Calubag Mariah F, Ademi Ismail, Green Cara L, Jayarathne Hashan S M, Manchanayake Dulmalika N H, Le Sandra M, Lialios Penelope, Breuer Lucia E, Yakar Shoshana, Babygirija Reji, Sonsalla Michelle M, Grunow Isaac, Yeh Chung-Yang, Liu Yang, Knopf Bailey A, Ricke William A, Liu Teresa T, Sadagurski Mariana, Lamming Dudley W
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
bioRxiv. 2025 Sep 4:2025.08.31.673254. doi: 10.1101/2025.08.31.673254.
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
膳食蛋白质是人类和啮齿动物代谢健康的关键调节因子。蛋白质限制的许多益处是通过减少膳食支链氨基酸（BCAAs；亮氨酸、缬氨酸和异亮氨酸）的摄入来介导的，限制BCAAs足以延长小鼠的健康寿命和寿命。虽然BCAAs通常被视为一个整体，但很明显它们具有不同的代谢作用，我们最近发现限制异亮氨酸足以延长雄性和雌性小鼠的健康寿命和寿命。在这里，我们测试了终生限制BCAA缬氨酸对健康衰老的影响。我们发现缬氨酸限制（Val-R）改善了C57BL/6J小鼠的代谢健康，促进了两性的瘦体重和血糖控制。为了研究Val-R在衰老过程中涉及的分子机制，我们进行了多组织转录谱分析和基因网络分析。虽然Val-R对雌性小鼠肝脏、肌肉和棕色脂肪组织的分子影响明显大于雄性，但雄性小鼠的基因富集与表型特征的关联更强。此外，我们发现表型变化与长寿相关的PI3K-Akt信号通路的多组织下调有关。Val-R降低了两性的虚弱程度，使雄性小鼠的寿命延长了23%，但没有延长雌性小鼠的寿命，这与PI3K-Akt信号通路在雄性中的特异性下调相一致。我们的结果表明，Val-R改善了两性小鼠健康寿命的多个方面，并延长了雄性小鼠的寿命，这表明模拟Val-R的干预措施可能对衰老和与年龄相关的疾病具有转化潜力。
