P66Shc signals to age

Abstract

Oxygen metabolism is thought to impact on aging through the formation of reactive oxygen species (ROS) that are supposed to damage biological molecules. The study of p66(Shc), a crucial regulator of ROS level involved in aging dysfunction, suggests that the incidence of degenerative disease and longevity are determined by a specific signaling function of ROS other than their unspecific damaging property.

Keywords: Aging; Life span; degenerative disease; oxidative stress.

Figure 1.. P66 ^Shc controls intracellular ROS metabolism.

at multiple sites. P66^Shc (in blue) stimulates ROS production by plasma membrane oxidases through the association with membrane receptor and Rac activation of phagocitic oxidases. Upon phosphorylation and consequent Pin-1-mediated conformational changes, p66^Shc (in red) translocates, through the TIM/TOM mitochondrial import machinery, within the mitochondrial inter-membrane space where it oxidizes reduced cytochrome c and catalyzes the partial reduction of O₂ to H₂O₂. Then, p66^Shc decreases the expression of ROS scavenging enzymes.

Figure 2.. Regulatory circuit of p66 ^Shc-mediated fat development.

The scheme recapitulates the pathway of p66^Shc that drives mitochondrial H₂O₂ and its relationship with insulin receptor signaling leading to fat accumulation. Food intake determines energetic substrate availability and insulin stimulates intracellular transduction pathways that regulate gene transcription in order to favor triglyceride accumulation. P66^Shc-mediated ROS production is directly boosted by insulin and in turn potentiates insulin receptor signaling, suppresses the expression of uncoupling proteins and beta oxidation enzymes leading to triglyceride accumulation.

Figure 3.. P66 ^Shc/ROS signaling determines fitness and aging associated dysfunctions.

P66^Shc/ROS signals to specific functions that improve fitness whilst these same functions may increase disease risk chronically (such as obesity related disorders) and contribute to trigger p66^Shc-mediated cell death. Then, increased disease risk and cell loss rate contribute to aging dysfunctions.