Institute for Human Genetics, Charité - University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
J Proteome Res. 2010 Jul 2;9(7):3551-60. doi: 10.1021/pr100059j.
Biological aging is often described by its phenotypic effect on individuals. Still, its causes are more likely found on the molecular level. Biological organisms can be considered as reliability-engineered, robust systems and applying reliability theory to their basic nonaging components, proteins, could provide insight into the aging mechanism. Reliability theory suggests that aging is an obligatory trade-off in a fault-tolerant system such as the cell which is constructed based on redundancy design. Aging is the inevitable redundancy loss of functional system components, that is proteins, over time. In our study, we investigated mouse brain development, adulthood, and aging from embryonic day 10 to 100 weeks. We determined redundancy loss of different protein categories with age using reliability theory. We observed a near-linear decrease of protein redundancy during aging. Aging may therefore be a phenotypic manifestation of redundancy loss caused by nonfunctional protein accumulation. This is supported by a loss of proteasome system components faster than dictated by reliability theory. This loss is highly detrimental to biological self-renewal and seems to be a key contributor to aging and therefore could represent a major target for therapies for aging and age-related diseases.
生物衰老通常通过其对个体的表型影响来描述。然而，其原因更可能在分子水平上找到。生物有机体可以被认为是可靠性工程设计的、稳健的系统，将可靠性理论应用于其基本的非衰老组件（如蛋白质）可以深入了解衰老机制。可靠性理论表明，衰老对于细胞等容错系统来说是一种强制性的权衡，该系统是基于冗余设计构建的。衰老就是随着时间的推移，功能性系统组件（即蛋白质）的冗余逐渐丢失。在我们的研究中，我们从胚胎第 10 天到第 100 周研究了小鼠大脑的发育、成年和衰老。我们使用可靠性理论来确定不同蛋白质类别随年龄的冗余损失。我们观察到在衰老过程中蛋白质冗余呈近线性下降。因此，衰老可能是由非功能蛋白质积累引起的冗余损失的表型表现。这一观点得到了一个事实的支持，即蛋白酶体系统组件的损失速度快于可靠性理论所规定的速度。这种损失对生物自我更新非常不利，似乎是衰老的一个关键因素，因此可能是衰老和与年龄相关疾病治疗的主要靶点。
