Aging: Molecular Pathways and Implications on the Cardiovascular System

Figure 7

Metabolic control involved in aging and on the cardiovascular system. IGF-1, mTOR, AMPK, SIRT1, p53, and ROS are key regulators in metabolic control. Many of these pathways are complex involving crosstalk between them, with many paradoxical effects. The stimulation of the IGF-1 pathway by insulin promotes PI3K/AKT pathway activation, which induces the exclusion of FOXO from the nucleus, inhibiting its function; in addition, IGF-1 activates eNOS, increasing NO availability, improving the vascular function. IGF-1 also activates the RAS/p38MAPK pathway inducing mechanisms of cell growth and proliferation. Finally, IGF-1 stimulates vesicles containing GLUT-4 to the cell membrane, promoting the uptake of glucose, the main cellular energy substrate. There are also other two glucose transporters that help in glucose uptake such as GLUT-1 and GLUT-3; the last one can be downregulated by p53 via Nf-kB. Under normal conditions, mostly, pyruvate is directed to the mitochondria, producing ATP by OXPHOS. In age, NAD⁺ levels decrease, driving towards a loss in SIRT1 activity, resulting in mitochondrial dysfunction via PGC-1α/β and HIF-α. Thus, pyruvate is directed to lactate production, even in the presence of O₂, a process known as “the Warburg effect”. This metabolic shift is essential for increasing biomass, stimulating cell growth, proliferation, and differentiation, which promote angiogenesis. In this way, a mitochondrial dysfunction results in a decreased ATP production, activating AMPK. This protein stimulates autophagy, generating energy for the cell. In addition, it stimulates p53, which inhibit the uptake and conversion of glucose, to stimulate OXPHOS activity, generating an antiproliferative effect. Finally, ROS produced by mitochondrial dysfunction stimulates several signalling pathways, such as AMPK, but also activates AKT, which stimulates mTOR, being the redox potential the major regulator of this balance.