The search for evolutionary developmental origins of aging in zebrafish: A novel intersection of developmental and senescence biology in the zebrafish model system

Abstract

Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and regulation. We wish to ascertain whether we can identify such genes promptly in a comprehensive manner. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates.

The short-lived African turquoise killifish: an emerging experimental model for ageing

“…In addition, owing to their capacity of regenerating the heart, tail and spinal cord ( Asnani and Peterson, 2014 ; Becker et al, 1997 ; Poss et al, 2003 , 2002 ), they are also used as models for regenerative medicine ( Goessling and North, 2014 ). These attributes have naturally paved the way for zebrafish to also be introduced as a model for studying ageing ( Anchelin et al, 2011 ; Gilbert et al, 2014 ; Kishi, 2011 ; Kishi et al, 2003 ; Van Houcke et al, 2015 ). The model displays key hallmarks of ageing, including age-dependent mitochondrial dysfunction, telomere deterioration (loss of the terminal portions of the chromosomes) and protein oxidation ( Kishi et al, 2003 ).…”

Dopaminergic modulation of working memory and cognitive flexibility in a zebrafish model of aging-related cognitive decline

“…Zebrafish (Danio rerio) have recently emerged as a promising model of cognitive aging (Gerhard, 2007;Yu et al, 2006). Zebrafish live on average for ~3 years, but can have a life span as long as 4-5 years under laboratory conditions (Kishi, 2011).…”

Successful optic nerve regeneration in the senescent zebrafish despite age-related decline of cell intrinsic and extrinsic response processes

“…Their robust regenerative capacity continues to drive comparative research, and a remarkably high similarity in the signaling pathways underlying CNS regeneration in mammals and zebrafish has already been unraveled Elsaeidi et al, 2014;Fleisch et al, 2011;Wang and Jin, 2011). Now, they are also increasingly valued in gerontology, as it is recently established that zebrafish -like most vertebrates -are subject to processes of gradual aging (Gerhard, 2003;Gerhard and Cheng, 2002;Keller and Murtha, 2004;Kishi, 2011;Kishi et al, 2003;Van houcke et al, 2015). Indeed, also in these small teleosts, reparative capacities diminish with aging.…”