Gene expression in the liver of female, but not male mice treated with rapamycin resembles changes observed under dietary restriction

Abstract

It is well known that in mice the extension in lifespan by rapamycin is sexually dimorphic, in that it has a larger effect in females than males. In a previous study we showed that in male C57BL6 mice, rapamycin had less profound effects in both gene expression and liver metabolites when compared to dietary restriction (DR), but no data was available in females. Because recent studies showed that rapamycin increases longevity in a dose dependent manner and at every dose tested the effect remains larger in females than in males, we hypothesized that rapamycin should have a stronger effect on gene expression in females, and this effect could be dose dependent. To test this hypothesis, we measured the changes in liver gene expression induced by rapamycin (14 ppm) with a focus on several genes involved in pathways known to play a role in aging and that are altered by DR. To investigate whether any effects are dose dependent, we also analyzed females treated with two additional doses of rapamycin (22 and 42 ppm). We observed striking differences between male and female in gene expression at 14 ppm, where females have a larger response to rapamycin than males, and the effects of rapamycin in females resemble what we observed under DR. However, these effects were generally not dose dependent. These data support the notion that female mice respond better to rapamycin, and at least with the set of genes studied here, the effect of rapamycin in females resemble the effect of DR.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0909-7) contains supplementary material, which is available to authorized users.

Brain Protein Synthesis Rates in the UM-HET3 Mouse Following Treatment With Rapamycin or Rapamycin With Metformin

“…Increased P/T RpS6 in young male mice was the only response to RAP that was unique to either sex in our study. Lack of sexual divergence in response to treatment with RAP is somewhat atypical (25,26) and it has been shown that female mice have greater levels of RAP in the blood compared to males at a given dose (25). However, our findings may be explained by the use of an 8-week treatment in the current study rather than lifelong treatment.…”

“…Female mice have elevated blood levels of RAP at a given dose compared to males (25) and late-life treatment with RAP increased median lifespan 18% in females compared to 10% in males (24). In addition, RAP increased the expression of genes involved in slowed aging and protein turnover in the livers of female but not male C57BL/6 mice (26). In contrast, treatment with RAP+MET results in similar extension of lifespan in both sexes (2).…”

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

“…Comparative microarray analysis among several genetic models (Svensson et al ., 2011; Hofmann et al ., 2015), pharmacological interventions (Miller et al ., 2014; Yu et al ., 2015), and dietary interventions (Bartke et al ., 2007) known to extend lifespan has not revealed consistent shared features at the level of transcriptional changes, including mRNA levels for enzymes from the DNA repair response such as MGMT and NDRG1. These observations are consistent with our qRT–PCR analysis, which showed no significant changes in NDRG1 and MGMT mRNA expression in the Snell, GHRKO, and PAPPA‐KO mice with respect to controls (Fig.…”

“…We hypothesized that higher expression of MGMT and NDRG1 may be a common feature shared by Snell, GHRKO, and PAPPA‐KO mice, and that mTOR activity could be a key upstream regulator of MGMT and NDRG1 expression. Microarray analysis of the mRNA gene expression profiles of many different models of slow‐aging mice have not led to a consensus on common pathway(s) central to the aging process, including mice whose lifespan has been increased by mTOR reduction by drugs (Yu et al ., 2015) or dietary interventions (Swindell, 2008). However, it is plausible that improved DNA repair may be one important common feature (Meira et al ., 2014).…”

Mitochondria, Estrogen and Female Brain Aging

“…During the development, mRNA expression pattern of Sirt3 was similar in cortex, cerebellum and hippocampus, with Sirt3 mRNA levels being fairly consistent from embryonic day 18 (E18) until 24 months of age (Sidorova-Darmos et al, 2014 ). Unfortunately, sex differences were not investigated in the study of Sidorova-Darmos et al ( 2014 ), since the sex was not specifically determined for E18, postnatal days (PN) 2, PN7 or PN21 stages, while only female rats were used for the 3 and 24 month tissue samples, but Sirt3 mRNA levels were similar at least in liver tissue from male and female mice at the age of 11 months (Yu et al, 2015 ). Braidy et al ( 2015 ) investigated changes in the protein levels of various sirtuins in the aged female rat brain.…”