Efficiency of Protein Renewal Is Limited by Feed Intake and Not by Protein Lifetime in Aging Caenorhabditis elegans

Protein turnover maintains the proteome's functional integrity. Here, protein turnover efficiency over time in wild-type Caenorhabditis elegans was assessed using inverse [¹⁵N]-pulse labeling up to 7 days after the egg-laying phase at 20 °C. Isotopic analysis of some abundant proteins was executed favoring data quality over quantity for mathematical modeling. Surprisingly, isotopic enrichment over time reached an upper limit showing an apparent cessation of protein renewal well before death, with protein fractions inaccessible to turnover ranging from 14 to 83%. For life span modulation, worms were raised at different temperatures after egg laying. Mathematical modeling of isotopic enrichment points either to a slowdown of protein turnover or to an increasing protein fraction resistant to turnover with time. Most notably, the estimated time points of protein turnover cessation from our mathematical model were highly correlated with the observed median life span. Thrashing and pumping rates over time were linearly correlated with isotopic enrichment, therefore linking protein/tracer intake to protein turnover rate and protein life span. If confirmed, life span extension is possible by optimizing protein turnover rate through modulating protein intake in C. elegans and possibly other organisms. While proteome maintenance benefits from a high protein turnover rate, protein turnover is fundamentally energy-intensive, where oxidative stress contributes to damage that it is supposed to repair.