Hunger, an innate physiological sensation, has played a crucial role throughout human evolution, ensuring survival by driving individuals to seek food and maintain their energy levels. However, the modern world, with its abundance of food options and easy access to calorically dense meals, presents a stark contrast to the conditions in which we evolved. This juxtaposition has led to a significant challenge: the strong impulse of hunger and its satiation, once vital for survival, has become a detriment to human health. The consequences are evident in the rising global prevalence of obesity, a condition closely associated with various age-related pathologies that can dramatically shorten lifespan. Despite the challenges posed by the modern world’s food abundance and its negative impact on health and lifespan, intriguing research has emerged that harnesses the very sensation of hunger in an attempt to extend both.

Various interventions, such as calorie restriction, intermittent fasting, and amino acid restriction, have demonstrated their potential to extend lifespan, with hunger playing a common but not well-characterized role. In a recent study by researchers from the University of Michigan, the fascinating connection between hunger and lifespan extension was further explored, using fruit flies as a model organism [Weaver KJ, Holt RA, Henry E, et al. Effects of hunger on neuronal histone modifications slow aging in Drosophila. Science, 2023: 380(6645):625-632].

Fruit flies, scientifically known as Drosophila melanogaster, have long served as a valuable model organism for studying various biological phenomena. Their short lifespan, genetic tractability, and shared biological mechanisms with humans make them ideal for research purposes. While it’s important to acknowledge the limitations of extrapolating findings from flies to humans, this research nonetheless provides valuable insights that can guide further investigations.

BCAAs are Critical Modulators of Lifespan

The study conducted by Weaver et al. delves into the intriguing relationship between branched-chain amino acid (BCAA) restriction and the lifespan of fruit flies. BCAAs, namely leucine, isoleucine, and valine, are essential amino acids that play crucial roles in protein synthesis and cellular metabolism. These amino acids are vital building blocks for the synthesis of proteins in the body and are involved in numerous physiological processes.

In the context of the study, the researchers focused on exploring how restricting BCAA intake affected the lifespan of fruit flies. By manipulating the availability of BCAAs in the diet of fruit flies, the scientists aimed to elucidate the impact of BCAA restriction on their lifespan and to uncover potential mechanisms involved.

BCAA restriction was found to have a significant impact on fruit fly lifespan. Surprisingly, the results revealed a somewhat paradoxical effect. While calorie restriction is a well-known method to extend lifespan, the fruit flies on a low-BCAA diet exhibited increased appetite and food consumption, a phenomenon known as hyperphagia. Consequently, this increased food intake led to a greater caloric intake compared to flies on a regular diet. Additionally, the low-BCAA diet also resulted in a higher intake of amino acids, making up for the low-BCAA deficit. This would suggest that the activation of hunger and its resultant downstream effects are critical to the enhanced longevity of these animals and might act independently of the nutrients they consume.

Further investigation revealed that isoleucine, one of the BCAAs, acts as a critical signal of food consumption. Depletion of isoleucine triggered an elevation in hunger levels, leading to increased food intake. Remarkably, isoleucine restriction alone induced a state of heightened hunger and extended the lifespan of fruit flies.

Hunger and its Role in Lifespan Extension

To understand the underlying mechanisms of hunger-induced lifespan extension, the researchers delved into the intricate workings of a specific subset of fruit fly neurons known as R50H05 neurons. These neurons are responsible for sensing hunger and transmitting signals related to food-seeking behavior. To investigate the role of these hunger-sensing neurons, the researchers employed the powerful and innovative technique of optogenetics.

Optogenetics involves genetically modifying neurons to express light-sensitive proteins called opsins, which allows precise control over neural activity using light stimulation. Optogenetics provides a unique opportunity to dissect complex neural circuits and unravel the direct effects of specific neurons on various physiological processes.

In the case of this study, the researchers genetically engineered the R50H05 neurons in fruit flies to express opsins that respond to specific wavelengths of light. This genetic modification enabled the scientists to selectively activate the hunger-sensing neurons using light, independently of food availability or dietary manipulations. By using light as a tool to precisely control the activity of the hunger-sensing neurons, the researchers were able to investigate their impact on lifespan extension.

Through optogenetic stimulation of the R50H05 neurons, the researchers observed a remarkable extension of fruit fly lifespan. This finding suggested that the activation of these specific hunger-sensing neurons alone was sufficient to promote longevity, even in the absence of changes in food intake or dietary composition. The use of optogenetics in this study shed light on the critical role played by the R50H05 neurons in regulating lifespan and highlighted the potential for manipulating hunger-related neural circuits as a means of extending lifespan.

The research conducted by Weaver et al. provides intriguing insights into the connection between hunger and lifespan extension. Despite the paradoxical nature of increased food consumption, the restriction of specific BCAAs, particularly isoleucine, appears to be a key driver in triggering hunger-related pathways that promote longevity in fruit flies. By activating neurons associated with hunger sensation, independent of nutritional factors, the researchers demonstrated the ability to extend lifespan. While these findings are preliminary and further studies are warranted, they shed light on the complex interplay between hunger and aging, opening doors for potential therapeutic interventions and strategies for promoting healthy aging.