EAGER: The molecular basis of aging: The role of allele-specific gene expression, protein folding, and protein stability on the progression of aging

导致衰老的分子机制尚不清楚。提出的理论将衰老归因于有害突变或受损大分子的积累，归因于生命早期某些后来有害的基因的差异优势，或者归因于生命早期用于繁殖的新陈代谢能量与用于修复和维护的能量之间的年龄相关权衡。这些模式并不是相互排斥的，每一种模式都可能在衰老过程中发挥作用。通过对模式生物的研究，我们知道衰老与能量代谢降低、蛋白质转化率降低、蛋白质周转率降低以及受损蛋白质的堆积有关。这种蛋白质损伤被认为是新陈代谢的自然副产品，寿命可能与代谢率呈负相关。首席研究员(PI)就衰老的分子基础提出了一种新的观点。PI假设，随着年龄的增长，受损的蛋白质越来越难以被细胞降解和消除。细胞通过增强蛋白质代谢基因的表达来应对受损蛋白质的积累，这些基因编码参与蛋白质折叠的伴侣蛋白和参与蛋白质降解的酶。增强的蛋白质折叠能力被认为是为了减少细胞蛋白质质量控制机制，该机制将不稳定蛋白质的表达降至最低，从而产生一个正反馈循环，导致产生更多受损或未折叠的蛋白质。对该系统的调节可能是在蛋白质及其mRNA的分解，也可能是在基因表达水平上，假设表观遗传机制已经进化到下调编码不稳定蛋白质的mRNAs。建议的工作模式是，不稳定或弱折叠蛋白的受控表达(即等位基因特异表达)是年轻状态的关键质量控制组件，这种状态在老年个体中消失，使老年个体不那么精力充沛，更容易生病。这一老化模型预测，在通过卡路里限制延长寿命的过程中，以及在延长寿命的蠕虫和果蝇突变体中，等位基因特异的基因表达和蛋白质质量控制将保持不变。该模型还预测，通过实验识别特定等位基因的表达，并结合相对蛋白质稳定性的计算分析，将成为监测和评估衰老进程的有效方法。这个分子模型可以很容易地通过以老鼠、蠕虫和苍蝇为研究对象的计算和湿实验室相结合的方法进行测试。这一新理论的概念验证具有重要的更广泛的影响，导致了解决衰老过程的新计算方法的发展，这可能提供诊断和计算方法来减轻遗传有害基因对人类的影响。

The molecular mechanisms responsible for aging remain unclear. Proposed theories ascribe aging to a buildup of deleterious mutations or damaged macromolecules, to the differential advantage of some genes early in life that are later detrimental, or to an age-related trade-off between metabolic energy used early in life for reproduction versus energy used for repair and maintenance. These models are not mutually exclusive and each may play a role in the aging process. From studies of model organisms it is known that aging is associated with a decrease in energy metabolism, decreased rates of protein translation, lower protein turnover, and a buildup of damaged proteins. This protein damage is proposed to be a natural by-product of metabolism and lifespan may be inversely correlated with metabolic rate. The Principal Investigator (PI) proposes a novel idea about the molecular basis of aging. The PI hypothesizes that damaged proteins that accumulate with aging are increasingly difficult for cells to degrade and eliminate. Cells respond to the accumulation of damaged proteins by enhancing the expression of protein metabolism genes encoding chaperonins involved in protein folding and enzymes involved in protein degradation. The enhanced protein folding capability is proposed to decrease a cellular protein quality control mechanism that minimizes expression of unstable proteins, thus creating a positive feedback loop that causes even more damaged or unfolded proteins to be created. Regulation of the system could be at either the breakdown of the protein and its mRNA, or at the level of gene expression assuming epigenetic mechanisms have evolved to down-regulate mRNAs encoding unstable proteins. The proposed working model is that controlled expression of unstable or weakly folding proteins (i.e., allele-specific gene expression) is a critical quality-control component of the youthful state that is lost in aging individuals, making the aged individual less vigorous and more susceptible to disease. This aging model predicts that allele-specific gene expression and protein quality control will be maintained during lifespan extension by caloric restriction as well as in worm and fruit fly mutants with extended lifespan. The model also predicts that identification of allele-specific gene expression experimentally coupled with computational analysis of relative protein stability will serve as an efficient assay to monitor and assess the progression of aging. This molecular model can be readily tested by combined computational and wet-lab approaches focused on mice, worms, and flies. Proof-of-concept of this novel theory has important broader impacts, leading to the development of new computational approaches for addressing the aging process which may provide diagnostic and computational approaches to mitigate the impact of inherited deleterious genes in humans.