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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\u2014decades before clinical onset. However, this early benefit is paired with accelerated striatal decline, suggesting that mHTT drives an early \u201cability\u201d that transitions into a \u201cliability.\u201d 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.<\/jats:p>","DOI":"10.1177\/18796397251391069","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T15:44:38Z","timestamp":1762357478000},"page":"201-213","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Early life functional advantage coupled with accelerated aging: The case for antagonistic pleiotropy in Huntington's disease"],"prefix":"10.1177","volume":"15","author":[{"given":"Jordan L","family":"Schultz","sequence":"first","affiliation":[{"name":"Carver College of Medicine at the University of Iowa"},{"name":"Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA"},{"name":"Department of Pharmacy Practice and Science, The University of Iowa College of Pharmacy, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peg C","family":"Nopoulos","sequence":"additional","affiliation":[{"name":"Carver College of Medicine at the University of Iowa"},{"name":"Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA"},{"name":"Stead Family Department of Pediatrics at the University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1806"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2024.04.001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26364"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70088-7"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pscychresns.2019.07.003"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc2888"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30143-5"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008066"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029809"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23980"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcn.2017.11.008"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26039"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2004.00241.x"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27046"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21369"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1957.tb02911.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01436004"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-12-160"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-180309"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37102-8"},{"key":"e_1_3_2_22_2","first-page":"5789424","article-title":"Motor and nonmotor symptoms of Parkinson's disease: antagonistic pleiotropy phenomena derived from alpha-synuclein evolvability?","volume":"2018","author":"Takamatsu Y","year":"2018","unstructured":"Takamatsu Y, Fujita M, Ho GJ, et al. 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