Fanconi anaemia as a human model of accelerated epigenetic and immune ageing

TL;DR

Fanconi anaemia accelerates aging processes in humans, offering insights into how DNA repair failure, metabolism, and immunity interact to speed up aging and cancer risk.

Contribution

Fanconi anaemia is proposed as a human model to study the sequence and interdependence of aging hallmarks, including genome instability and immune dysfunction.

Findings

FA links DNA repair failure to mitochondrial metabolism and immune dysfunction, accelerating epigenetic drift and cancer risk.

Nutrient-sensing cofactors like vitamin D and NAD⁺ modulate chromatin resilience and immune resilience in FA.

FA serves as a 'time-lapse' model to study biological aging and test precision-prevention strategies.

Abstract

Fanconi anaemia (FA) is a DNA-repair disorder that compresses multiple hallmarks of ageing into childhood and early adulthood. Persistent genomic instability in FA precipitates oxidative stress, inflammatory remodelling, and metabolic reprogramming, which together erode epigenetic integrity and immune competence. Here we provide evidence FA-specific DNA-repair failure is linked to mitochondrial metabolism, nutrient-sensing networks, and immune dysfunction. In this context, we discuss how these interactions accelerate epigenetic drift and cancer susceptibility. We propose FA as a human “time-lapse” model to separate the sequence and interdependence of selected ageing hallmarks, such as genome instability, epigenetic deregulation, stem cell exhaustion, and immunosenescence, which together contribute to a markedly increased risk of early cancer development. We further highlight nutrigenomic mechanisms, including vitamin D-dependent chromatin remodelling and redox-sensitive cofactors, that modulate epigenetic states and immune resilience. Framing FA within the broader framework of ageing biology suggests testable biomarkers and precision-prevention strategies aimed at stabilising the epigenome, delaying carcinogenesis, and prolonging healthspan.

•Compression of ageing hallmarks like genome instability, epigenetic drift and immunosenescence into early life.•Persistent DNA damage couples to metabolic/mitochondrial stress to reshape the epigenome and immune function.•Nutrient-sensing and redox-dependent cofactors (e.g., NAD⁺, α-ketoglutarate, vitamin D) modulate chromatin resilience.•Providing a “time-lapse” human model to benchmark biological-age biomarkers and test preventive strategies.•Extending conceptual and translational implications to therapy-induced ageing and population cancer risk.

Compression of ageing hallmarks like genome instability, epigenetic drift and immunosenescence into early life.

Persistent DNA damage couples to metabolic/mitochondrial stress to reshape the epigenome and immune function.

Nutrient-sensing and redox-dependent cofactors (e.g., NAD⁺, α-ketoglutarate, vitamin D) modulate chromatin resilience.

Providing a “time-lapse” human model to benchmark biological-age biomarkers and test preventive strategies.

Extending conceptual and translational implications to therapy-induced ageing and population cancer risk.

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