Pharmacological Approaches to Decelerate Aging: A Promising Path

A interesting overview of the major anti-aging drug candidates and aging pathway details. I disagree with them including resveratrol and aspirin in the list… and missing many others like canagliflozin, acarbose, 17alpha estradiol, etc.

With regard to rapamycin it says:

4. Drugs with Antiaging Properties

4.1. Rapamycin

Rapamycin was first identified as an antifungal metabolite [124] and was found in a bacterium (Streptomyces hygroscopicus) that inhabited in the Easter Island (Rapa Nui) soil [124]. Immunosuppressive, antiproliferative, and anticancer properties of rapamycin was later on discovered [125]. The Food and Drug Administration (FDA) approved rapamycin as the first pharmacological agent that influences longevity in the mammalian species [126].

As said previously, mTOR plays a substantial role in aging and longevity. The role of mTOR signaling pathway in longevity and extend of life span has been studied in Caenorhabditis elegans [127, 128], Drosophila melanogaster [129], Saccharomyces cerevisiae [130, 131], and mice [132–135] [136]. In general, inhibition of the mTOR pathway, either genetically or pharmacologically, has shown to increase lifespan in different species [137]. The antiaging effects of rapamycin are exerted through various mechanisms, but the main route of action of rapamycin on the aging process is through inhibition of mTOR pathway. As mentioned, activation of SIRT1 and AMPK occurs following inhibition of mTOR, so rapamycin can also be indirectly effective in the aging process by activating SIRT1 and AMPK following inhibition of the mTOR pathway [82, 84, 138]. Regarding the inhibition of mTOR pathway, rapamycin inhibits both mTORC1 and mTORC2. However, its effect on mTORC2 is more complex. mTORC2 is rapamycin-insensitive. Rapamycin can inhibit mTORC2 indirectly and under prolonged exposure [139, 140]. Rapamycin binds to the cyclophilin FKBP12 and creates FKBP12-rapamycin complex. FKBP12-rapamycin complex interacts with FRB domain (FKBP12-rapamycin binding domain) of mTOR and ultimately inhibits mTORC1 activity [141, 142]. ULK1, elf4E, and S6K are downstream molecules of the mTORC1 pathway that regulate protein and nucleotide synthesis, as well as autophagy [91–94]. AKT and SKG1 are located downstream of the mTORC2 pathway, which are involved in cell survival, cell proliferation, and metabolism [89]. Figure 3 depicts antiaging mechanisms of rapamycin.

Figure 3

Mechanistic effect of rapamycin on longevity. The antiaging effects of rapamycin are mediated by inhibition of mTORC1. …

Rapamycin exerts its antiaging properties in the following manners:

  • (1) Prolonging lifespan and slowing down aging.
  • (2) Prolonging lifespan by influencing nonaging factors such as metabolic diseases and fatal neoplastic diseases

Full Research Paper: