Angiotensin-Converting Enzyme Inhibitors and Metabolic Aging: A Drosophila Perspective

Abstract

Aging is characterized by a progressive decline in physiological function that impairs performance and increases vulnerability to disease and mortality. Delaying this deterioration is key to promoting healthy aging. Age-associated functional decline is closely linked to alterations in intermediary metabolism, including disrupted lipid metabolism and impaired mitochondrial function. Counteracting these metabolic changes, particularly those affecting basal metabolic rate and energy utilization, may be a feasible strategy to extend healthspan. The Renin-Angiotensin System (RAS), which controls blood pressure through Angiotensin II, an octapeptide hormone generated from Angiotensin I by Angiotensin-Converting Enzyme (ACE), has been identified as a potential target for aging therapies. ACE inhibitors, such as the commonly prescribed vasodilator lisinopril, have been shown to exert beneficial effects on healthspan. Disentangling their systemic effects from direct cellular actions on intermediary metabolism is challenging in humans but can be pursued in model organisms. Drosophila melanogaster expresses two ortholog of mammalian ACE, Ance and Acer, which have diverged to acquire different functions. Since fundamental cellular processes are evolutionarily conserved and flies have an open circulatory system, Drosophila provides a versatile model for translational studies on ACE inhibition and aging. Recent studies in Drosophila reveal sex-, age-, and genetic background-specific effects of lisinopril on metabolic rates and aging-related organismal phenotypes. Integrating preclinical findings from Drosophila with clinical studies will be essential to define the therapeutic potential of RAS inhibition in extending lifespan and delaying aging.

Keywords: Drosophila; aging; metabolism; renin-angiotensin system blockade.

Figure 1

Canonical and non-canonical renin–angiotensin system (RAS) pathways in humans. Renin cleaves angiotensinogen to angiotensin I, which is converted by ACE to angiotensin II in the canonical pathway. Ang II binding to AT1R mediates vasoconstriction, aldosterone release, inflammation, and cell growth. ACE inhibitors block the conversion of angiotensin I to angiotensin II and prevent the degradation of bradykinin. Angiotensin receptor blockers prevent Ang II from binding AT1R. In the non-canonical axis, ACE2 converts angiotensin II to Ang (1-7), which signals via Mas to drive vasodilation, anti-inflammatory, and anti-proliferative activities. The dynamic balance between these axes is critical not only for blood pressure control but also for influencing aging trajectories, metabolic health, and tissue resilience.

Figure 2

Neuroprotective and functional effects of ACE inhibitors in Drosophila Alzheimer’s disease models. Treatment with ACE inhibitors (e.g., lisinopril, captopril) reduces neuronal cell death and improves memory in flies overexpressing human amyloid precursor protein and β-secretase in the neuron system. Lisinopril also enhances locomotor function, associated with reduced oxidative stress and improved mitochondrial dynamics in muscle tissue.

Figure 3

Lisinopril modulates metabolic rate in a genotype-, age-, and sex-specific manner through conserved and tissue-specific mechanisms in D. melanogaster. (A) Exposure to lisinopril alters whole-body metabolic rate in Drosophila Genetic Reference Panel (DGRP) lines, with responses varying by genotype, age, and sex. Increased metabolic rate is associated with elevated cold resistance and upregulation of uncoupling proteins (Ucp4b and Ucp4c) in the heads of male flies, suggesting a thermogenic mechanism potentially mediated by bradykinin-like peptides. (B) Tissue-specific RNAi knockdown of Ance, the Drosophila ortholog of ACE, in the nervous system and Malpighian (renal) tubules results in opposite effects on metabolic rate. The metabolic effects of lisinopril are abolished in Ance-deficient tissues in a sex- and age-dependent manner. These findings underscore the importance of tissue context in ACE inhibitor action and support the utility of Drosophila for dissecting gene x drug interactions.