A new study of protein turnover suggests that hyperfunction theory may better explain aging than the familiar and sensible damage-accumulation hypothesis. This finding is surprising because much aging research has supported the idea that the gradual accumulation of damage to all kinds of molecules is the primary cause of aging. Escalating damage, it has been thought, could cause the progressive failure of cell processes, finally leading to deterioration and death.
If this familiar idea is accepted, it follows that increased degradation of damaged proteins and replacement by resynthesized proteins—protein turnover—could minimize this escalating protein damage, therefore slowing down the aging process. But according to a recent study, the relationship between protein turnover and aging is not so simple.
At the Braeckman lab for aging physiology at Ghent University, researchers study aging in Caenorhabditis elegans, a roundworm with a maximal lifespan expectancy of only two weeks. A single mutation, discovered many years ago, can double the worm's lifespan. However, the underlying molecular mechanism for this doubling is not well understood.
Ineke Dhondt, Ph.D., a researcher in the Braeckman team, investigated the protein turnover hypothesis in this long-lived mutant. This was done in collaboration with the Pacific Northwest National Laboratory. The international scientific team studied rates of protein synthesis and degradation of individual proteins in the long-lived daf-2 mutant by combining SILeNCe (stable isotope labeling by nitrogen in C. elegans) and mass spectrometry.
Intriguingly, the researchers observed slower synthesis and degradation rates for the majority of proteins in the long-lived worm. Proteins with unchanged turnover rates were found too. The increased protein turnover, as predicted by the hypothesis, could not be found. This calls into question the story of damage accumulation that could be avoided by degradation and re-synthesis of proteins.
Details appeared September 13 in the journal Cell Reports, in a pair of articles. One was entitled, “FOXO/DAF-16 Activation Slows Down Turnover of the Majority of Proteins in C. elegans”; the other, “Proteome-wide Changes in Protein Turnover Rates in C. elegans Models of Longevity and Age-Related Disease.”
“Lowering translational efficiency extends rather than shortens the lifespan in C. elegans,” noted the first study. “Intriguingly, the majority of proteins displayed prolonged half-lives in daf-2 [the long-lived mutant], whereas others remained unchanged, signifying that longevity is not supported by high protein turnover.”
In the second article, the authors report that the researchers at the Braeckman lab determined protein turnover rates in C. elegans models of longevity and Parkinson’s disease, using both developing and adult animals. The article discussed how protein turnover rates are affected in worm models of aging.
“Whereas protein turnover in developing, long-lived daf-2(e1370) worms is about 30% slower than in controls,” the article stated, “the opposite was observed in day 5 adult worms, in which protein turnover in the daf-2(e1370) mutant is twice as fast as in controls.”
In the Parkinson’s model, the article continued, protein turnover is reduced proportionally over the entire proteome, suggesting that the protein homeostasis network has a strong ability to adapt. Apparently, local expression of an aggregation-prone protein affects global proteome turnover.
The slowdown of protein dynamics and decreased abundance of the translational machinery, the authors of the studies concluded, may point to the importance of anabolic attenuation in lifespan extension, as suggested by the hyperfunction theory.
The hyperfunction theory, an alternative idea that has emerged in biogerontology in recent years, allows that molecular damage does occur. The theory, however, also holds that such damage probably is not the primary cause of aging. Moreover, the theory states that the synthesis of biomolecules is less orchestrated in aging individuals, leading to uncoordinated synthesis of irrelevant macromolecules (hypertrophy), causing a progressive decline of cell functionality.
The mutation in the long-lived worm studied in this research is located in a gene responsible for the stimulation of growth processes; thus, it seems plausible that lower growth in this mutant results in decreased hypertrophy and therefore slowing of the aging process. It is likely that aging is not caused by damage accumulation, but rather by derailed growth and developmental processes.