A recent study by Loic Verlingue and colleagues, published in the September 9 issue of Aging Cell. 2016 Sep 9 (doi: 10.1111/acel.12504), presents a comprehensive approach to examine the molecular determinants of lifespan using a Boolean model of geroconversion.
“The pharmaceutical inhibition of mTOR (comprising mTORC1 and/or mTORC2) is the most reproducible intervention to expand lifespan in preclinical models and correlates with a reduction of cell senescence proportions in many species including humans (Harrison et al., 2009; Anisimov et al., 2010; Popovich et al., 2014; Warner, 2015). Still, the pro-proliferative activity of mTORC1 is conceptually difficult to reconcile with its role in permanent growth arrest. Moreover, a prophylactic mTOR inhibition may inevitably expose individuals to well-known treatment’s toxicities (MacDonald & RAPAMUNE Global Study Group, 2001; Mahe et al., 2005; Ferte et al., 2011). Modeling the dose-related benefits and
risks of rapamycin treatment in the molecular network that controls senescence could therefore contribute to healthy lifespan expansion strategies for humans.”
“Geroconversion is a specific type of cell senescence resulting from the inappropriate activation of growth signals in nonproliferative cells.”
Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV (2010) Rapamycin extends maximal lifespan in cancer-prone mice. Am. J. Pathol. 176, 2092–2097.
Ferte C, Paci A, Zizi M, Gonzales DB, Goubar A, Gomez-Roca C, Massard C, Sahmoud T, Andre F, Soria J-C (2011) Natural history, management and pharmacokinetics of everolimus-induced-oral ulcers: insights into compliance issues. Eur. J. Cancer 47, 2249–2255.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395.
Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV (2014) Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol. Ther. 15, 586–592.
MacDonald AS & RAPAMUNE Global Study Group (2001) A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 71, 271–280.
Mahe E, Morelon E, Lechaton S, Sang K-HLQ, Mansouri R, Ducasse M-F, Mamzer-Bruneel M-F, de Prost Y, Kreis H, Bodemer C (2005) Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 79, 476–482.
Warner HR (2015) NIA’s intervention testing program at 10 years of age. Age (Dordr) 37, 22.