The mTOR pathway is necessary for survival of mice with short telomeres

Abstract

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc −/−) have an hyperactivated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc −/− livers. Treatment of G2-Terc −/− mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc −/− mice also decreases longevity, in contrast to lifespan extension in single S6K1 −/− female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.

Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair‐deficient mice

“…A scenario where the anti‐aging effect primarily results from its anti‐cancer effect would match with our data, as Ercc1 ∆/− mice show accelerated aging without development of neoplasia throughout their (brief) life span (Dollé et al, 2011; Marteijn et al, 2014) rendering an anti‐cancer drug ineffective in modifying life span of these progeroid DNA repair‐deficient mice. mTOR was recently shown to be required for the survival of mice with short telomeres (Ferrara‐Romeo et al, 2020). Although the Ercc1 ∆/− mice age accelerated, they and related progeria patients do not have shortened telomeres (Zhu et al, 2003).…”

DNA- and telomere-damage does not limit lifespan: evidence from rapamycin

“…Similarly, rapamycin does not extend but even slightly shortens lifespan in telomerase-deficient mice, which die young from poor growth and intestinal atrophy caused by telomere shortening [ 3 ]. (As we will discuss, this is predictable by hyperfunction theory.)…”

“…(As we will discuss, this is predictable by hyperfunction theory.) While shortening lifespan by 18% in unnatural telomerase-deficient mice, in the same study in natural mice, rapamycin increased lifespan by 39% and healthspan by 58% (measured as tumor-free survival) [ 3 ]. In dozens of independent studies, rapamycin has not failed to extend lifespan in normal mice [ 4 ].…”

“…This prediction has been confirmed. In dozens of studies, rapamycin prolongs lifespan and healthspan in mice [ 3 , 30 – 65 ]. Rapamycin extends lifespan in C elegans [ 66 ] and Drosophila [ 67 – 69 ].…”

The goal of geroscience is life extension

“…The higher the dose, the longer lifespan [ 57 , 61 , 70 ]. In one exception that emphasizes the rule, rapamycin slightly shortened lifespan in artificial mice lacking telomerase that failed to grow and die young but not from aging [ 68 ]. As predicted by theory [ 2 ], rapamycin, which slows growth and cell proliferation, will be unfavorable during developmental growth in mice that fail to grow.…”