Shringarpure Reshma, Davies Kelvin J A
Ethel Percy Andrus Gerontology Center and the Division of Molecular & Computational Biology, the University of Southern California, Los Angeles, CA 90089-0191, USA.
Free Radic Biol Med. 2002 Jun 1;32(11):1084-9. doi: 10.1016/s0891-5849(02)00824-9.
A significant body of evidence supports a key role for free radicals in causing cumulative damage to cellular macromolecules, thereby contributing to senescence/aging, and a number of age-related disorders. Proteins are recognized as major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported for many experimental aging models, as measured by several markers for protein oxidation. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the proteasome. However, severely oxidized, cross-linked proteins are poor substrates for degradation and actually inhibit the proteasome. Considerable evidence now indicates that proteasome activity declines during aging, as the protease is progressively inhibited by binding to ever increasing levels of oxidized and cross-linked protein aggregates. Cellular aging probably involves both an increase in the generation of reactive oxygen species and a progressive decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence.
大量证据支持自由基在对细胞大分子造成累积损伤从而导致衰老及多种与年龄相关疾病方面发挥关键作用。蛋白质被认为是氧化损伤的主要靶点（除了DNA和脂质），并且在许多实验性衰老模型中，已报道了氧化蛋白质的积累，这是通过几种蛋白质氧化标记物来衡量的。在年轻健康个体中，适度氧化的可溶性细胞蛋白质会被蛋白酶体选择性且快速地降解。然而，严重氧化、交联的蛋白质是较差的降解底物，实际上还会抑制蛋白酶体。现在有大量证据表明，随着蛋白酶体逐渐被与不断增加的氧化和交联蛋白质聚集体的结合所抑制，其活性在衰老过程中会下降。细胞衰老可能既涉及活性氧生成的增加，又涉及蛋白酶体活性的逐渐下降，从而导致氧化损伤蛋白质聚集体的逐渐积累，最终导致细胞功能障碍和衰老。
