寒冷激活一个BH 2代谢网络促进长寿和蛋白质稳态
寒冷激活一个BH2代谢网络促进长寿和蛋白质稳态
作者： 小柯机器人 发布时间：2026/10/25 20:48:44
本期文章：《自然》：Online/在线发表
2026年10月21日，德国科隆大学David Vilchez等科学家在《自然》发表研究，揭示了寒冷通过BH2代谢网络促进长寿和蛋白质稳态。
适度寒冷温度可跨物种延长寿命并促进健康，但这些益处背后的分子机制仍不清楚。在此，研究人员在秀丽隐杆线虫中定义了一个由代谢物驱动的、多组织信号系统，将寒冷温度与增强的长寿和蛋白质稳态联系起来。寒冷温度上调生物蝶呤合成酶CAT-4（人类中的GCH1），增加二氢生物蝶呤（BH2）的产生，BH2是生物活性辅因子四氢生物蝶呤（BH4）的可运输储备库。BH2在肌肉中产生，并被运输到远端组织（包括肠道和神经元），在那里由补救酶DHFR-1转化为BH4。BH4作为苯丙氨酸羟化酶PAH-1的必需辅因子，促进酪氨酸合成并延长寿命。这一BH2–BH4轴还阻止衰老过程中疾病相关蛋白聚集及随后的神经元功能障碍。重要的是，即使在正常或升高温度下，仅在肌肉中增加BH2合成就足以促进长寿并抑制远端组织中的病理性蛋白聚集。在人类细胞中，补充BH2或酪氨酸可减少与亨廷顿病相关的polyQ扩展蛋白的聚集，以及导致肌萎缩侧索硬化的TDP-43和FUS突变变体的聚集。总之，这些发现将BH2鉴定为一种寒冷诱导的代谢物，其合成、组织间运输和转化为生物活性BH4可维持机体范围的蛋白质稳态并延长寿命。
附：英文原文
Title: Cold activates a BH2 metabolic network promoting longevity and proteostasis
Author: Lee, Hyun Ju, Doan, Cansu, Koyuncu, Seda, Wehrmann, Markus, Artan, Murat, Petrovic, Dunja, Loureiro, Rute, Sahu, Amit Kumar, Schnubel, Joana, Grobushkin, Pavel, Prymidis, Dimitrios, Georgomanolis, Theodoros, Sokol, Agnieszka, Yang, Ming, Hoppe, Thorsten, Frezza, Christian, Vilchez, David
Issue&Volume: 2026-10-21
Abstract: Moderately cold temperatures extend lifespan and promote health across species1,2,3, yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2–BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington’s disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.
DOI: 10.1038/s41586-026-11152-9
Source: https://www.nature.com/articles/s41586-026-11152-9