Linking functional decline of telomeres, mitochondria and stem cells during ageing

Abstract

The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere ‘capping’ function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, ‘stemness’ and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.

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

“…Above a threshold, telomere erosion results in the arrest of cellular proliferation and the dysfunction of renewable tissues. For this reason, telomerase activity and recombination‐based processes that maintain telomere length are critical for tissue homeostasis (Sahin & Depinho, 2010). In fact, mutations in either the gene encoding the telomerase catalytic subunit (telomerase reverse transcriptase, TERT), or the telomerase RNA gene (TERC) are found in patients with dyskeratosis congenita who have short telomeres and show accelerated aging and reduced lifespan (Kirwan & Dokal, 2009).…”

“…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). …”

The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence

“…Among their evolved adaptations are elaborate cellular protective programs that ensure stem cell integrity, tissue homeostasis, and organismal survival (Biteau, Hochmuth & Jasper, 2008; Brown et al., 2013; Ito et al., 2004; Rando, 2006; Renault et al., 2009; Rossi, Jamieson & Weissman, 2008; Rossi et al., 2007; Sahin & Depinho, 2010; Sperka, Wang & Rudolph, 2012; Walter et al., 2015). The mitochondrial unfolded protein response (UPR mt ), a cellular protective program that ensures proteostasis in the mitochondria, has recently emerged as a regulatory mechanism for adult stem cell maintenance that is conserved across tissues (Berger et al., 2016; Mohrin et al., 2015; Zhang et al., 2016).…”

A novel source of tetraploid cancer cell precursors: telomere insufficiency links aging to oncogenesis

“…Unless a specific enzyme, telomerase, becomes activated, at each cellular division, part of the telomere is lost. The telomere shortening mechanism limits human somatic cells (that usually do not express telomerase) to a fixed number of divisions and hence participates in the pathogenesis of aging (Sahin and Depinho, 2010). One of the fundamental biological differences between humans and laboratory mice (Mus musculus) constitutes in the fact that the former have relatively short telomeres, whereas the latter possess long telomeres.…”

“…One of the fundamental biological differences between humans and laboratory mice (Mus musculus) constitutes in the fact that the former have relatively short telomeres, whereas the latter possess long telomeres. Knockout of one of the subunits of telomerase, terc or tert, hence has no effect on the health or life span of the first generation of mice, yet limits their health and longevity after the third generation (Sahin and Depinho, 2010). In contrast to late-generation Terc À/À p53 þ / þ mice, late-generation Terc À/À p53 À/À (or p53 þ /À ) mice show increased tumor incidence (Blasco et al, 1997;Artandi et al, 2000).…”