Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells

Abstract

A functional decline in tissue stem cells and mitochondrial dysfunction have each been linked to aging and multiple aging-associated pathologies. However, the interplay between energy homeostasis, stem cells, and organismal aging remains poorly understood. Here, we report that expression of the single-subunit yeast alternative NADH dehydrogenase, ndi1, in Drosophila intestinal stem and progenitor cells delays the onset of multiple markers of intestinal aging and extends lifespan. In addition, expression of ndi1 in the intestine increases feeding behavior and results in organismal weight gain. Consistent with increased nutrient uptake, flies expressing ndi1 in the digestive tract display a systemic reduction in the activity of AMP-activated protein kinase (AMPK), a key cellular energy sensor. Together, these results demonstrate that ndi1 expression in the intestinal epithelium is an effective strategy to delay tissue and organismal aging.

Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut

“…Second, we identified that Su(H)GBE + EBs are the progenitors of ECs, instead of EEs, by using a novel lineage-tracing system: T-TRACE. To rule out the possibility that some Su(H)GBE low EBs may be the progenitors of EEs, we performed a lineage-tracing experiment using another EB Gal4 driver, 5966GS (Guo et al, 2014;Hur et al, 2013;Kapuria et al, 2012;Mathur et al, 2010), and further confirmed that 5966GS + EBs are also not the progenitors of EE cells. Third, we identified a transit cell type called pre-EE (or EE progenitor), which expresses both the ISC marker Dl and the EE marker Pros.…”

“…The 5966GS is expressed in EBs and ECs, but is excluded from ISCs and EEs (Fig. 3C,C′) (Guo et al, 2014;Hur et al, 2013;Kapuria et al, 2012;Mathur et al, 2010). We cultured the adult flies on food with RU486 at room temperature (∼22°C).…”

Stem cell aging: mechanisms, regulators and therapeutic opportunities

“…These data indicate that age-related mitochondrial dysfunction is reversible and contributes to dysfunction in aged tissues. On the basis of this result, one may extrapolate that ectopic expression of the single-subunit yeast alternative NADH dehydrogenase in Drosophila intestinal stem cells delays the onset of intestinal aging and extends lifespan by regulating the NAD + /NADH ratio in aged cells 119 . It will be interesting to determine whether the roles of NAD + and NADH dehydrogenase in age-dependent mitochondrial dysfunction are conserved in stem cells of different tissues and different species and whether similar strategies to manipulate the NAD + /NADH ratio in humans could have therapeutic benefit.…”

Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality

“…In aged flies, excessive proliferation of intestinal stem cells and the accumulation of mis-differentiated cells in the intestinal epithelium result in intestinal dysplasia (Biteau et al, 2008; Choi et al, 2008; Park et al, 2009), which limits organismal lifespan (Biteau et al, 2010; Hur et al, 2013; Rera et al, 2011; Wang et al, 2014). Previous studies have reported increased microbial loads in aged Drosophila populations (Broderick et al, 2014; Buchon et al, 2009; Guo et al, 2014; Ren et al, 2007) and that flies maintained axenically throughout life display reduced levels of dysplasia and other cellular markers of intestinal aging (Broderick et al, 2014; Buchon et al, 2009; Guo et al, 2014).…”