2.4 IIS Pathway
The IIS pathway acutely senses nutrient levels and regulates energy homeostasis by controlling the AMPK and mTOR pathway. The IIS pathway has been documented to play a major role in the control of lifespan in various invertebrate species. Specifically, C. elegans with mutations that inhibit IGF-1 signaling displayed an extended lifespan64. Mutations in the IIS pathway have also been reported to increase the lifespan of mice 65.
The IIS pathway is activated by the binding of insulin-like peptides (ILP) to the IIS tyrosine kinase receptors. At least 10 ILPs exist in mammals; of those, only insulin, insulin-like growth factor 1 (IGF-1), and IGF-2 are IIS tyrosine kinase receptor ligands. Insulin is produced in pancreas responding to increasing glycaemia 66. Glucokinase (GCK), a hexokinase that phosphorylates glucose to glucose 6-phosphate (G6P), and glucose transporter 2 (GLUT-2), serve as glycaemia sensors since they are only responsive to high glucose levels. The oral taste receptors T1R2-T1R3 sense glucose as well and initiate a signal transduction cascade to trigger insulin release. The release of insulin can also be enhanced by incretins, which are produced when fatty acids or amino acids are detected in the gut. The G protein coupled receptor 120 (GPR120) senses fatty acid and promotes the production of the incretin glucagon-like peptide-1 (GLP1). Amino acids can be sensed in the gut by the taste receptors T1R1-T1R3. Rather than inciting a gustatory sense in the brain, the detection triggers incretin release into the circulation 40.
In contrast to insulin, IGF-1 and IGF-2 are regulated by the growth hormone (GH), and both IGF and GH decline continuously to extreme low levels during advanced age. Multiple species have been demonstrated to have lower GH/IGF-1 signaling when their lifespan is extended. Reduced GH/IGF-1 signaling has also been observed during CR mode, suggesting the critical role of GH/IGF-1 signaling during life-extending strategies67. In addition to extending lifespan, GH can promote the hepatic production of IGF-1 and alter the insulin sensitivity by acting on the IIS pathway. Mice and humans with reduced GH/IGF-1 axis have been shown to have improved insulin sensitivity, protecting them from cancer and diabetes mellitus, two major ageing-related diseases68.
The activated IIS pathway branches off into the PI3K/Akt pathway and the Ras/MAPK pathway. The activated IIS tyrosine kinase receptor phosphorylates and activates PI3K, which generates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). PI(3,4,5)P3 then activates 3-phosphoinositide-dependent protein kinase-1 (PDPK1), which subsequently leads to the activation of Akt, whose regulatory functions on the FOXO transcription factors and the mTOR signaling pathway have been described above. The binding of ILPs to the IIS kinase receptors also sequentially starts the activation cascade of Ras, Raf, MAPK kinase 1 (MEK1) and MEK2, and extracellular signal‑regulated protein kinase 1 (ERK1) and ERK2, which are also known as mitogen-activated protein kinase 3 (MAPK3) and MAPK 1 38. ERK and its downstream target, RSK, are able to suppress TSC2 and enhance mTORC1 activity47.
Metformin
Metformin is a common oral antihyperglycemic drug that has been widely prescribed in the management of T2DM. This biguanide class drug exerts its glucose lowering effect via multiple mechanisms, including increasing insulin sensitivity, lowering hepatic glucose production, and decreasing intestinal glucose absorption 4. Metformin was discovered in 1922 and received its approval in 1994 in the US69. After decades of clinical use, metformin has been found to be generally safe and well-tolerated by humans. Each year, metformin is taken by more than 125 million people world-wide, making it one of the top 10 best-selling generic drugs 70. Common gastrointestinal discomforts such as nausea, loss of appetite, and vomiting often resolve spontaneously. The most serious side effect is lactic acidosis, but the incidence is very low 71.
In recent years, accumulating evidence has supported the safe and efficacious use of metformin beyond its glucose-lowering effects. Its usefulness ranges from countering tumorigenesis properties to inducing
ovulation in women with PCOS 72, 73. Moreover, metformin has been shown to extend lifespan in short-lived organisms as well as in diabetic patients, suggesting its great potential to become one of the first effective geroprotective agents on the market74, 75.
1 Mechanisms of metformin in improving healthspan