Journal article
Early life functional advantage coupled with accelerated aging: The case for antagonistic pleiotropy in Huntington's disease
Journal of Huntington's disease, Vol.15(2), pp.201-213
05/2026
DOI: 10.1177/18796397251391069
PMID: 41191025
Abstract
Recent findings suggest that neurodevelopment plays a critical role in Huntington's Disease (HD) pathogenesis. This review integrates data from human studies of children and young adults at risk for HD (the Kids-HD study) with the theory of antagonistic pleiotropy (AP), which posits that genes promoting early-life advantages may confer late-life risks. Longitudinal imaging of gene-expanded (GE) children and adolescents shows that mHTT is associated with larger cortical volumes, enhanced surface morphology, and superior cognitive performance-decades before clinical onset. However, this early benefit is paired with accelerated striatal decline, suggesting that mHTT drives an early "ability" that transitions into a "liability." Vertex-wise analyses reveal cortical enlargement in regions with dense glutamatergic projections to the striatum, implicating excitotoxicity as a mechanism linking development to degeneration. This pleiotropic pattern parallels evolutionary models, where genes like HTT may have an evolutionary trade-off where genes supporting growth and reproduction are favored over those that serve long-term somatic maintenance, leaving cells with diminished repair capacity and resulting in an accelerated aging process. Altogether, these findings support a novel framework in which mHTT accelerates both brain maturation and neurodegeneration, offering new insights into HD biology and therapeutic targets.
Details
- Title: Subtitle
- Early life functional advantage coupled with accelerated aging: The case for antagonistic pleiotropy in Huntington's disease
- Creators
- Jordan L Schultz - University of IowaPeg C Nopoulos - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of Huntington's disease, Vol.15(2), pp.201-213
- DOI
- 10.1177/18796397251391069
- PMID
- 41191025
- NLM abbreviation
- J Huntingtons Dis
- ISSN
- 1879-6400
- eISSN
- 1879-6400
- Publisher
- SAGE PUBLICATIONS INC
- Grant note
- National Institute of Neurological Disorders and Stroke: R01 NS055903 CHDI Foundation: 071108 National Institutes of Health: 1S10OD025025-01
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Kids-HD study was funded by the National Institute of Neurological Disorders and Stroke (R01 NS055903) and the CHDI Foundation (071108). The MRI equipment used in this study was funded by the National Institutes of Health (1S10OD025025-01).
- Language
- English
- Electronic publication date
- 11/05/2025
- Date published
- 05/2026
- Academic Unit
- Neurology; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9985024146902771
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