Rapamycin - An effective anti-aging agent?

Rapamycin

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Rapamycin was first discovered on Easter Island in the 1970s. When US
scientists treated old mice with rapamycin it extended their expected lifespan
by up to 38%. Rapamycin may have benefits of slowing down the ageing
process in older people. [5]

Rapamycin is an FDA-approved immunosuppressive and cardiology drug. It
is also an inhibtor of mammalian target of rapamycin (mTOR) pathway.
mTOR controls many processes involved in metabolism and response to
stress. Rapamycin may benefit animals at risk of cancers:

Target of rapamycin as a novel antitumor target
Cell growth (an increase in cell mass and size through macromolecular
synthesis) and cell cycle progression are generally tightly coupled, allowing
cells to proliferate continuously while maintaining their size. The target of
rapamycin is an evolutionarily conserved kinase that integrates signals from
nutrients (amino acids and energy) and growth factors (in higher
eukaryotes) to regulate cell growth and cell cycle progression coordinately.
[1] The mammalian target of rapamycin (mTOR) kinase is a key regulator of
cell growth and proliferation. Overexpression of the mammalian target of
rapamycin signaling pathway has been described in several tumor cells,
including the majority of acute myeloid leukemia (AML) cases. The
anti-tumor efficacy of mammalian target of rapamycin inhibitors was shown in
sevmammalian target of rapamycinl preclinical and clinical studies. [4]

In mammals, target of rapamycin is best known to regulate translation
through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic
translation initiation factor 4E-binding proteins. Consistent with the
contribution of translation to growth, target of rapamycin regulates cell,
organ, and organismal size. The identification of the tumor suppressor
proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched
in brain (Rheb) has biochemically linked the target of rapamycin and
phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for
the crosstalk that occurs between these pathways.[1]

Target of rapamycin is emerging as a novel antitumor target, since the target
of rapamycin inhibitor rapamycin appears to be effective against tumors
resulting from aberrantly high PI3K signaling. [1]

Example
Inhibition of the target of rapamycin signalling pathway by genetic or
pharmacological intervention extends lifespan in invertebrates, including
yeast, nematodes and fruitflies. [2]

Researchers reported that rapamycin extended median and maximal lifespan
of both male and female mice when fed beginning at 600 days of age. On
the basis of age at 90% mortality, rapamycin led to an increase of 14% for
females and 9% for males. The effect was seen at three independent test
sites in genetically heterogeneous mice, chosen to avoid genotype-specific
effects on disease susceptibility. Disease patterns of rapamycin-treated mice
did not differ from those of control mice. In a separate study, rapamycin fed
to mice beginning at 270 days of age also increased survival in both males
and females. Thus, rapamycin may extend lifespan by postponing death
from cancer, by retarding mechanisms of ageing, or both.[2]

Systemic lupus erythematosus and Sjogren's syndrome
Systemic lupus erythematosus and Sjogren's syndrome are chronic
inflammatory diseases characterized by the dysfunction of T cells, B cells,
and dendritic cells and the production of antinuclear autoantibodies. The
mammalian target of rapamycin in T and B cells has been successfully
targeted for treatment of systemic lupus erythematosus with rapamycin or
sirolimus both in patients and animal models. [3]

Acute myeloid leukemia
A study showed that rapamycin in concentrations of 1-10 nmol/l arrested the
cell cycle progression of Hl-60 cells in the G1 phase, without evident.
cytotoxic effect. At concentrations higher than 10 nmol/l, rapamycin exerted
a significant proapoptotic effect, with the collapse of mitochondrial potential
and caspase-3 activation.

Reference
[1] Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient
and growth factor signals and coordinator of cell growth and cell cycle
progression. Oncogene. 2004 Apr 19;23(18):3151-71. [2] 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.
Rapamycin fed late in life extends lifespan in genetically heterogeneous
mice. Nature. 2009 Jul 8. [3] Perl A. Emerging new pathways of pathogenesis
and targets for treatment in systemic lupus erythematosus and Sjogren's
syndrome. Curr Opin Rheumatol. 2009 Jul 4. [4] Janus A, Linke A, Cebula B,
Robak T, Smolewski P. Rapamycin, the mTOR kinase inhibitor, sensitizes
acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of
arabinozide cytarabine. Anticancer Drugs. 2009 Jul 6. [5] Tests raise life
extension hopes BBC 8 July 2009 00:00 UK