Aging is in fact regulated by specific genetic signaling transduction pathways. Simple changes in the environment (e.g. dietary restriction) can drastically extend lifespan, suggesting that several of these genetic pathways control longevity in response to changes in the surroundings.
Notch promotes the proliferation of myogenic progenitor cells, and inhibits their precocious terminal differentiation by inhibiting WNT via GSK3β activation. Conversely, during later stages of muscle repair and regeneration, WNT inactivation of GSK3β thereby promotes myoblast and myotube differentiation. Increased WNT is also reported to skew the differentiation of muscle stem cells (satellite cells) towards a fibroblast lineage, during muscle repair in an age-dependent manner.
PI3K/Akt signaling interacts with WNT pathway via the signaling molecule 14-3-3ζ, which acts as a facilitator of β-catenin activation by Akt, thus stabilizing the β-catenin complex and promoting its nuclear translocation. Akt can also negatively regulate GSK, thus attenuating its inhibitory effect on β-catenin and enhancing WNT signaling.
Consequently, this PI3K/Akt-WNT crosstalk, mediated by Akt, may become aberrant in aging as Akt phosphorylation is diminished in old rat aortas under uniaxial stretch, and in old BMSCs/osteoblasts under IGF-I treatment. Similarly, the hormoneinduced activation of both PI3K and Akt is impaired in rat enterocytes isolated from old animals. However, phosphorylation of both PI3K and Akt is reported to increase during aging of the rat kidney.
At the level of coordination between nervous and immune systems, age-specific changes in Hh signaling are also implicated in the pathophysiology of Multiple Sclerosis (MS) and Parkinson's disease (PD). Shh-N (N-terminal) levels are reduced in both grey and white matter from MS patients.