Selection for Postponed Senescence in Drosophila melanogaster Reveals Distinct Metabolic Aging Trajectories Modifiable by the Angiotensin-Converting Enzyme Inhibitor Lisinopril.

Aging is accompanied by profound changes in energy metabolism, yet the underlying drivers and modulators of these shifts remain incompletely understood. Here, we investigated how life-history evolution shapes metabolic aging and pharmacological responsiveness by leveraging Drosophila melanogaster lines divergently selected for reproductive timing. We measured organismal oxygen consumption rate and performed untargeted metabolomics in young and old flies of both sexes from long-lived "O" lines (selected for female late-life reproduction) and unselected "B" control lines. Males and females from the O lines maintained stable metabolic rates and largely preserved metabolite profiles with age, whereas B line flies showed age-related increases in oxygen consumption, citrate accumulation, and elevated levels of medium- and long-chain fatty acids, hallmarks of mitochondrial inefficiency and impaired lipid oxidation. Aged B flies also displayed elevated S-adenosylmethionine, reduced sarcosine, and diminished heme levels, indicating dysregulation of one-carbon metabolism and impaired heme biosynthesis. Furthermore, Vitamin B6 metabolites, pyridoxamine, pyridoxal, and 4-pyridoxate, increased with aging only in B line females. Motivated by evidence implicating the renin-angiotensin system in metabolic aging, we treated flies with the angiotensin-converting enzyme (ACE) inhibitor lisinopril. Lisinopril prevented the age-related rise in metabolic rate in B line females, aligning their metabolic phenotype with that of O line flies. This suggests that ACE inhibition may buffer against age-associated increases in metabolic rate and contribute to enhanced metabolic stability. Our results show that selection for delayed reproduction and increased lifespan modifies age-related metabolic trajectories and modulates physiological responses to pharmacological intervention.