Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus

Rithwik Narendra^{1

2}, Hoang Van Phan¹, Sarah L Patterson³, Ana Almonte-Loya^{4

5}, Emily C Lydon¹, Cristina Lanata⁶, Christina Love¹, Joonsuk Park², Michiko Shimoda⁷, Lisa Barcellos⁸, Honey Mekonen⁸, Angela Detweiler⁸, Padmini Deosthale¹, Norma Neff⁸, Lindsey A Criswell⁶, Lenka Maliskova⁴, Walter Eckalbar⁴, Gabriela K Fragiadakis^{3

5}, Jinoos Yazdany³, Maria Dall'Era³, Patricia Katz³, Chun Jimmie Ye³, Marina Sirota^{5

9}, Charles R Langelier^{1

10}

Affiliations

¹ Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA 94143, USA.
² University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Division of Rheumatology, University of California, San Francisco, San Francisco, CA 94118, USA.
⁴ UCSF Co-Labs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ National Human Genome Research Institute, Bethesda, MD 20894, USA.
⁷ Department of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
⁸ University of California, Berkeley, Berkeley, CA 94720, USA.
⁹ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Chan Zuckerberg Biohub San Francisco, San Francisco, CA 94158, USA.

PMID: 40561001
DOI: 10.1126/scitranslmed.adt5550

Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus

Rithwik Narendra et al. Sci Transl Med. 2025.

. 2025 Jun 25;17(804):eadt5550.

doi: 10.1126/scitranslmed.adt5550. Epub 2025 Jun 25.

Authors

Affiliations

¹ Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA 94143, USA.
² University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Division of Rheumatology, University of California, San Francisco, San Francisco, CA 94118, USA.
⁴ UCSF Co-Labs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ National Human Genome Research Institute, Bethesda, MD 20894, USA.
⁷ Department of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
⁸ University of California, Berkeley, Berkeley, CA 94720, USA.
⁹ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Chan Zuckerberg Biohub San Francisco, San Francisco, CA 94158, USA.

PMID: 40561001
DOI: 10.1126/scitranslmed.adt5550

Abstract

In the general population, aging is associated with an increase in systemic inflammation and chronic disease burden. However, in systemic lupus erythematosus (SLE), older age is uniquely associated with a decrease in disease activity, suggesting a distinct relationship between aging and inflammation. Using a multiomic approach, we compared aging-related changes in the peripheral blood immune profiles of 287 patients with SLE and 928 healthy controls. In patients with SLE, aging correlated with lower expression of interferon (IFN)-stimulated genes (ISGs) across multiple cell types, decreased plasma IFN-α2, and differential genome methylation. Both patients with SLE and controls demonstrated age-related declines in naïve T cells, but only patients with SLE exhibited increases in CD56^dim natural killer cells with older age. Of the genes both down-regulated and hypermethylated with older age, ISGs were disproportionately represented, suggesting a role for epigenetic silencing. Altogether, we found that patients with SLE exhibit unique aging-related decreases in IFN signaling that correlate with improved disease activity.

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Update of

Epigenetic attenuation of interferon signaling drives aging-related improvements in systemic lupus.
Narendra R, Phan HV, Patterson SL, Almonte Loya AL, Lanata C, Love C, Park J, Lydon EC, Shimoda MA, Barcellos L, Mekonen H, Detweiler A, Deosthale P, Neff N, Criswell LA, Maliskova L, Eckalbar W, Fragiadakis G, Yazdany J, Dall'Era M, Katz P, Ye CJ, Sirota M, Langelier CR. Narendra R, et al. medRxiv [Preprint]. 2025 Jan 28:2025.01.27.25321143. doi: 10.1101/2025.01.27.25321143. medRxiv. 2025. Update in: Sci Transl Med. 2025 Jun 25;17(804):eadt5550. doi: 10.1126/scitranslmed.adt5550. PMID: 39974140 Free PMC article. Updated. Preprint.

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Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus

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Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus

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