Innate Immune Activation as a Contributing Cause of Inflammaging, Reduced by Calorie Restriction
The immune system becomes ever more inflammatory with advancing age, a state known as inflammaging, even as it loses competence in destroying pathogens and unwanted cells. This sustained, unresolved inflammation is harmful, the cause of numerous harmful changes in cell function and failures of tissue maintenance. It accelerates the onset and progression of all of the common age-related conditions. This is caused in part by the pro-inflammatory signaling of senescent cells, present in increasing numbers in the aged body. Another important contribution, and a focus in today's open access paper, is the activation of innate immune cells by signs of cell dysfunction and damage such as DNA debris. These are known as damage associated molecular patterns (DAMPs), and their presence is characteristic of aging, provoking the innate immune system into overactivation.
What can be done to minimize inflammaging? Blocking specific inflammatory signals can reduce inflammation, as established therapies for autoimmune conditions demonstrate, but at the cost of further reducing the effectiveness of the immune system. This type of strategy blocks both necessary and excessive inflammation. Compare this with removal of senescent cells via senolytic therapies, an approach that does only remove the excessive inflammatory signaling. Is it possible to remove DAMPs, and thereby prevent activation of the innate immune system? Not at present. The only practical way to reduce DAMPs is to modestly slow aging as a whole, achieved via life-long strategies such as calorie restriction. We can hope that progress will be made towards better approaches in the years ahead, but this sort of strategy is not a focus in today's research community.
A prominent aging-associated condition is a chronic inflammation referred to as "inflammaging," a pro-inflammatory phenotype that accompanies aging in mammals. Inflammaging is a highly significant risk factor for most, if not all, aging-related diseases including obesity and type 2 diabetes, cardiovascular diseases, Alzheimer's disease, and cancer, as well as vulnerability to infectious disease and vaccine failure.
Dietary restriction (DR) decreases the calorie intake without inducing malnutrition. Lifetime DR is a non-pharmacological intervention that can extend the lifespan in a wide range of organisms. It has been shown that long-term DR (LTDR) also reduces some aspects of inflammation, leading to the hypothesis that a life-long energy accumulation can be the origin of chronic inflammation. A very recent study carried out in rats has shown that late-life DR attenuated aging-related changes in cell type composition and gene expression, and reversed the aging-associated increase of senescence markers and alterations of the immune system. However, it is still largely unknown which signaling pathways and networks regulate the induction of inflammaging across tissues and whether DR could have an impact on rescuing such systemic induction of inflammaging.
In this study we employ a transcriptome-wide and multi-tissue approach to analyze the influence of both LTDR and short-term DR (STDR) at old age on the aging phenotype. We were able to characterize a common transcriptional gene network driving inflammaging in most of the analyzed tissues. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. We also found that both DR interventions ameliorate this inflammaging phenotype, albeit with some differences mainly at tissue-specific level. Further chromatin accessibility analysis showed that DR can also rescue the aging-associated epigenetic alteration on the inflammaging-related genes, but not the genome-wide impairment of chromatin that accompanies old cells.
In this study, we showed that aging changed the transcriptome of different tissues and that DR was able to partially rescue the age transcriptome. DR intervention in late life has been recently shown to not provide as beneficial effects as long-life DR in lifespan and healthspan extension. For this reason, we compare old mice with mice treated with both a lifetime DR (LTDR) and a short-term DR at late life (STDR). We found that responses to the aging, LTDR, and STDR both in magnitude and functional aspects were tissue specific. LTDR has been previously shown to strongly prevent a pro-inflammatory phenotype in aged white adipose tissue pre-adipocytes, whereas a late-onset DR failed in preventing it. Our data show that LTDR was more effective in rescuing inflammaging in liver and kidney, while STDR mitigated aging-associated activation of inflammatory pathways more effectively in blood; in other tissues both LTDR and STDR prevented the pro-inflammatory phenotype to a similar extent.