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Background <p>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).</p> Results <p>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); <i>p</i> = 1.5 × 10<sup>–6</sup>). However, these showed significant enrichments of several biological functions and pathways related to renal tissue, lipoproteins, inflammatory and immune response.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Alessandro Gialluisi,
  • Alfonsina Tirozzi,
  • Simona Costanzo,
  • Danilo Licastro,
  • Augusto Di Castelnuovo,
  • Miriam Shasa Quiccione,
  • Stefania Falciglia,
  • Margherita Degasperi,
  • Teresa Panzera,
  • Sara Magnacca,
  • Mariarosaria Persichillo,
  • Fabrizia Noro,
  • Chiara Cerletti,
  • Maria Benedetta Donati,
  • Giovanni de Gaetano,
  • Licia Iacoviello,
  • Marialaura Bonaccio,
  • Americo Bonanni,
  • Amalia De Curtis,
  • Francesco Gianfagna,
  • Jos Vermylen,
  • Renzo Pegoraro,
  • Antonio G. Spagnolo,
  • Deodato Assanelli,
  • Livia Rago,
  • Sabatino Orlandi,
  • Marialaura Bonaccio,
  • Francesca Bracone,
  • Giuseppe Di Costanzo,
  • Simona Esposito,
  • Anwal Ghulam,
  • Francesco Gianfagna,
  • Martina Morelli,
  • Maria Loreto Muñoz,
  • Venegas,
  • Antonietta Pepe,
  • Emilia Ruggiero,
  • Amalia De Curtis,
  • Concetta Civitillo,
  • Alisia Cretella,
  • Francesca Bracone,
  • Giuseppe Di Costanzo,
  • Martina Morelli

摘要

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.