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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
mTOR function (129). This indicates the existence of diseases, solid tumors, cardiovascular metabolic diseases
overlapping mechanisms of action for rapamycin and DR. and obesity have been observed even in humans.
Rapamycin treatment decreases body weight and food Rapamycin also prevented from degenerative brain
intake in mice (130) but the increase in longevity induced changes in an Alzheimer disease mouse model and
by the drug is independent of the decrease in food intake improved anxiety and depression in normal mice (134).
per se. However, since the longevity extension effect of Although some detrimental effects of the drug have been
DR (up to 40 %) is much larger than that of rapamycin described, the positive effects are much more diverse and
(around 11 %), rapamycin controls only part of the final extensive. In any case the global effect of rapamycin is
aging effector mechanisms increasing longevity during DR positive since both mean and maximum longevity are
or affects them with smaller intensity than DR, or does not increased.
affect similarly all mammalian organs. Most likely DR
targets also other cytosolic pre-nuclear longevity signaling DR increases longevity and lowers mitROSp, FRL, and
molecules (see section 9) different from mTOR that are oxidative stress (29), as well as mTOR function (59). And
not targeted by rapamycin. Alternatively, there is evidence intermittent rapamycin administration, like intermittent
that DR directly modifies some of the most likely effectors DR, also extends lifespan of female mice (135). Decreased
of aging like mitROSp, by-passing the nuclear aging mTOR downstream activity could constitute one of the
program (section 9), e.g, by decreasing mitochondrial various signaling mechanisms through which DR
matrix NADH due to lower concentrations of complex I- decreases aging rate (129, 136, 137). In agreement with
this, knocking out the gene coding the ribosome protein
linked substrates like pyruvate (see sections 5 and 6). kinase S6K (a main target of mTOR signaling) slowed
aging of bone, immune, and motor functions, and led to a
In addition to increasing longevity, there is a general larger than normal longevity (138). In many cases the
consensus that rapamycin attenuates age-associated nuclear gene response to these signals (see section 9)
declines in some measures of cardiac, immune, muscular, slows the aging rate. Among them, the decrease in
and cognitive function (122, 131). The increase in mitROSp produced by both DR and rapamycin can be
longevity induced by rapamycin was initially unexpected, important. In agreement with this concept, rapamycin
because rapamycin was used, together with other drugs, in dietary treatment, at the same dose that increased longevity
post-transplant therapy (132). Strikingly, increases (instead (121), decreased hepatic mitROSp (Figure 5A) and FRL at
of decreases) in various immune activities have been also complex I both in mice subjected to a diet that induced
observed at low rapamycin doses (129, 133). It is now fatty liver (53) as well as in middle aged mice receiving
known that mTOR inhibition in mammals has positive
functional effects in the majority of the physiological standard (LabDiet 5LG6 w) diets (139; Table 1).
systems (129, 131), and protection from degenerative
@Real Academia Nacional de Farmacia. Spain 63
