Abstract
BackgroundComparative aging studies, particularly those that include species of exceptional resistance to aging processes, can potentially illuminate novel senescence-retarding mechanisms. In recent years, protein homeostasis (proteostasis) has been implicated in fundamental aging processes. Here we further evaluate the relationship between proteostasis and longevity in a selection of bivalve mollusks and mammals with maximum longevities ranging from 3 to 507 years.Methods & ResultsWe experimentally examined proteostasis using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a reporter, as it is ubiquitously expressed, highly conserved, and conveniently assayed. The ability to maintain this enzymatic function was tested with increasing concentrations of the chaotropic agent urea, revealing a robust relationship with longevity in bivalves and mice. While our shortest-lived mollusk and mouse lost all activity by 2.5 and 3.5 M urea respectively, the longest-lived mollusk species, Arctica islandica, still preserved 45% of its basal function even at 6 M urea. To confirm that GAPDH proteostasis has a broad association with longevity, we also investigated a selection of primate species ranging in maximum longevity from 22 to 122 years. They outperformed the mouse at all concentrations, but among the primates results were variable at low urea doses. Still, at 6 M urea baboon and human samples retained 10% of their activity while both mouse and marmoset samples had no activity.Mechanism of Exceptional Stress ResistanceTo explore possible mechanisms of the exceptional stress resistance of A. islandica GAPDH we enzymatically removed post-translational glycosylation, but observed no decrease in stability. We also removed molecules smaller than 30 kDa, which includes most small heat shock proteins, but again did not compromise the exceptional stress resistance of Arctica GAPDH.ConclusionWhile the mechanism underlying A. islandica’s exceptional stress resistance remains elusive, this research identifies an experimental system that may reveal hitherto unknown mechanisms of protein homeostasis.
Highlights
Long-lived species possess a wealth of untapped research potential for gerontology
We experimentally examined proteostasis using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a reporter, as it is ubiquitously expressed, highly conserved, and conveniently assayed
To confirm that GAPDH proteostasis has a broad association with longevity, we investigated a selection of primate species ranging in maximum longevity from 22 to 122 years
Summary
Long-lived species possess a wealth of untapped research potential for gerontology. Traditional animal models are short-lived and highly susceptible to basic aging processes. They deteriorate and die rapidly which from one perspective enhances their experimental utility. Humans are already highly resistant to basic aging processes, so the senescence-retarding interventions effective in traditional models may not be as successful at improving and prolonging human health. It is in exceptionally long-lived species that we may discover mechanisms of exceptional senescence-resistance. Comparative aging studies, those that include species of exceptional resistance to aging processes, can potentially illuminate novel senescence-retarding mechanisms. We further evaluate the relationship between proteostasis and longevity in a selection of bivalve mollusks and mammals with maximum longevities ranging from 3 to 507 years
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