MAINTENANCE OF PROTEOSTASIS AS A PILLAR OF SLOWED AGING: LESSONS FROM LONG-LIVED MURINE MODELS

摘要

Loss of proteostasis is associated with age-related chronic disease. Accumulation of protein damage with age is the consequence of cell stresses and limited mechanisms for protein repair. However, when relatively high rates of protein turnover are maintained, damaged proteins are likely to be more quickly degraded and replaced with newly synthesized proteins, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in incomplete conclusions, devoid of insights about how the newly synthesized proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides key mechanistic insight about proteins earmarked for newly proliferating cells versus for replacement of damaged and degraded proteins. Using this approach with a number of long-lived murine models shows that, compared to controls, energetic resources are directed more toward somatic maintenance at the cost of cell proliferation.