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Review
. 2020 Jan 1;75(1):4-13.
doi: 10.1093/gerona/glz060.

Is Rapamycin a Dietary Restriction Mimetic?

Archana Unnikrishnan  1 , Kavitha Kurup  1 , Adam B Salmon  2   3 , Arlan Richardson  1   4
Affiliations
Review

Is Rapamycin a Dietary Restriction Mimetic?

Archana Unnikrishnan et al. J Gerontol A Biol Sci Med Sci. .

Abstract

Since the initial suggestion that rapamycin, an inhibitor of target of rapamycin (TOR) nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, Caenorhabditis elegans, Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice. The current data show that dietary restriction and rapamycin have different effects on many pathways and molecular processes. In addition, these interventions affect the lifespan of many genetically manipulated mouse models differently. In other words, while dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction and rapamycin will have a greater effect on lifespan than either manipulation alone.

Keywords: Dietary restriction; Insulin sensitivity; Lifespan; Rapamycin; TOR.

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Figures

Figure 1.
Figure 1.
Effect of DR and rapamycin on mTOR signaling and autophagy. The mTOR pathway was assessed in liver samples by measuring levels of phosphorylated S6 respect to the total S6 and autophagy by measuring levels of LC3II and LC3I (LC3II/LC3I ratio). At 2 months of age, male C57BL/6 mice were fed either ad libitum (AL, blue), 60% of AL (DR, red), 14 ppm rapamycin (Rapa, green), or DR and rapamycin (DR+Rapa, orange) for 6 months. The mice were fasted for 16 hours before they were used in this study. The data were obtained from 10 mice per group and expressed as mean ± SD; an asterisk denotes those values that are significantly different from AL mice at the p ≤ .05 level. There was no significant difference between the DR, Rapa, or DR+Rapa groups. The data for the AL, DR, and Rapa mice taken from Fok et al. (43) while the data for the DR+Rapa mice were generated at the same time but not published.
Figure 2.
Figure 2.
Effect of DR and rapamycin on glucose and insulin tolerance. The data were obtained from male mice described in Figure 1, and data are expressed as mean ±SEM for 10 mice per group. The values that are significantly different (p ≤ .05) from AL mice is shown by the asterisks. The data for the AL (blue), DR (red), and Rapa (green) mice taken from Fok et al. (43) while the data for the mice treated with both rapamycin and DR (orange) were generated at the same time but not published.
Figure 3.
Figure 3.
Effect of DR and rapamycin on the liver transcriptome. The principle component analysis of transcriptome data obtained from the livers of AL (blue), DR (red), rapamycin (green) and DR + rapamycin (orange) mice are shown for the top three principle components. Using linear discrimination predictor and the quadratic discriminant analysis, the PCA data were statistically analyzed. The DR group showed perfect separation of 1 between either the AL group or the rapamycin group. The rapamycin group showed a separation of 0.8 from the AL group, which indicates separation but some overlap between the two groups. Similarly, when the DR group was compared with the DR + rapamycin group a separation of 0.8 was observed. However, when the DR + rapamycin group was compared to either the rapamycin group or AL group, a perfect separation of 1 was observed. Data were taken from Fok et al. (70)
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