Over 20 years ago it was discovered that mutations in
daf-2 and
age-1 double the lifespan in worms [
3,
4].
Daf-2 encodes the only insulin/IGF-1 receptor expressed in worms and
age-1 is the catalytic subunit of the downstream phosphoinositide 3-kinase (PI3K). Substantial evidence has been provided that IIS is an evolutionarily conserved pathway that regulates lifespan across many species like flies, worms, and mice [
3‐
6]. Decreased IIS in nonhuman organisms has been associated with extended lifespan and protection against oxidative stress-mediated age-dependent damage [
5,
6]. IIS activates PI3K and Akt kinase. Akt-mediated phosphorylation activates the kinase mammalian target of rapamycin complex 1 (mTORC1) activating its effector S6 kinase 1 (S6K1) involved in the up-regulation of protein synthesis and cell proliferation. Furthermore, activated Akt stimulates specific phosphorylation of FoxO proteins in the nucleus leading to their extrusion into the cytoplasm [
5]. FoxO transcription factors have emerged as a convergence point of IIS, nutrient availability and oxidative stress [
6]. Increased expression of DAF-16, the ortholog of human FoxO proteins in the worm
Caenorhabditis elegans, due to a mutation of the insulin/IGF-1 receptor
daf-2 has been found to significantly increase the worm's lifespan [
2,
3]. Male and female heterozygous IGF-1 receptor knockout mice
Igf1r
+/-
live 16% and 33% longer than wild-type males and females, respectively [
7]. Thus, convincing experimental evidence obtained from invertebrates and nonhuman vertebrates taught us that down-regulated IIS is of critical importance for metabolic homeostasis, improved oxidative stress responses and longevity.
The pathogenesis of age-related diseases has been associated with an impaired capacity to counteract cellular damage induced by oxidative stress. In T2D some of the consequences of an oxidative environment are the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction [
8]. Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and the cell's own antioxidant protection. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis [
9]. FoxO proteins are pivotal regulators of oxidative stress resistance and activate the expression of manganese superoxide dismutase and catalase [
5]. Moreover, FoxO1 at the promoter level induces expression of
Hmox1 (heme oxygenase 1) thereby decreasing mitochondrial respiration and ROS formation [
5]. Thus, increased IIS with down-regulated nuclear FoxO levels impairs adequate elimination of ROS, a critical mechanism involved in the promotion of acne, T2D and cancer.