RT Journal Article
SR Electronic
T1 Sex-specific regulation of metabolic health and vertebrate lifespan by AMP biosynthesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.10.475524
DO 10.1101/2022.01.10.475524
A1 Gwendoline Astre
A1 Tehila Atlan
A1 Uri Goshtchevsky
A1 Kobi Shapira
A1 Adi Oron-Gottesman
A1 Tomer Levy
A1 Ariel Velan
A1 Erez Y Levanon
A1 Joris Deelen
A1 Itamar Harel
YR 2022
UL http://biorxiv.org/content/early/2022/01/10/2022.01.10.475524.abstract
AB The loss of energy homeostasis seen during aging, is causally linked to multiple age-related pathologies. The AMP-activated protein kinase (AMPK) directly senses cellular energy levels, which are reflected in the ratio between AMP:ATP. However, the genetic regulation of vertebrate aging by the AMPK pathway remains poorly understood. Here, we manipulate ATP production by mutating APRT, a key enzyme in AMP biosynthesis, and extend vertebrate lifespan in a male-specific manner. Using a multi-omics approach, we demonstrate that the APRT mutation restores metabolic plasticity, and identify a distinct transcriptional signature linking mitochondria with the sex-related differences in longevity. Accordingly, APRT mutant cells display a reduction in mitochondrial functions and ATP levels, and an increase in AMPK activity, resembling a persistent state of energy starvation. In-vivo, a fasting-like response was observed exclusively in male mutants, including resistance to a high-fat diet. Finally, intermittent fasting eliminated the longevity benefits mediated by the APRT mutation in males. Together, these data identify AMP biosynthesis as a sex-specific mediator of vertebrate longevity and metabolic health.Competing Interest StatementThe authors have declared no competing interest.