Reduced APRT Expression Extends Life in Killifish

Researchers here note that reducing APRT expression affects extends life in short-lived killifish via mechanisms likely related to the calorie restriction response. This regulation of the pace of aging in response to nutrient availability is arguably the most well studied aspect of the biology of aging, but the production of calorie restriction mimetic strategies (such as this one) seems unlikely to result in meaningful therapies for humans. Short-lived species exhibit a much greater extension of life span in response to a low calorie diet than occurs in long-lived species like our own. Mice can live as much as 40% longer when calorie restricted, but humans gain only a few years at most. It seems likely that many of the mechanisms involved in extending life in short-lived species are already turned on all the time in long-lived species.

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.

Using the turquoise killifish 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 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.

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. 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.