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The epigenetics of frailty

    Madia Lozupone

    *Author for correspondence:

    E-mail Address: madia.lozupone@gmail.com

    Department of Translational Biomedicine & Neuroscience ‘DiBraiN’, University of Bari Aldo Moro, Bari, Italy

    ,
    Vincenzo Solfrizzi

    Cesare Frugoni Internal & Geriatric Medicine & Memory Unit, University of Bari Aldo Moro, Bari, Italy

    ,
    Rodolfo Sardone

    Local Healthcare Authority of Taranto, Taranto, Italy

    ,
    Vittorio Dibello

    Cesare Frugoni Internal & Geriatric Medicine & Memory Unit, University of Bari Aldo Moro, Bari, Italy

    Department of Orofacial Pain & Dysfunction, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    ,
    Fabio Castellana

    Cesare Frugoni Internal & Geriatric Medicine & Memory Unit, University of Bari Aldo Moro, Bari, Italy

    ,
    Roberta Zupo

    Cesare Frugoni Internal & Geriatric Medicine & Memory Unit, University of Bari Aldo Moro, Bari, Italy

    ,
    Luisa Lampignano

    Local Healthcare Authority of Bari, ASL Bari, Bari, Italy

    ,
    Ilaria Bortone

    Department of Translational Biomedicine & Neuroscience ‘DiBraiN’, University of Bari Aldo Moro, Bari, Italy

    ,
    Antonio Daniele

    Department of Neuroscience, Catholic University of Sacred Heart, Rome, Italy

    Neurology Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

    &
    Francesco Panza

    **Author for correspondence:

    E-mail Address: f_panza@hotmail.com

    Cesare Frugoni Internal & Geriatric Medicine & Memory Unit, University of Bari Aldo Moro, Bari, Italy

    Published Online:https://doi.org/10.2217/epi-2023-0279

    The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures – including physical exercise, psychosocial factors and diet – may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

    Plain language summary

    The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.

    Tweetable abstract

    Frailty is considered the outcome of environmental epigenetic factors on biological aging caused by a mismatch between chronological age and DNA methylation age. Research on the epigenetic biomarkers of this process is underway.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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