Clark RI et al. (2017) Cell Mol Life Sci "Role of gut microbiota in aging-related health decline: insights from invertebrate models."

Walker DW, Clark RI

[Cell Mol Life Sci, 2017]

Studies in mammals, including humans, have reported age-related changes in microbiota dynamics. A major challenge, however, is to dissect the cause and effect relationships involved. Invertebrate model organisms such as the fruit fly Drosophila and the nematode Caenorhabditis elegans have been invaluable in studies of the biological mechanisms of aging. Indeed, studies in flies and worms have resulted in the identification of a number of interventions that can slow aging and prolong life span. In this review, we discuss recent work using invertebrate models to provide insight into the interplay between microbiota dynamics, intestinal homeostasis during aging and life span determination. An emerging theme from these studies is that the microbiota contributes to cellular and physiological changes in the aging intestine and, in some cases, age-related shifts in microbiota dynamics can drive health decline in aged animals.

Hur JH et al. (2010) Aging (Albany NY) "Aging: Dial M for Mitochondria."

Walker DW, Hur JH, Cho J

[Aging (Albany NY), 2010]

A major goal of aging research is to identify interventions that prolong lifespan in distantly related organisms. In recent years, genetic studies in both nematodes and rodents have reported that moderate inactivation of genes important for mitochondrial electron transport chain (ETC) function can promote longevity. We performed an RNAi screen to probe the role of ETC components in modulating lifespan in the fruit fly Drosophila melanogaster. In this Research Perspective, we discuss our findings and how they may relate to similar studies in worms and mice.

Hur JH et al. (2014) J Bioenerg Biomembr "Complex-I-ty in aging."

Stork DA, Walker DW, Hur JH

[J Bioenerg Biomembr, 2014]

The role of mitochondrial complex I in aging has been studied in both C. elegans and Drosophila, where RNAi knock down of specific complex I subunits has been shown to extend lifespan. More recently, studies in Drosophila have shown that an increase in mitochondrial activity, including complex I-like activity, can also slow aging. In this review, we discuss this apparent paradox. Improved maintenance of mitochondrial activity, mitochondrial homeostasis, may be responsible for lifespan extension in both cases. Decreased electron transport chain activity caused by reducing complex I subunit expression prompts an increase in stress response signaling that leads to enhanced mitochondrial homeostasis during aging. Increased complex I activity, as well as mitochondrial biogenesis, is expected to both directly counteract the decline in mitochondrial health that occurs during aging and may also increase cellular NAD(+) levels, which have been linked to mitochondrial homeostatic mechanisms through activation of sirtuins. We suggest that manipulations that increase or decrease complex I activity both converge on improved mitochondrial homeostasis during aging, resulting in prolonged lifespan.

Rera M et al. (2013) Ageing Res Rev "Organ-specific mediation of lifespan extension: more than a gut feeling?"

Walker DW, Rera M, Azizi MJ

[Ageing Res Rev, 2013]

Multicellular organisms are composed of an interactive network of various tissues that are functionally organized as discrete organs. If aging were slowed in a specific tissue or organ how would that impact longevity at the organismal level? In recent years, molecular genetic approaches in invertebrate model systems have dramatically improved our understanding of the aging process and have provided insight into the preceding question. In this review, we discuss tissue and organ-specific interventions that prolong lifespan in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. These interventions include reduced Insulin/IGF-1 signaling, knockdown of genes important for mitochondrial electron transport chain function and, finally, up-regulation of the Drosophila PGC-1 homolog. An emerging theme from these studies is that the intestine is an important target organ in mediating lifespan extension at the organismal level.

Brownlee DJA et al. (1996) Parasitol Today "Nematode neuropeptides: Localization, isolation and functions."

Holden-Dye L, Brownlee DJA, Walker RJ, Fairweather I

[Parasitol Today, 1996]

Historically, peptidergic substances (in the form of neurosecretions) were linked to moulting in nematodes. More recently, there has been a renewal of interest in nematode neurobiology, initially triggered by studies demonstrating the localization of peptide immunoreactivities to the nervous system. Here, David Brownlee, Ian Fairweather, Lindy Holden-Dye and Robert Walker will review progress on the isolation of nematode neuropeptides and efforts to unravel their physiological actions and inactivation mechanisms. Future avenues for research are suggested and the potential exploitation of peptidergic pathways in future therapeutic strategies