proteasomal degradation with age, thereby impairing the RIG-I primary signaling pathway for type I IFNs. Monocytes from older adults also fail to effectively upregulate the interferon regulatory transcription factor IRF8, compromising their ability to participate in IFN induction through secondary RIG-I signaling [26]. Such RIG-I signaling defects in multiple cell types could likely contribute to increased risk for infection and morbidity and mortality from viral infections in the context of aging. As the innate immune system helps instruct appropriate responses of the adaptive immune system, these innate signaling defects may also contribute to impaired adaptive immunity and vaccine efficacy during aging.
Energy Balance and Inflammation Regulation
Recent progress targeting metabolic programming suggests potential treatment strategies to enhance immune responses in older adults. While several non-pharmaceutical dietary interventions have demonstrated improved longevity in animal models, including calorie restriction, fasting-mimicking diet, and ketogenic diet, few have investigated their impact on immune function during aging [94–97], and this area presents opportunities for future investigation. Many lifespan-extending interventions induce a negative energy balance in which energy expenditure exceeds energy consumption [98–101]. In this adaptive starvation response, the body switches from glucose to lipid breakdown to support energetic requirements via production of short-chain fatty acids such as ketone bodies. Accordingly, ketogenic diets comprised almost entirely of fat and protein actually promote fat break down and weight loss because of this adaptation to low-glucose availability. In addition to serving as an alternative fuel source, the most abundant ketone body, βhydroxybutyrate, potently inhibits NLRP3 inflammasome activation in macrophages, monocytes, and neutrophils from adult and older humans and mice [21, 102] and extends lifespan in Caenorhabditis elegans [103]. Notably, two studies recently reported increased lifespan and improved cognition in old mice fed a ketogenic diet [95, 96]. This highlights the importance of whole-body metabolism in regulating age-related inflammation and presents a critical window for future exploration.
Immune Cell Energy Metabolism
Metabolic programming in immune cells is a critical determinant of their downstream functions and mounting a robust immune response is energetically expensive. Increased glycolysis is generally associated with elevated proinflammatory activity, whereas fatty acid oxidation and oxidative phosphorylation is associated with quiescence and anti-inflammatory functions [104]. At the population level, a balance between these programs allows for proinflammatory immune-mediated pathogen clearance, while preserving tissue repair functions and long-lived immunity in the case of adaptive immune cells. In addition to the importance of overall metabolic programming, specific metabolites such as succinate, itaconate, and β-hydroxybutyrate regulate immune cell function [105, 106]. Therefore, targeting immune cell metabolism represents an attractive strategy for modulating immune responsiveness and vaccine efficacy. It should be noted that the simplified model presented here is derived from mostly in vitro studies and whether this programming balance occurs in vivo or is maintained during aging is not known. Future studies are needed to test whether basal metabolic programming and/or activation-induced metabolic upregulation in innate immune cells is retained during aging and what cues stimulate this reprogramming.
Bioactive Lipids
In addition to metabolic programming, dietary metabolites can have important cell signaling functions. While we have focused on innate immune activation defects that contribute to increased infection susceptibility in the elderly, an equally important aspect of the innate immune system is the resolution of inflammation. Key to resolution is a family of pro-resolution bioactive lipid mediators synthesized from omega-3 fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – the resolvins, lipoxins, and maresins [107]. Aged mice exhibit delayed bacterial clearance and have reduced levels of these pro-resolving lipid metabolites [108]. Innate immune cells are capable of metabolizing DHA and EPA to generate these metabolites, and this improves efferocytosis in human monocytes [108]. Finally, MerTK-dependent ERK activation induces pro-resolving lipoxin LXA4 production in human monocyte-derived macrophages [109]. Perhaps age-related changes in tissue milieu can be restored by improving inflammation resolution in the elderly. Future investigations in this domain are warranted to explore their potential for dampening chronic inflammation during aging to improve innate immunity.
Perspectives and Future Directions
The impact of chronic inflammation on innate immunity, both within immune cells and their tissue microenvironment, highlight a critical area for future investigation and potential novel therapeutic interventions. As we have described, multiple interconnected deficits arise during aging, both within innate immune cell subsets and the tissue milieu, to impair in vivo innate immunity in the elderly. With these complex layers of regulation, it remains challenging to fully define mechanisms of innate immune deficiencies. Collectively, these defects lead to poor priming of the adaptive immune system, culminating in poor immune protection and vaccination in the elderly. Given that in vitro stimulation of isolated circulating immune cells probably does not fully reflect their responsiveness within the tissue milieu, future studies will require appropriate in situ tissue studies and animal models. Along with development of new approaches to define age-related defects in innate immunity, a critical priority is novel therapeutic interventions targeting systemic inflammation to address immune dysfunction and enhance healthy life-span.
Acknowledgements
The authors wish to thank their research groups and members of the Yale Center for Research on Aging for helpful discussions and many colleagues whose work could not be cited. This work was supported in part by grants from the NIH (AI 089992 and AG055362 to R.R.M. and A.C.S., and K99-AG058801 to E.L.G.).
Disclosure Statement
The authors have no relevant financial disclosures to report.
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