More Life Extension in Flies By Manipulating Intestinal Tissue Gene Expression

A number of methods of life extension in flies involve altering the expression of specific genes in intestinal tissues only. For example, upregulating PGC-1 in intestinal stem cell populations makes flies live up to 50% longer, possible due to altered mitochondrial activity. The behavior of mitochondria shows up in many genetic and other manipulations of life span in laboratory animals, and mitochondrial damage is thought to be one of the root causes of degenerative aging. In flies the aging of the intestine appears to be very important in the context of overall aging and mortality, and is possibly the driving central organ failure that determines when most individuals die.

In the open access paper quoted below, researchers move on from PGC-1 to instead insert the yeast gene NDI1 into fly intestines, which also shows a resulting extension of life. This was done to confirm that PGC-1 manipulation works to extend life through alteration of mitochondrial function: NDI1 has been used in investigations of mitochondrial function for some years. To pick one example, scientists have in the past introduced NDI1 into mammalian cells to investigate its ability to improve mitochondrial function. So it's not at all surprising to see similar results in flies:

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

A decline in mitochondrial activity has been implicated in multiple degenerative diseases of aging. These findings raise the intriguing possibility that strategies to stimulate mitochondrial activity during aging may delay the onset of pathology and extend healthspan. 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. However, due to the extensive interactions that PGC-1 has with multiple aspects of metabolism, the possibility persists that endogenous dPGC-1 interactions, other than its role as a regulator of mitochondrial activity, play a role in the cellular and/or organismal phenotypes that we observed.

Unlike dPGC-1, ndi1 is exogenous, from a different kingdom, with no known homologs in animals, so any changes that result from ndi1 expression can reasonably be expected to be from the function of ndi1 as an NADH dehydrogenase. A previous study reported that ubiquitous expression of ndi1 using a constitutive driver line can increase fly lifespan. However, studies of the genetics of aging and lifespan determination are prone to confounding effects due to uncontrolled differences in genetic background between test and control lines. Using an inducible gene expresion system, which eliminates this issue, we failed to observe lifespan extension upon ubiquitous expression, but instead observed that neuron-specific expression of ndi1 can extend lifespan.

In the present study, we have extended this approach and show that expression of ndi1 in adult intestinal stem and progenitor cells can reduce whole tissue ROS levels, improve tissue homeostasis, delay the onset of intestinal barrier dysfunction, and extend the lifespan of flies. Therefore, a major conclusion of this study is that an increase in mitochondial NADH dehydrogenase activity alone in [intestinal stem cells] can delay both tissue and organismal aging, possibly by limiting pro-proliferative ROS levels in the intestinal epithelium.

Interestingly this manipulation is about as far as you can get from calorie restriction and growth-hormone related longevity manipulations that lead to smaller individuals: these longer-lived flies eat more and are larger that their unmodified peers.

Long-lived flies expressing ndi1 in [intestinal stem cells] have behavioral, physiological, and biochemical correlates of increased nutrition, showing increased feeding, weight, metabolic stores, and decreased systemic activation of AMPK. Importantly, ndi1-mediated weight gain can be observed upon adult-onset expression in [intestinal stem cells]. Moreover, both increased sensitivity to elevated temperatures, and resistance to starvation of the long-lived flies are wholly consistent with larger flies (with lower surface-to-mass ratios) and improved nutrient absorption and storage. Further studies using radioactive tracers of specific nutrients may provide clues as to whether increased total caloric uptake or differential absorption of specific nutrients play a role in the increased longevity of ndi1 expressing flies. Regardless of whether total caloric intake or absorbed nutrient composition plays a bigger role, one indication that improved nutrition plays a role in increasing lifespan is the ability of flies expressing ndi1 in [intestinal stem cells] to retain body weight and metabolic stores with age.

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