Mice Fed Rapamycin Have an Increase in Lifespan Associated with Major Changes in the Liver Transcriptome

Abstract

Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes (<300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (>4,500) changed significantly in females. Using multidimensional scaling and heatmap analyses, the male mice fed rapamycin were found to segregate into two groups: one group that is almost identical to control males (Rapa-1) and a second group (Rapa-2) that shows a change in gene expression (>4,000 transcripts) with more than 60% of the genes shared with female mice fed Rapa. Using ingenuity pathway analysis, 13 pathways were significantly altered in both Rapa-2 males and rapamycin-fed females with mitochondrial function as the most significantly changed pathway. Our findings show that rapamycin has a major effect on the transcriptome and point to several pathways that would likely impact the longevity.

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…5A,D). While the basis for this difference is unknown, higher mTORC1 signaling in female C57BL/6J.Nia mice correlates with both their slightly shorter lifespan relative to males, and to the greater increase in lifespan female mice show following treatment with rapamycin (Turturro et al ., 1999; Fok et al ., 2014). The differences observed here may also contribute to the sexually dimorphic impact of S6K1 deletion on lifespan (Selman et al ., 2009).…”

“…We were also unable to examine how the effect of dietary rapamycin on mTOR signaling might change with age due to insufficient supply of aged mice. However, we note that our study represents the first extensive analysis of age‐associated changes in mTOR signaling in a mouse strain (C57BL/6J.Nia) that is demonstrated to live longer following rapamycin treatment (Fok et al ., 2014). Future longitudinal studies using advanced techniques (e.g., in vivo imaging) to track how mTOR signaling changes with age and rapamycin in individual mice that are permitted to live a natural lifespan may shed light on how mTOR signaling at the individual level correlates with lifespan.…”

“…We conclude that aging does not result in a generalized increase in mTOR signaling in C57BL/6J.Nia mice, a strain in which dietary rapamycin significantly extends lifespan and rejuvenates the aging heart (Dai et al ., 2014; Fok et al ., 2014). We do observe age‐associated increases in mTOR signaling in specific tissues of C57BL/6J.Nia mice, and the beneficial effects of rapamycin on longevity in this strain may be due in part to the blunting of age‐associated increases in mTOR signaling in specific tissues such as adipose and HSCs (Chen et al ., 2009).…”

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

“…It has a lifespan‐prolonging effect in several studies on different model organisms, including S. cerevisiae (Powers et al ., 2006; Medvedik et al ., 2007), C. elegans (Robida‐Stubbs et al ., 2012), D. melanogaster (Moskalev & Shaposhnikov, 2010), and M. musculus (Harrison et al ., 2009; Fok et al ., 2014; Miller et al ., 2014). It has acceptable acute toxicity – mouse LD50 oral > 2500 mg kg −1 (Vezina et al ., 1975) – although it can induce a range of reversible but concerning side effects (Soefje et al ., 2011).…”

Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin

“…1 Rapamycin extends life span in mice. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Furthermore, rapamycin delays the onset of cancer in mice. [3][4][5][6][7][9][10][11][12][13]15,18 Rapamycin and everolimus (a rapamycin analog) decrease the risk of cancer in humans, who receive these rapalogs to prevent transplant rejection.…”