Ageing research reviewsJun 4, 2026

Signs of Faster Biological Aging Linked to Brain Diseases: A Systematic Review

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 5, 2026

Abstract

Seventy-nine studies examined the relationship between epigenetic age acceleration (EAA) and neurological diseases.

EAA reflects the difference between biological and chronological age, influenced by genetic, environmental, and disease factors.
Fifteen different epigenetic clocks, including Horvath, Hannum, and PhenoAge, were utilized in the studies.
Alterations in EAA were commonly observed in neurological diseases, but the strength of associations varied by the type of clock used, the tissue examined, and the specific outcomes measured.
Measures derived from the central nervous system exhibited more consistent relationships with neuropathological indicators compared to those derived from blood.
Genetic and causal analyses yielded limited and inconsistent evidence for direct causal connections between EAA and neurological conditions.

Simplified

BACKGROUND: DNA methylation-based epigenetic clocks estimate biological age. Epigenetic age acceleration (EAA), the difference between epigenetic and chronological age, reflects cumulative genetic, environmental, and disease-related influences. EAA has emerged as a potential biomarker of ageing and disease mechanisms. This systematic review synthesises evidence for EAA across neurological diseases.

METHODS: This review followed PRISMA guidelines (PROSPERO: CRD42023464954). MEDLINE, Embase, Web of Science, and Scopus were searched from inception to October 2025. Eligible studies included adult human cohorts with neurological disease applying methylation-based epigenetic clocks and reporting clinical, neuroimaging, neuropathological, prognostic, or causal outcomes. Screening, data extraction, and risk-of-bias assessments were conducted independently in duplicate using Joanna Briggs Institute tools. Due to heterogeneity, findings were synthesised narratively.

RESULTS: Seventy-nine studies were included across multiple neurological conditions. Fifteen clocks were applied, most commonly Horvath, Hannum, and PhenoAge. EAA was frequently altered in neurological disease, although associations varied by clock, tissue, and outcome. Central nervous system-derived measures showed more consistent relationships with neuropathological indices, whereas blood-based measures were more heterogeneous. Genetic and causal analyses provided limited and inconsistent evidence for direct causal effects.

CONCLUSIONS: EAA captures biological ageing signatures relevant to neurological disease, but interpretation is context dependent. Current evidence does not support routine clinical use. Improved standardisation and validation may clarify the role of epigenetic ageing in neurological disease vulnerability.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

PubMed

Signs of Faster Biological Aging Linked to Brain Diseases: A Systematic Review

Abstract

Full Text

Funding

Competing interests

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