Calorie restriction is a mechanism proven to extend lifespan in multiple model organisms (see our blog on calorie restriction and aging). However, a key question that remains is how? An even more intriguing question is why is calorie restriction more effective in extending lifespan in some organisms than others, or not at all? Diet-induced obesity is becoming an epidemic, particularly in the United States. Not surprisingly, as overeating increases, so does the incidence of obesity and related diseases. There is evidence that restricting dietary intake makes it possible to stave off obesity and a number of other diseases that one would not expect to be associated with diet such as cancer, neurodegeneration, and kidney disease. How does dietary restriction (DR) accomplish this? And is it a healthy practice for humans? Dr. Pankaj Kapahi at the Buck Institute has dedicated the core of his lab’s research to these questions. The Kapahi lab primarily utilizes fruit flies (Drosophila melanogaster) to understand the genetic mechanisms responsible for the beneficial effects of DR.

Obesity is an ever-increasing epidemic in the United States. (Source wikimedia)

Obesity is an ever-increasing epidemic in the United States. (Source wikimedia)

DR is the process of limiting total or specific nutrients without causing malnutrition. One of the primary mechanisms by which DR affects the aging process is through the Target of Rapamycin (TOR) pathway. TOR has been shown to regulate growth and metabolism in multiple species by contributing to mRNA translation when upregulated. Nutrient intake contributes to TOR activity. So under normal feeding conditions, TOR remains active, leading to mRNA translation and growth in flies. However, under DR conditions, TOR activity is downregulated resulting in a reduction in growth and an extension in lifespan. This slowing of growth is due to TOR’s role in inhibiting activity of translational repressor 4E mRNA binding protein (4E-BP). Low TOR activity causes 4E-BP hypophosphorylation, which inhibits mRNA translation and reduces fly growth.

One might expect that under DR conditions, obesity would be prevented by a decrease in fat formation. However, this is not the case. The Kapahi Lab tracked the presence of labelled 14C from dietary glucose intake to triglyceride formation. What they found is that triglycerides are produced more rapidly in flies undergoing DR. So why aren’t these flies obese? And how is dietary restriction beneficial if it leads to higher levels of fat accumulation? The answer is that these flies have a higher metabolic rate than normally fed flies. Flies on DR that build fat quickly also break down fat at a similar pace. This metabolic shift occurs because the flies on DR are more active than flies fed a normal diet, and thus are “burning” more fat. This benefit of a higher metabolism appears to be correlated with increased lifespan.

To further demonstrate how metabolism affects lifespan, the Kapahi lab showed that increased 4E-BP activity under DR conditions causes higher fat turnover due to increased mitochondrial function. It was also found that by hindering the flies’ ability to fly, lifespan extension by DR was abolished. This indicates that exercise may be a necessary component to achieving beneficial effects of DR and may explain why studies in more complex organisms, such as mice and primates, do not always show the same lifespan extension effects of DR. It’s possible that the activity of these organisms is limited by housing constraints, and thus they cannot achieve the full benefits of DR. As a result, it is difficult to tell what effects, if any, DR may have on complex organisms and humans.

Although there are still many mysteries as to how healthspan and lifespan can be influenced by nutrients, there is one thing that is evidently clear: practicing healthy eating habits and regular exercise are the keys to a long and healthy life. Sweets and TV may be more satisfactory in the short term, but a healthy diet and exercise can allow you to enjoy a better quality of life in the long run.

For more on the Buck Institute Geroscience Courses, check out our article here, and the SAGE Geroscience webpage!