In the general human population, aging is associated with a rise in systemic inflammation, primarily involving innate immune pathways related to interferon (IFN), toll-like receptor, and cytokine signaling. In systemic lupus erythematosus (SLE), a prototypical systemic autoimmune disease, aging is distinctly associated with improvements in disease activity, suggesting a unique relationship between aging and inflammation in this disease. Using a multi-omic approach incorporating transcriptional profiling, single cell RNA sequencing, proteomics and methylation analysis, we studied age-related changes in the immune profiles of 287 SLE patients between 20 and 83 years old, and compared the results against 928 healthy controls aged between 21 and 89 years old. In contrast to the increase in inflammatory gene expression that occurs with aging in most healthy adults, SLE patients exhibited the opposite. Most notable was a decrease in type I IFN signaling that was evident across multiple cell types, with CD56-dim natural killer (NK) cells, CD4+ effector memory T cells, and naive B cells exhibiting the most significant differences. We found that aging in SLE patients was also associated with decreased IFN-a2 and IFN-l1 levels, and differential methylation of the genome. Notably, of the genes both downregulated and hypermethylated with older age, IFN-related genes were disproportionately represented, suggesting that age-related decreases in IFN signaling were driven in part by epigenetic silencing. Both SLE patients and healthy controls demonstrated age-related declines in naive T cells and lymphoid progenitor cells, but only SLE patients demonstrated age-related increases in CD56-dim NK cells. Taken together, our work provides new insight into the phenomenon of inflammaging and the unique clinical improvement in disease activity that occurs in SLE patients as they age.

The authors have declared no competing interest.

This work was supported by the US NIH (R01 AR069616, K23HL138461-01A1, K23AT011768,) the US CDC (U01DP0670), and the CZ Biohub.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UCSF Institutional Review Board approved this study (protocol number 14-14429) and informed consent was received prior to enrollment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Genecounts derived from bulk RNA-seq data in the CLUES cohort are available from Gene Expression Omnibus (GEO) under accession number GSE277909. Genecounts from the Rotterdam Study control group are available under GEO accession GSE33828. scRNA-seq genecounts and fastq files are available under GEO accession GSE174188. Annotated scRNA-seq data are available at: https://cellxgene.cziscience.com/collections/436154da-bcf1-4130-9c8b-120ff9a888f2. Source data are provided in the source data file accompanying this manuscript. All code is available via Github at: https://github.com/infectiousdisease-langelier-lab/CLUES_aging.

https://cellxgene.cziscience.com/collections/436154da-bcf1-4130-9c8b-120ff9a888f2.