PT  - JOURNAL ARTICLE
AU  - Gwendoline Astre
AU  - Tehila Atlan
AU  - Uri Goshtchevsky
AU  - Kobi Shapira
AU  - Adi Oron-Gottesman
AU  - Tomer Levy
AU  - Ariel Velan
AU  - Margarita Smirnov
AU  - Joris Deelen
AU  - Erez Y Levanon
AU  - Itamar Harel
TI  - Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis
AID  - 10.1101/2022.01.10.475524
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.10.475524
4099  - http://biorxiv.org/content/early/2022/03/22/2022.01.10.475524.short
4100  - http://biorxiv.org/content/early/2022/03/22/2022.01.10.475524.full
AB  - Energy homeostasis is disrupted with age, which then fuels multiple age-related pathologies. The AMP-activated protein kinase (AMPK) is the primary sensor of cellular energy in eukaryotes. However, the genetic regulation of vertebrate aging by AMPK remains poorly understood. Here, we manipulate energy levels in the turquoise killifish by mutating APRT, a key enzyme in AMP biosynthesis. These manipulations produced a male-specific lifespan extension and restored metabolic plasticity. Exploring the observed sex differences using an integrated omics approach implicated the mitochondria as an important player. Mechanistically, APRT regulated mitochondrial functions and AMPK activity, mimicking energy starvation in heterozygous cells. A fasting-like state was also detected, particularly in heterozygous males, which leads to resistance to high-fat diet. Finally, life-long intermittent fasting eliminated the male-specific longevity benefits mediated by the APRT mutation. These observations identify the AMP/AMPK axis as a sex-specific regulator of vertebrate longevity and metabolic health.Competing Interest StatementThe authors have declared no competing interest.