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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.
Highlights
Identifying the molecular and cellular mechanisms that underlie organismal aging represents an urgent biomedical challenge
To examine the impact of targeted expression of ndi1 in intestinal stem cell lineages (ISCs and EBs), we first used the constitutive esgGAL4 driver line and observed a significant extension of lifespan in both female (Figures 1C and S1C-D) and male flies (Figures S1E-F) compared to controls. esgGal4 expression is restricted to intestinal stem cells (ISCs) and EBs in the intestine, it is expressed in stem cells within malpighian tubules, germline and somatic stem cells in the testis, and in salivary glands [22]
In support of this idea, we recently reported that overexpression of the fly PGC-1 homolog, dPGC-1, in ISC lineages is sufficient to preserve intestinal homeostasis during aging and extend fly lifespan [11]
Summary
Identifying the molecular and cellular mechanisms that underlie organismal aging represents an urgent biomedical challenge Towards this goal, considerable attention has been focused on the progressive decline in stem cell functions [1] and, separately, mitochondrial activity [2] that occurs during aging. We have characterized the role of the Drosophila PGC-1 homolog (dPGC-1/spargel), a key regulator of mitochondrial energy metabolism, in the maintenance of ISC quiescence, intestinal integrity, and lifespan determination [11]. Given the diverse roles that PGC-1 plays in metabolism [12], the question of whether an increase in mitochondrial activity alone, in ISC lineages, is sufficient to confer these phenotypic outcomes remains to be determined. Ndi expression in ISCs/EBs improves tissue homeostasis in the aging intestine and confers increased longevity at the organismal level, demonstrating that increased NADH dehydrogenase activity alone is sufficient to produce these beneficial effects. We show that enhanced mitochondrial complex I activity in ISC lineages can simultaneously alter feeding behavior in adult flies and prolong lifespan
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