Tildrakizumab Partially Reverses Epigenetic Aging in Psoriasis, Pilot Study Shows

A 52-week open-label study found tildrakizumab-asmn (Ilumya; Sun Pharmaceutical Industries) partially reversed a marker of epigenetic aging in patients with moderate to severe plaque psoriasis. The interleukin-23 (IL-23) inhibitor lowered a mortality-associated DNA methylation clock by a median of 0.3 years at week 28 and 0.5 years at week 52, according to results published in the Journal of the American Academy of Dermatology. The reduction paralleled clinical clearance, with mean Psoriasis Area and Severity Index (PASI) scores falling from 18.8 at baseline to 1.9 at week 52. The new data offer the first prospective evidence tying IL-23 inhibition to partial reversal of a mortality-predictive aging signature.¹

Tildrakizumab Trial Design and Epigenetic Aging Results

The single-center, phase 4 trial (NCT05110313) enrolled 20 adults aged 35 years and older with moderate to severe plaque psoriasis, defined by a PASI score of 12 or higher and body surface area involvement of 10% or greater. Participants received tildrakizumab-asmn 100 mg subcutaneously at weeks 0, 4, 16, and 28, following the approved dosing label. Ten age- and sex-matched adults without psoriasis served as a baseline comparison group.¹

Researchers profiled genome-wide DNA methylation in peripheral blood using the Illumina MethylationEPIC v2.0 array to calculate multiple epigenetic clocks, including several trained to predict all-cause mortality. At baseline, patients with psoriasis showed significantly greater epigenetic age deviation than controls on mortality-predictive clocks, including PCGrimAge (P = .008), CpGPTPCGrimAge3 (P = .019), CpGPTGrimAge3 (P = .019), and GrimAge2 (P = .049). The pace of biological aging, measured by DunedinPACE, was also elevated in patients with psoriasis (P = .049).¹

Following treatment, PCGrimAge deviation fell by a median of 0.3 years at week 28 (P = .005) and 0.5 years at week 52 (P = .04), a reduction persisting 24 weeks after the final injection. Clinical response tracked alongside the biological change, with mean PASI scores dropping from 18.8 at baseline to 2.2 at week 28 and 1.9 at week 52.¹

Secondary Epigenetic Markers and Safety Monitoring with Tildrakizumab

Additional DNA methylation markers shifted alongside the primary mortality clocks. A smoking-exposure surrogate and an inflammation-linked marker (PCPAI1) improved by week 28, and a marker of tissue inhibitor of metalloproteinases-1 (PCTIMP1) reached significance by week 52 (P = .026).¹

Clocks tracking chronological rather than biological age, including AltumAge and PCHorvath1, continued to advance at the expected rate during treatment. The authors said this pattern supports specificity of the mortality-clock findings rather than a uniform slowdown of all methylation signals.¹

The study protocol included routine safety monitoring at each visit, including complete blood counts, liver enzymes, renal function tests, and tuberculosis (TB) screening, consistent with the approved tildrakizumab-asmn label. (The official FDA label does not mandate routine laboratory screening prior to starting treatment, but Ilumya’s prescribing information recommends TB screening before initiating treatment.)

Study Limitations: Size and Follow-up Assessments

The published results did not report adverse event rates or discontinuations, and the authors described the analysis as a pilot study limited by its small sample size. They noted the control group was assessed at a single time point and post-week-28 treatment exposure was not collected prospectively, limiting interpretation of the week 52 findings.¹

"The observed reversal of PCGrimAge with IL-23 inhibition might be biologically and clinically meaningful," the authors wrote.¹

Authors Compare Their Findings to Other Interventions

The authors compared the findings with other pharmacologic aging interventions. The 0.3-year PCGrimAge reduction at 28 weeks exceeded the 0.06-year change reported in the COSMOS multivitamin-mineral trial² but was smaller than the 2.7-year reduction reported with semaglutide in HIV-associated lipohypertrophy.³ They said the results support DNA methylation clocks as treatment-sensitive biomarkers in immune-mediated disease, with potential relevance to personalized, long-term psoriasis management.¹

Conclusion

Psoriasis carries an elevated, cardiovascular-risk-independent mortality burden, and this trial's partial reversal of a mortality-predictive DNA methylation clock with IL-23 inhibition adds a mechanistic layer to what dermatologists know about biologic therapy and cardiometabolic risk.¹

Confirmation in larger, controlled cohorts is needed before DNA methylation clocks could inform treatment selection or counseling, but the durability of the PCGrimAge effect through week 52 supports further investigation. Until then, the authors concluded that “these findings may have significant implications for personalized treatment strategies focusing on long-term health of individuals with psoriasis.”¹

References

1. Macit B, Benca-Bachman CE, Qureshi A, et al. The effects of tildrakizumab in the epigenetic aging deviation of psoriasis: a 52-week open-label study.J Am Acad Dermatol.2026;19:S0190-9622(26):03368-2. doi:10.1016/j.jaad.2026.08.051

2. Li S, Hamaya R, Zhu H, et al. Effects of daily multivitamin-multimineral and cocoa extract supplementation on epigenetic aging clocks in the COSMOS randomized clinical trial. Nat Med. 2026;32(3):1012-1022. doi:10.1038/s41591-026-04239-3

3. Corley MJ, Dwaraka VB, Pang APS, et al. Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy. Nat Commun. 2026;17(1):6606. doi:10.1038/s41467-026-72861-3