Editorial: The connections of immune metabolic mechanisms with aging-related diseases
Ozlem Tufanli1† 
Changjun Yin
Emiel P. C. Van der Vorst
Ismail Cimen- 1Altos Labs, Bay Area Institute of Science, Redwood City, CA, United States
- 2Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- 3Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
- 4Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- 5Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen, Germany
- 6Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
Editorial on the Research Topic
The connections of immune metabolic mechanisms with aging-related diseases
Introduction
Aging is a complex phenomenon that causes the accumulation of cellular damage, leading to an increased incidence of major age-related diseases such as cancer, neurodegenerative, cardiovascular diseases (CVD), and immune system diseases (Guo et al., 2022). The main features of aging are known to be metabolic alterations at cellular and systemic levels (Bevilacqua et al., 2023). Metabolic pathways of glucose, lipid, and amino acids have considerable importance in immune cell functions, such as differentiation, migration, and immune responses (Pearce and Pearce, 2013). Immune cells through metabolic pathways produce molecules, metabolites, and energy necessary for the events related with a new cellular state (Riffelmacher et al., 2018). Metabolites are indispensable factors for the immune system involved in both metabolic circuits and signaling cascades. In mammals, the endocrine and nervous systems as well as the microbiota release various metabolites such as neurotransmitters, hormones, bile acids, short-chain fatty acids, and indoles, all of which impact the biology and behavior of immune cells, largely by acting on specific receptors (Zhang et al., 2022).
Among these metabolites, short-chain fatty acids (SCFAs) play an important role in aging related diseases such as cardiovascular diseases (CAD). In this Research Topic, Guo et al. focus on the specific effects of butyrate in human aortic endothelial cells (HAOECs). Butyrate is a gut microbiota-derived metabolite that is associated with vascular integrity and development of CAD. The authors elucidated a mechanism through which butyrate is acting on vascular integrity. They found that butyrate treatment induced phosphorylation of several tyrosine sites on vascular endothelial cadherin (VEC) in HAOECs, with the largest effect seen on tyrosine-731. By performing chemical inhibition and siRNA knockdown experiments, they further demonstrated that the butyrate-induced phosphorylation of VEC was mediated by c-Src kinase and (free fatty acid receptor 2)/FFAR3 (free fatty acid receptor 3) receptors. The butyrate-induced VEC phosphorylation was ultimately associated with remodeling of junctional VEC and increased endothelial cell permeability. Hence, the study sheds light on the potential impacts of butyrate on CAD Guo et al..
Additionally, caloric restriction (CR) might also affect the aging process by favorably influencing human health, and it is of critical importance for defining the underlying signaling mechanisms of aging (Kim et al., 2020). A recent study has reported that CR imprints immune cells for gaining better control of Mycobacterium tuberculosis (MTB) growth, activating proteolytic processes, being more energetic, and remaining protected against oxidative damage. Moreover, immune cells acquire the capacity to control immunometabolic alterations triggered by MTB infection (Palma et al., 2021). Mechanisms that prolong longevity via CR modulation of autophagic function or epigenetic modifications have also gradually been investigated. In the context of aging, Zhai et al. summarized CR-induced autophagy and epigenetic modifications on both DNA and histones to explore the molecular mechanism of CR to delay aging and age-related diseases, and the interactions between autophagy and epigenetic modifications. Furthermore, they described several calorie-restriction mimetics (CRMs) that exert similar actions on the regulation of autophagy and the epigenome. Precise regulation of autophagy and understanding its molecular interactions with epigenetic modifications may potentially reveal new rejuvenation approaches that can be further explored in the future Zhai et al.
Another process that influences immunometabolism of both innate and adaptive immune cells, and immune responses is autophagy and autophagy-related processes. Santovito et al. have compiled the evidence supporting the role of autophagy in cardiac homeostasis, aging, and cardio immunological response to cardiac injury. As reported in this review, age related dysregulation of autophagy related signaling pathways enhances susceptibility to aging-associated cardiac dysfunction. In addition to this evidence, many studies proved that manipulation of autophagy through several mechanisms such as, ubiquitous overexpression of Atg5, transgenic overexpression of Parkin (mitophagy related gene) reduced aging associated cardiac damage and increased the lifespan in mice. Although strong evidence highlights the potential benefits of autophagy manipulation to revert age-induced cardiac dysfunction, the role of autophagy in ischemia-reperfusion injury is still not entirely understood. Furthermore, autophagy has a crucial role in orchestrating immune cell function and their response to cardiac injury and ischemia. In the final part of this review, the authors summarized recent advances in targeting autophagy in cardiac diseases. Studies suggest that the level of autophagy should be in an optimal zone to be able to get benefit from autophagy targeting drugs. Autophagy levels that are outside of this therapeutic window (higher or lower) can pose a deleterious effect on health. However, there is still a great medical need to identify such proper therapeutical window especially in diseased conditions and for well-tolerated pro-autophagic drugs Santovito et al.
Both innate and adaptive immune cells aggregate to the adventitia and sense atherosclerotic plaques. A more recent study demonstrated that the adventitial neuroimmune cardiovascular interfaces (NICIs) forms a biologically active anatomically discernible structure in which the immune system interacts with both the diseased artery and the nervous system in a tripartite complex tissue network (Mohanta et al., 2022). Mohanta et al. have provided original contributions to this Research Topic by discussing the neuroimmune cardiovascular interfaces in atherosclerosis. Early studies showed that the majority of immune cells accumulated in the adventitia region of late-stage atherosclerosis and large B cell aggregates observed in advanced diseased artery segments. The authors termed these aggregates artery tertiary lymphoid organs (ATLOs) and through a series of imaging and functional experiments, they showed that ATLOs harbor multiple B cell subtypes, plasma cells and separate T cell areas. Axon endings are also highly enriched in these areas, showing sympathetic nervous system restructuring. This expanded axonal network increases with aging. They proposed a direct crosstalk between the diseased arterial wall and both the immune and the nervous system in tripartite rather that bidirectional interactions. As reported in this review further studies should be directed to elucidate more detailed morphology and function of NICIs and characterize the axon tips in the adventitia Mohanta et al.
In summary, this Research Topic highlights several immune-metabolic mechanisms, like metabolites, caloric restriction, autophagy and neuroimmune cardiovascular interfaces that play a key role in aging and aging-related diseases, providing and discussing novel findings fueling this field of research.
Author contributions
OT: Investigation, Writing–original draft. MC: Investigation, Writing–original draft. CY: Writing–review and editing, Conceptualization. EV: Conceptualization, Writing–review and editing. IC: Conceptualization, Supervision, Writing–review and editing, Investigation, Writing–original draft.
Funding
The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Altos Labs Bay Area Institute. This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University to EV. National Natural Science Foundation of China (82270480) to CY
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Bevilacqua, A., Ho, P.-C., and Franco, F. (2023). Metabolic reprogramming in inflammaging and aging in T cells. Life Metab. 2, 28. doi:10.1093/lifemeta/load028
Guo, J., Huang, X. Q., Dou, L., Yan, M. J., Shen, T., Tang, W. Q., et al. (2022). Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther. 7, 391. doi:10.1038/s41392-022-01251-0
Kim, D. H., Bang, E., Jung, H. J., Noh, S. G., Yu, B. P., Choi, Y. J., et al. (2020). Anti-aging effects of calorie restriction (CR) and CR mimetics based on the senoinflammation concept. Nutrients 12, 422. doi:10.3390/nu12020422
Mohanta, S. K., Peng, L., Li, Y. F., Lu, S., Sun, T., Carnevale, L., et al. (2022). Neuroimmune cardiovascular interfaces control atherosclerosis. Nature 605, 152–159. doi:10.1038/s41586-022-04673-6
Mohanta, S. K., Yin, C. J., Weber, C., and Habenicht, A. J. R. (2023). Neuroimmune cardiovascular interfaces in atherosclerosis. Front. Cell Dev. Biol. 11, 1117368. doi:10.3389/fcell.2023.1117368
Palma, C., La Rocca, C., Gigantino, V., Aquino, G., Piccaro, G., Di Silvestre, D., et al. (2021). Caloric restriction promotes immunometabolic reprogramming leading to protection from tuberculosis. Cell Metab. 33, 300–318.e12. doi:10.1016/j.cmet.2020.12.016
Pearce, E. L., and Pearce, E. J. (2013). Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643. doi:10.1016/j.immuni.2013.04.005
Riffelmacher, T., Richter, F. C., and Simon, A. K. (2018). Autophagy dictates metabolism and differentiation of inflammatory immune cells. Autophagy 14, 199–206. doi:10.1080/15548627.2017.1362525
Keywords: immune cells, metabolic mechanisms, immunometabolism, aging-related diseases, metabolites
Citation: Tufanli O, Citir M, Yin C, Van der Vorst EPC and Cimen I (2023) Editorial: The connections of immune metabolic mechanisms with aging-related diseases. Front. Cell Dev. Biol. 11:1295264. doi: 10.3389/fcell.2023.1295264
Received: 15 September 2023; Accepted: 19 September 2023;
Published: 27 September 2023.
Edited and reviewed by:
Ana Cuenda, Spanish National Research Council (CSIC), SpainCopyright © 2023 Tufanli, Citir, Yin, Van der Vorst and Cimen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ismail Cimen, icimen@altoslabs.com
†These authors have contributed equally to this work and share first authorship