Stabilizing protein networks: a method to extend lifespan?

One of the hallmarks of aging is a loss of proteostasis, or a switch to an alternate stable state where protein levels are disregulated. The switch between states is also a hallmark of bifurcation equations. This paper presents three main results. (1) We analyze the bifurcations and stability of all possible 3- and 4-node regulatory motifs across biologically realistic parameter values to determine which network sub-components are at risk of destabilizing the system. (2) We discover an unexpected rule that the total volume stable parameter space is a poor predictor of motif frequency in mice and humans, but the "clumpiness" of the stable region is an excellent one. (3) The known 60 slowed/40 sped-up split on protein turnover under calorie restriction disproportionately favors significant regulators, leading to most motifs being slowed and stabilized, maintaining proteostasis and likely responsible for the extended lifespan of individuals on a CR diet.