Biosynthesis is the key to longevity and metabolic health in vertebrates

Science and Health

A new study by researchers at the Hebrew University of Jerusalem (HU) has opened up exciting possibilities for developing interventions to combat age-related metabolic diseases and enhance healthy aging.

These far-reaching implications significantly advance our understanding of the intricate interplay among energy metabolism, aging and lifespan regulation. 

Led by Dr. Itamar Harel from HU’s Silberman Institute, it uncovered new knowledge about the role of AMP biosynthesis in the lifespan and metabolic health of vertebrates. It was published in the journal Cell Metabolism under the title “Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate.”

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 mice yielded unfavorable outcomes. In search of an alternative approach, the research team focused on manipulating the upstream nucleotide pool to modulate energy homeostasis – a biological process that involves the coordinated regulation of food intake (energy inflow) and energy expenditure (energy outflow).

Itamar Harel (credit: ITAMAR HAREL)

Fishy findings

Using the turquoise killifish – a large group of small fish found in Africa, southern Europe and America in which the mother releases undeveloped eggs – as their model organism, the team targeted and mutated 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 (the sum of constituents within a cell) 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 heterozygous fish exhibited remarkable traits such as enhanced nutrient sensitivity, reduced ATP levels, and activation of AMPK. These findings highlight the potential of agitating AMP biosynthesis to modulate vertebrate lifespan and promote metabolic health.

Harel expressed his enthusiasm by saying that “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 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.