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Review
. 2024 Feb;16(3):189-202.
doi: 10.2217/epi-2023-0279. Epub 2023 Dec 19.

The epigenetics of frailty

Madia Lozupone  1 , Vincenzo Solfrizzi  2 , Rodolfo Sardone  3 , Vittorio Dibello  2   4 , Fabio Castellana  2 , Roberta Zupo  2 , Luisa Lampignano  5 , Ilaria Bortone  1 , Antonio Daniele  6   7 , Francesco Panza  2
Affiliations
Review

The epigenetics of frailty

Madia Lozupone et al. Epigenomics. 2024 Feb.

Abstract

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.

Keywords: DNA methylation; diet; epigenetics; frailty; multimorbidity; psychosocial.

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.

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