Rapamycin

Sirolimus is the generic name for the natural product rapamycin, produced by a strain of Streptomyces hygroscopicus isolated from a soil sample collected on Rapa Nui (Easter Island). ^[1] Although it was first isolated as an antifungal agent, subsequent studies revealed immunosuppressive and antiproliferative activities, and demonstration of its immunosuppressive activity in animal models of organ transplantation led to clinical trials and regulatory approval for prophylaxis of renal graft rejection. ^[1] Rapamycin is a Food and Drug Administration (FDA)-approved inhibitor of the protein kinase mechanistic target of rapamycin (mTOR). ^[2]

Sirolimus forms a complex with the intracellular protein FKBP12, and this complex blocks the activation of the kinase TOR, with downstream events blocking cell-cycle progression at the junction of the G1 and S phases. ^[1] The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors, and regulates many fundamental cell processes from protein synthesis to autophagy. ^[3] Deregulated mTOR signaling is implicated in the progression of cancer and diabetes as well as the aging process. ^[3]

Inhibition of mTOR with rapamycin promotes health and longevity in diverse model organisms. ^[2] Rapamycin slows aging and extends life span in a variety of species from worm to mammals. ^[4] In an assessment of interventions to slow ageing grouped by the robustness of preclinical and some clinical results, rapamycin is placed in the top tier of candidates. ^[5] For human aging, clinical trials have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging, and work remains to be done before mTOR inhibitors could become part of the standard of care for diseases of aging. ^[2] Beyond transplantation, sirolimus (an mTOR inhibitor) has been approved for the treatment of lymphangioleiomyomatosis, a destructive lung disease affecting primarily women that is caused by mutations leading to hyperactivation of mTOR complex 1. ^[6]

In clinical studies of rapamycin given as an immunosuppressant, no dose-limiting toxicity was observed and only asymptomatic thrombopenia and hyperlipemia were reported. ^[7] Immunosuppressant drugs as a class, including the mTOR inhibitors sirolimus and everolimus, can cause side effects such as hypertension, infection, and hyperlipidemia. ^[8] In kidney transplantation, mTOR inhibitors have yielded mixed results, with improved kidney function tempered by a higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. ^[9]