The Buck Institute for Research On Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.
USC Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90191, USA.
Geroscience. 2024 Oct;46(5):4585-4602. doi: 10.1007/s11357-024-01169-1. Epub 2024 May 16.
Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans, even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases.
蛋白质稳态的丧失是模型生物衰老的一个高度保守特征，导致不可溶性蛋白质聚集体的积累。蛋白质不可溶性也是包括阿尔茨海默病（AD）在内的主要与年龄相关的神经退行性疾病的一个统一特征，在 AD 中，数以百计的不可溶性蛋白质与聚集的淀粉样β（Aβ）结合在老年斑中。尽管衰老和 AD 风险之间存在联系，但迄今为止的治疗方法忽略了衰老驱动的广义蛋白质不可溶性作为一个促成因素。然而，在模型生物中衰老时变得不可溶性的蛋白质能够在体外加速 Aβ 聚集并延长体内寿命。在这里，我们使用一种无偏蛋白质组学方法来研究 Aβ 与与年龄相关的蛋白质不可溶性之间的关系。具体来说，我们发现 Aβ 的表达在秀丽隐杆线虫中驱动了全蛋白质组范围的蛋白质不可溶性，即使在年轻动物中也是如此，而且这种不可溶性蛋白质组与正常衰老驱动的不可溶性蛋白质组非常相似，我们将这个易损的亚蛋白质组称为核心不可溶性蛋白质组（CIP）。我们表明，CIP 富含能够在体内修饰 Aβ 毒性的蛋白质，这表明在 AD 背景下可能存在一个恶性正反馈循环。重要的是，我们使用人类全基因组关联研究（GWAS）表明，CIP 富含不仅与神经退行性疾病有关，而且与广泛的慢性、与年龄相关的疾病（CARDs）有关的生物学过程。这提供了暗示性的证据表明，与年龄相关的蛋白质稳态丧失可能在一般 CARD 风险中发挥作用。最后，我们表明，保护肠道的代谢物尿石素 A 可以缓解 Aβ 毒性，支持其在痴呆症和与年龄相关的疾病的临床试验中使用。
