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. 2025 Nov 14;17(1):190.
doi: 10.1186/s13148-025-02007-7.

Does polypharmacy affect epigenetic aging in older people? Evidence from a longitudinal epigenome-wide methylation study

Alessandro Gialluisi  1   2 , Alfonsina Tirozzi  3 , Simona Costanzo  3   4 , Danilo Licastro  5 , Augusto Di Castelnuovo  3 , Miriam Shasa Quiccione  3 , Stefania Falciglia  6 , Margherita Degasperi  5 , Teresa Panzera  3 , Sara Magnacca  3 , Mariarosaria Persichillo  3 , Fabrizia Noro  3 , Chiara Cerletti  3 , Maria Benedetta Donati  3 , Giovanni de Gaetano  3 , Licia Iacoviello  3   7 ; Moli-sani Study Investigators
Collaborators, Affiliations

Does polypharmacy affect epigenetic aging in older people? Evidence from a longitudinal epigenome-wide methylation study

Alessandro Gialluisi et al. Clin Epigenetics. .

Abstract

Background: Polypharmacy, defined as taking ≥ 5 different daily medications, is common in older adults and has been linked with neuropsychiatric/neurological and other health conditions. To clarify the potential molecular implications, we tested the hypothesis that polypharmacy may influence DNA methylation (DNAm) patterns in aging, in a longitudinal Italian cohort (N = 1,098; mean (SD) age at recruitment: 58.8 (5.6) years, 51.3% women; median (IQR) follow-up 12.6 (1.1) years).

Results: We tested associations of polypharmacy with several DNAm aging clocks (Hannum, Horvath, GrimAge, DNAmPhenoAge, DunedinPACE), through linear mixed models incrementally adjusted for age, sex, education, prevalent health conditions and lifestyles, leukocyte counts and residual batch effects. This revealed significant positive associations of GrimAge acceleration and DunedinPACE with the switch to polypharmacy status during follow-up (Beta (SE): 0.024 (0.008) and0.0012 (0.0004)). While the association of GrimAge was driven by a DNAm-based surrogate of tissue inhibitor metalloproteinase 1 (TIMP-1), no significant association was detected for component CpGs of DunedinPACE. When we tested associations of polypharmacy with 668,413 CpGs epigenome-wide, we observed no statistically significant findings (top hit: cg07675998; chr11q13.1; Beta (SE) = 0.009 (0.002); p = 1.5 × 10-6). However, these showed significant enrichments of several biological functions and pathways related to renal tissue, lipoproteins, inflammatory and immune response.

Conclusions: These findings suggest an influence of polypharmacy on accelerated epigenetic aging and on altered methylation patterns in the genome, suggesting a potential implication of pathways related to renal tissue development, lipoproteins and cholesterol homeostasis, inflammatory and immune response, in line with previous proteomic analyses of polypharmacy mouse models. These observations also suggest potential targets for mitigating disruptive effects of polypharmacy on elderly health.

Keywords: Aging; Chronic health conditions; Elderly; Epigenetic clocks; Inflammation; Neurodegenerative and neuropsychiatric disease; Polypharmacy.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the IRCCS Neuromed (28/02/2018). All participants provided written informed consent. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Participants’ flowchart of the study. Abbreviations: QC = quality control
Fig. 2
Fig. 2
Correlation plots of the tested epigenetic clocks. Pearson’s correlations (r > 0.001) are reported for the epigenetic clocks tested for association with polypharmacy. Legend: CA = chronological age; EEAA = extrinsic epigenetic age acceleration. IEAA = intrinsic epigenetic age acceleration
Fig. 3
Fig. 3
Results of the epigenome-wide association scan (EWAS) with polypharmacy. a Manhattan and b quantile–quantile (QQ) plot of the epigenome-wide association analysis. CpGs with suggestive associations (p < 10–6) are highlighted
See this image and copyright information in PMC

References

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URLS
    1. Farmastat (source #1): https://www.farmastat.it/ (Accessed April 20, 2024)
    1. Farmastat (source #2): https://www.marnonet.it/mws_home.aspx (Accessed April 20, 2024)
    1. R software: https://www.r-project.org/ methylclock package: https://www.bioconductor.org/packages/release/bioc/html/methylclock.html
    1. PC-based clocks scripts: https://github.com/MorganLevineLab/PC-ClocksPC-based clocks scripts: https://github.com/MorganLevineLab/PC-Clocks
    1. DunedinPACE package: https://github.com/danbelsky/DunedinPACE/tree/main