Short-term dietary restriction in old zebrafish changes cell senescence mechanisms

Abstract

Brain aging is marked by a decline in cognitive abilities and associated with neurodegenerative disorders. Recent studies have shown, neurogenesis continues into adulthood but is known to be decreasing during advancing age and these changes may contribute to cognitive alterations. Advances, which aim to promote better aging are of paramount importance. Dietary restriction (DR) is the only non-genetic intervention that reliably extends life- and health-span. Mechanisms of how and why DR and age affect neurogenesis are not well-understood, and have not been utilized much in the zebrafish, which has become a popular model to study brain aging and neurodegenerative disease due to widely available genetic tools. In this study we used young (8-8.5months) and old (26-32.5months) zebrafish as the model to investigate the effects of a short-term DR on actively proliferating cells. We successfully applied a 10-week DR to young and old fish, which resulted in a significant loss of body weight in both groups with no effect on normal age-related changes in body growth. We found that age decreased cell proliferation and increased senescence associated β-galactosidase, as well as shortened telomere lengths. In contrast, DR shortened telomere lengths only in young animals. Neither age nor DR changed the differentiation patterns of glial cells. Our results suggest that the potential effects of DR could be mediated by telomere regulation and whether these are beneficial or negative remains to be determined.

Stress reactivity elicits a tissue-specific reduction in telomere length in ageing zebrafish (Danio rerio)

“…Although we report TL shortening at 18 months of age in both brain and heart tissue, previous research using zebrafish has not observed age-dependent differences in TL until fish are at least 2 years of age (41,70).Furthermore, others have shown no TL effect of age in the brain of zebrafish (39). Failure to detect telomere shortening in brain tissues could be a consequence of the lower rate of cell renewal and neurogenesis in the adult brain compared to heart making detection difficult (39,63,69).The lack of consistency in zebrafish findings highlights possible differences in the technique used to assess telomere length, on the rate of telomere attrition between strains (40,41) and animal facilities, which should all be carefully considered. Furthermore, we have combined data from a sibling populations of young and ageing zebrafish, thus allowing for samples to be processed simultaneously, which assures similar storage time and reagents used, critical consideration for the study of telomere biology (71).…”

“…Zebrafish have emerged as a promising animal model to explore telomere dynamics due to important similarities with humans. These include high genomic conservation (37), agedependent telomere shortening (38)(39)(40), and, unlike mice, similar telomere lengths to humans (41,42). Furthermore, the zebrafish hypothalamic-pituitary-interrenal (HPI) axis is analogous to its human counterpart, the HPA axis (43).…”

Zebrafish Aging Models and Possible Interventions

“…Changes in cellular proliferation may affect cognitive processing in the aged individual, and thus, zebrafish provide a good model for understanding mechanisms that regulate cell turnover in the brain. It has been observed by our research group and others that in both young and old adult zebrafish, neurogenesis is observed in the telencephalon, however, there is a significant decline in old adults [67,68]. This decrease is attributed to the lengthening of cell cycle and decrease in the number of radial glia cells with self-renewal capability.…”

“…Telomere shortening [66] Decrease in telomerase activity [66] Cellular and synaptic Decrease in neurogenesis Cognitive decline and altered behavior [67,68] Impaired oligodendrogenesis [67] Altered balance in excitatory/inhibitory transmission [75] age-related alterations in epigenetic patterns [58]. One well established epigenetic marker of aging is gradual decrease in global DNA methylation [59].…”

Celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish

“…The regulation of these effects on reducing aging phenotypes is thought to be in part through 30 the action of the Sirtuin family of acetyltransferases (Guarente, 2013), mTOR (Blagosklonny, 2010) 31 and Insulin receptor/Foxo signaling (Kim et al, 2015;Mouchiroud et al, 2013). In fish models, the 32 effects of dietary restriction on aging and age-related pathologies have been mainly tested in zebrafish, 33 in which most studies use overall dietary restriction as means of nutritional regulation (Adams and 1 Kafaligonul, 2018;Arslan-Ergul et al, 2016;Novak et al, 2005). Such treatment regimens have 2…”