Why Lupus May Ease With Age for Some Older Adults

For decades, systemic lupus erythematosus has defied easy prediction.

Its immune-fueled attacks on the kidneys, heart, skin, and joints often strike in early adulthood and persist for years. But for some older adults, lupus symptoms mysteriously ease in their 60s and 70s. Now, scientists at UC San Francisco believe they know why: the immune system’s overactive antiviral defenses start to quiet with age.

Turning Down the Volume on Interferons

In a study published in Science Translational Medicine, researchers analyzed blood samples from nearly 300 lupus patients across the age spectrum and compared them to over 900 healthy controls. They focused on a group of genes known as interferon-stimulated genes (ISGs), which produce powerful antiviral proteins but can also trigger autoimmune damage in lupus.

“I see my younger lupus patients in their 20s, 30s, and 40s every few months, monitoring them closely for signs of severe disease, but many of my older patients just once a year to touch base,” said Dr. Sarah Patterson, assistant professor of medicine in UCSF’s division of rheumatology. “If patients make it through those risky decades, they sometimes see a dramatic improvement.”

The research showed that in healthy individuals, inflammation-related gene expression increased slowly over time—a trend known as “inflammaging.” But in lupus patients, these same immune genes started abnormally high in mid-life and then declined with age, especially those related to interferons.

Key Findings From the Study

• In lupus patients, expression of interferon-stimulated genes dropped significantly with age
• Plasma levels of interferon-alpha-2, a major inflammatory molecule, also declined
• These changes were linked to specific DNA methylation patterns, suggesting an epigenetic switch
• Only lupus patients—not healthy controls—showed these unique age-related changes

“Inflammaging seemed to be reversed in the lupus patients,” said Dr. Charles R. Langelier, senior author and associate professor of medicine at UCSF. “But it wasn’t fully reversed. The lupus patients still had a greater level of inflammatory signaling compared to healthy adults in older age.”

Epigenetics and the Path to Relief

The team found that interferon-related genes were not only expressed less but also showed signs of being epigenetically silenced through DNA methylation. That suggests aging may trigger changes in gene regulation that naturally dial back lupus inflammation.

Both healthy and lupus groups showed expected age-related declines in naïve T cells, which are important for immune defense. But only lupus patients saw an increase in a specific subset of natural killer cells with age, possibly contributing to symptom relief.

Next Steps: Timing Therapies to Age

The UCSF team now plans to explore whether medications that block interferons should be tailored to a patient’s age. Since younger adults with lupus have high interferon activity, they may benefit more from these drugs than older adults whose immune systems are already calming down.

The researchers also hope their multiomic approach can be used to study other age-related diseases with immune components, including rheumatoid arthritis, atherosclerosis, and COPD.

“We’re learning that aging doesn’t just increase inflammation in everyone the same way,” said Patterson. “For some diseases, like lupus, age may actually bring relief.”

Journal and Funding Information

Journal: Science Translational Medicine

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

DOI: 10.1126/scitranslmed.adt5550

Funding: NIH (R01 AR069616, K23AT011768, P30 AI027763), CDC, and the Chan Zuckerberg Biohub