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Gustavo Barja de Quiroga

Figure 5. Rapamycin fully reverses the age-related increases in mitROSp and mtDNA fragments inside nuclear DNA. Rapamycin
dietary treatment, at the same dose that increases mouse longevity (14 mg/Kg diet, Ref. 121), totally abolished the A) age-related increase
in mitROSp, and B) the accumulation of mtDNA fragments inside nDNA in the liver of middle-aged mice (16 months of age). In part B

the pictures show single representative hepatocyte nuclei corresponding to: a) YOUNG; b) MID; c) MIDRAPA; red signals come from
mtDNA; green signals from minor satellite mouse centromeric sequence (MiSat) were used as controls; white bar is equal to 2µm. MID =
Middle aged mice. MIDRAPA = middle aged mice treated with rapamycin during 7 weeks. a: significantly different from Young group; b:
significantly different from Middle group; * P<0.05, *** P<0.001. The qualitative and quantitative similarity of the changes induced by
rapamycin in both parameters suggest a cause-effect relationship between them. Modified from ref. 139.

Moreover, this drug completely reversed age-related middle aged humans.
increases in mitROSp (Figure 5A), and the age-related
increase in the insertion of mtDNA fragments inside In summary, it is most interesting that all the (four)
nDNA, in the liver of middle aged mice (139; Figure 5B; experimental manipulations which consistently and
see also section 8). In the same investigation, it also reproducibly increase both mean and maximum longevity
completely reversed age-related decreases in the in mammals, DR, PR, MetR and rapamycin, decrease
autophagocytosis marker ATG13 (Figure 6A), and mitROSp and FRL at complex I and mtDNA damage
partially reversed the accumulation of the best tissue (Table 1). This strongly supports the antioxidant-
marker of aging, lipofuscin, in the liver (Figure 6B). independent version of MFRTA exposed in this review that
Rapamycin also increases mouse longevity when the focuses on: i) the rates of ROS production (initiation) at
treatment is started at middle age, with an effect similar to mitochondria; and ii) cellular components highly resistant
that observed starting at 9 months (119, 121), agreeing to (oxidative) modifications like less unsaturated
again with the decreases observed in mitROSp also in membrane fatty acids (low DBI). These two traits of the
middle aged mice (139). All those results, taken together, updated MFRTA could be accompanied by a third related
are most remarkable since there is currently strong interest factor in long-lived animals, iii) increased autophagy (see
in finding drugs with positive effects on longevity in section 9).

Figure 6. Rapamycin totally reverses the age-related decrease in autophagy and partially reverses the increase in lipofuscin
accumulation. Rapamycin dietary treatment of middle aged mice (16 months of age), at the same dose that increases mouse longevity (14
mg/Kg diet, Ref. 121) totally abolished A) the age-related decrease in the autophagocytosis marker protein ATG13, and B) partially
reversed the age-related accumulation of lipofuscin (B) in the liver of middle-aged mice (16 months of age). In part B the pictures show
single representative hepatocytes corresponding to: a) YOUNG; b) MID; c) MIDRAPA; bright red signals come from lipofuscin; the
nucleus is seen in blue colour; white bar is equal to 10µm. MID = Middle aged mice. MIDRAPA = middle aged mice treated with
rapamycin during 7 weeks. a: significantly different from Young group; b: significantly different from Middle group; * P<0.05; *** P<0.001.

64 @Real Academia Nacional de Farmacia. Spain