AMP biosynthesis regulates vertebrate lifespan and metabolic health

Dr. Itamar Harel from the Silberman Institute at the Hebrew University of Jerusalem recently led a study that has provided fresh insights into the significance of AMP biosynthesis in the lifespan and metabolic health of vertebrates.

The study’s findings have wide-ranging implications and significantly advance our understanding of the intricate interplay between energy metabolism, aging, and lifespan regulation. They also open up exciting possibilities for developing interventions to combat age-related metabolic diseases and improve healthy aging. The research has been published in the journal Developmental Cell.

Aging often leads to disturbances in metabolic balance, which contribute to various health problems. The AMP-activated protein kinase (AMPK) plays a crucial role in regulating cellular energy and organismal metabolism. However, previous attempts to genetically manipulate the AMPK complex in mice did not yield favorable outcomes.

In search of an alternative approach, the research team focused on manipulating the upstream nucleotide pool to modulate energy balance.

To investigate this, they used the turquoise killifish as a model organism and targeted and mutated APRT, a key enzyme involved in AMP biosynthesis.

Remarkably, this manipulation resulted in a significant extension of lifespan in male killifish that carried a single copy of the mutation. The study also employed an integrated omics approach, revealing rejuvenation of metabolic functions in the aged mutant fish. These included the adoption of a fasting-like metabolic profile and enhanced resistance to a high-fat diet.

At the cellular level, the mutant fish exhibited remarkable traits such as heightened nutrient sensitivity, reduced ATP levels, and activation of AMPK. These findings highlight the potential of perturbing AMP biosynthesis to modulate vertebrate lifespan and promote metabolic health.

Dr. Itamar Harel stated, “This is the first long-lived genetic model in killifish, underscoring the potential of this emerging model for aging research. Genetic manipulation of AMP biosynthesis in the turquoise killifish reveals remarkable effects on lifespan and metabolic health. Our study unravels the intricate interplay between energy metabolism, aging, and lifespan regulation, offering exciting possibilities for the development of interventions to combat age-related metabolic diseases and enhance healthy aging.”

However, the study also made an intriguing observation. The benefits of extended lifespan and rejuvenated metabolic functions were nullified when lifelong intermittent fasting was applied. Additionally, the longevity effects were specific to each sex. This discovery underscores the complex underlying mechanisms and emphasizes the delicate balance required to optimize health outcomes, which may differ between males and females.

The research sheds new light on the potential of targeting APRT as a promising strategy to improve metabolic health and extend lifespan in vertebrates. Further investigations in this field hold promise for the development of interventions that enhance healthy aging and combat age-related metabolic diseases.

Source: Hebrew University of Jerusalem

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