Telomere dysfunction induces metabolic and mitochondrial compromise

Abstract

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…Interestingly, PGC‐1α levels are increased by exercise in muscle (Safdar et al., 2011) and PGC‐1α is considered to be a key player in mitochondrial changes induced by exercise (Safdar et al., 2011; Ventura‐Clapier, Mettauer, & Bigard, 2007). In addition, PGC‐1α extends health span and life span of a mouse model of premature aging arising from mitochondria defects (Sahin et al., 2011). Importantly, in line with the mitochondrial decline, PGC‐1α expression decreases during muscle aging in different species, including humans (Ghosh et al., 2011; Kang, Chung, Diffee, & Ji, 2013; Short et al., 2005; Vina et al., 2009).…”

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…Consistently, late‐generation (G3 and beyond) TERT (Rudolph et al ., 1999) or TERC‐deficient mice (TERT −/− and TERC −/− , respectively) are short living and show reduced fertility, early alopecia, kyphosis, anemia, and lymphopenia (Wong et al ., 2003). Interestingly, TERC −/− mice present altered mitochondrial functions, including increased production of reactive oxygen species (ROS) from the electron transfer chain (ETC) (Passos et al ., 2010; Sahin et al ., 2011). Thereby, telomeres have been suggested to play a role in controlling mitochondrial ROS accumulation and oxidative stress during aging (Sahin & Depinho, 2010).…”

“…Moreover, it has been shown that treating mouse embryos with chemicals able to induce mitochondrial dysfunction and ROS accumulation, led to telomere loss and chromosomal instability, which was prevented by a concomitant treatment with N ‐acetylcysteine, a compound that improves ROS scavenging (Liu et al ., 2002). However, other mutations in genes involved in ROS metabolism, such as SOD2 haploinsufficiency, do not cooperate with telomere dysfunction (Guachalla et al ., 2009), and the treatment with N ‐acetylcysteine does not rescue progeric phenotypes of late‐generation TERT‐deficient mice (Sahin et al ., 2011). …”

Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism

“…Recently, Dr. Ron DePinho (MD Anderson/Dana Farber) proposed a new theory for aging based on his experiments with telomerase-deficient mice [73][74][75][76] ( Fig. 8).…”