July 19, 2023—A recent study led by Dr. Itamar Harel, a researcher in the Experimental Biology of Vertebrate Aging & Age-Related Diseases and Genetics at the Hebrew University of Jerusalem (HU)’s Silberman Institute of Life Sciences, revealed new insights into the role of Adenosine monophosphate (AMP) biosynthesis in the lifespan and metabolic health of vertebrates. The study’s findings have far-reaching implications, significantly advancing our understanding of the intricate interplay between energy metabolism, aging, and lifespan regulation. Moreover, the study opens up exciting possibilities for developing interventions to combat age-related metabolic diseases and enhance healthy aging. 

Aging is commonly associated with disruptions in metabolic homeostasis, which contribute to various health issues. The AMP-activated protein kinase (AMPK) plays a critical role in cellular energy regulation and organismal metabolism. However, previous attempts to genetically manipulate the AMPK complex in biological models yielded unfavorable outcomes. In search of an alternative approach, the research team focused on manipulating the upstream nucleotide pool to modulate energy homeostasis. 

Using the turquoise killifish as its model organism, the team targeted and mutated adenine phosphoribosyltransferase (APRT), a key enzyme involved in AMP biosynthesis. Remarkably, this manipulation resulted in a significant extension of lifespan in heterozygous male killifish. The study further employed an integrated omics approach (providing biological insight based on statistical inference), revealing rejuvenation of metabolic functions in the aged, manipulated fish. These included the adoption of a fasting-like metabolic profile and enhanced resistance to a high-fat diet. 

At the cellular level, the heterozygous fish exhibited remarkable traits such as enhanced nutrient sensitivity, reduced ATP (adenosine triphosphate, the source of energy at the cellular level) measurements, and activation of AMPK. These findings highlight the potential of perturbing AMP biosynthesis to modulate vertebrate lifespan and promote metabolic health. 

Dr. Harel expressed his enthusiasm, stating, “This is the first long-lived genetic model in killifish, highlighting the potential is this emerging model for aging. 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 unveiled an intriguing observation. The benefits of extended lifespan and rejuvenated metabolic functions were nullified when lifelong intermittent fasting was applied. Furthermore, the longevity phenotypes were sex specific. This discovery underscores the complex underlying mechanisms and emphasizes the delicate balance required for optimizing health outcomes, which would be different in males and females. 

The research sheds new light on the potential of targeting APRT as a promising strategy for promoting metabolic health and extending 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. 

The research team consisted of Dr. Itamar Harel, Tehila Atlan, Dr. Gwendoline Astre, Dr. Adi Oron-Gottesman, Uri Goshtchevsky, Ariel Velan and Tomer Levy – Silberman Institute of Life Sciences, the Hebrew University of Jerusalem; Margarita Smirnov – Department of Fisheries and Aquaculture, Ministry of Agriculture and Rural Development; Kobi Shapira and Prof. Erez Y. Levanon – Faculty of Life Sciences, Bar-Ilan University; Dr. Joris Deelen – Max Planck Institute for Biology of Ageing. 

Dr. Harel is a Zuckerman Faculty Scholar and was recently awarded the prestigious European Research Council starting grant by the European Union.  

For more about the study, see “Genetic Perturbation of AMP Biosynthesis Extends Lifespan and Restores Metabolic Health in a Naturally Short-Lived Vertebrate,” in the journal, Developmental Cell.