Investigating Healthy Aging in Killifish: Unlocking the Mystery of Eternal Fasting

A recent study conducted by the Max Planck Institute sheds light on the peculiar phenomenon of perpetual fasting in aging killifish. This research has implications for understanding the aging process in humans and offers potential avenues for promoting healthier aging. The study’s findings suggest that activating a specific subunit of AMP kinase can reverse the effects of continuous fasting in older fish, leading to improved health and longevity.

Fasting interventions, involving cycles of fasting and refeeding, are generally known to enhance overall health. However, the effectiveness of these interventions diminishes in older animals. The Max Planck Institute’s research focuses on the intriguing question of why this is the case.

By closely examining the lifespan of killifish, renowned for their rapid aging, researchers at the Max Planck Institute for Biology of Ageing in Cologne have made significant discoveries. They found that older killifish deviate from the typical fasting and refeeding pattern observed in their youth. Instead, they remain in a perpetual fasting state, even when consuming food. Interestingly, this state can be reversed by genetically activating a specific subunit of AMP kinase, a crucial cellular energy sensor.

The outcome of this genetic modification was remarkable. The aging killifish experienced substantial improvements in their overall health and lived longer, underscoring the importance of both fasting and refeeding in conferring health benefits. These processes appear to operate through the AMP kinase pathway.

While numerous studies have shown the positive impact of reduced calorie intake or periodic fasting in various model organisms, it remains challenging for humans to consistently limit their food intake over a lifetime. To determine the most effective timing for fasting interventions, researchers introduced fasting at different ages, revealing that the benefits diminish as animals grow older.

The research team from Cologne, Germany, focused on understanding age-related fasting effects in killifish, known for their remarkably rapid aging process. They conducted experiments by fasting both young and old fish for several days or providing them with twice-daily feedings. Their investigations centered on the visceral adipose (fat) tissue of the older fish, which exhibited reduced responsiveness to feeding.

It was found that the inability to respond effectively to the feeding phase placed the fat tissue of older fish in a continuous fasting mode. This resulted in the shutdown of energy metabolism, reduced protein production, and impaired tissue renewal. Surprisingly, even while consuming food, the older fish remained in this fasting state.

A key discovery emerged when researchers examined the differences between the fat tissue of young and old fish, revealing a specific protein called AMP kinase. This cellular energy sensor comprises various subunits, with the γ1 subunit showing reduced activity with age. When scientists enhanced the activity of the γ1 subunit through genetic manipulation, it counteracted the fasting-like state in the older fish, promoting better health and increased longevity.

Remarkably, a connection was established between the γ1-subunit and human aging. Lower levels of this particular subunit were observed in samples from elderly individuals. Moreover, the study found a correlation: individuals who were less frail in old age tended to have higher levels of the γ1-subunit.

However, it’s essential to note that further research is required to determine if the γ1-subunit is directly responsible for healthier aging in humans. The next phase of investigation will involve searching for molecules that can activate this subunit, with the aim of exploring their potential to positively influence the aging process.

Reference: “Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity” by Roberto Ripa, Eugen Ballhysa, Joachim D. Steiner, Raymond Laboy, Andrea Annibal, Nadine Hochhard, Christian Latza, Luca Dolfi, Chiara Calabrese, Anna M. Meyer, Maria Cristina Polidori, Roman-Ulrich Müller and Adam Antebi, 13 November 2023, Nature Aging. DOI: 10.1038/s43587-023-00521-y

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• Max Planck Institute for Biology of Ageing
• Nature Aging: Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity