin sensitivity of these animals was considerably higher than sham controls during aging. Reduced levels of glucose and IGF-1 have been associated with stress resistance and an antiaging effect.
Heart weight normalized to body weight was increased in old mice in comparison with young mice, and heart weight was higher in WT in comparison with NLRP3-/-. Cardiac hypertrophy measured by the left ventricular wall thickness was significantly increased in elderly WT when compared to NLRP3-/- mice. From electron microscopic analysis, we corroborated that the numbers of accumulated autophagosomes were reduced in hearts from NLRP3-/- old mice. This could be explained by where NLRP3 inhibition induced improved autophagy quality in the heart during aging.