Telomeres in aging and disease: lessons from zebrafish

Abstract

Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased risk of cancer. For the last two decades, this link has been mostly investigated using mice that have long telomeres. However, zebrafish has recently emerged as a powerful and complementary model system to study telomere biology. Zebrafish possess human-like short telomeres that progressively decline with age, reaching lengths in old age that are observed when telomerase is mutated. The extensive characterization of its well-conserved molecular and cellular physiology makes this vertebrate an excellent model to unravel the underlying relationship between telomere shortening, tissue regeneration, aging and disease. In this Review, we explore the advantages of using zebrafish in telomere research and discuss the primary discoveries made in this model that have contributed to expanding our knowledge of how telomere attrition contributes to cellular senescence, organ dysfunction and disease.

Keywords: Aging; Cancer; Disease; Telomerase; Telomeres; Zebrafish.

Fig. 1.

Telomeres shorten at different rates, anticipating local and systemic tissue dysfunction in zebrafish aging. Telomeres shorten naturally over time in specific zebrafish organs, such as the gut and muscle (but not testes), regardless of differences in proliferation rates. This shortening, together with the accumulation of local telomere damage, precludes the onset of tissue-dysfunction events in aging, including intestinal inflammation and sarcopenia. Critically short telomeres in the gut and muscle might prove to be sufficient in disrupting homeostasis in unrelated tissues, where telomeres do not shorten, by generating systemic signals (purple) of dysfunction that create a ‘disease-permissive’ environment.

Fig. 2.

Pathways modulated by the short-telomere–p53 axis. Telomere dysfunction, as well as exogenous genotoxic agents and deficiencies in DNA repair, activates p53 (Chin et al., 1999), causing PUMA-mediated apoptosis (Sperka et al., 2012) and p21 cell-cycle arrest, and, consequently, cell senescence (Choudhury et al., 2007). p53 upregulation also leads to impairments in energy homeostasis and potential suppression of IGF-1 signalling, which result in repression of master regulators (such as PGC1α/β) of mitochondrial biogenesis. This leads to mitochondrial dysfunction and, consequently, increased ROS levels, which promote further damage at telomeres. ROS, reactive oxygen species. For further information and references, see the main text.

Fig. 3.

The role of telomerase, telomeres and senescent cells in zebrafish heart regeneration. Cryoinjury in zebrafish mimics aspects of human myocardial infarction. (A) In wild-type fish, cardiomyocyte proliferation is sharply increased in response to tissue damage, accompanied by an increase in tert gene expression, hyperactivation of telomerase and a transient elongation of telomeres (3 dpi). Additionally, there is an accumulation of senescence cells, limited to the injured region (3 dpi) that is cleared upon wound closure (60 dpi) (Bednarek et al., 2015). Senescent cells release growth factors and cytokines, which might activate the motility and proliferation of surrounding cells, potentiating tissue remodelling. (B) Aged cardiac tissues, modelled by the absence of telomerase (tert^−/−), are not amenable to tissue remodelling, reflecting a combination of factors, such as proliferative defects, accumulation of DNA-damaged cells and increased senescence (3 dpi and 60 dpi). The difficulty in handling and clearing damaged and senescent cells might overload the tissue with the senescence-associated secretory phenotype (SASP), which potentially contributes to a persistent chronic inflammatory microenvironment that further aggravates tissue dysfunction and impairs proper wound closure (Bednarek et al., 2015).