# Reserpine prolongs lifespan but compromises locomotion and heat-stress resilience in Drosophila melanogaster

## TL;DR

Reserpine extends the lifespan of fruit flies but reduces their movement and ability to survive heat stress.

## Contribution

The study reveals a trade-off between lifespan extension and stress resilience with reserpine in Drosophila.

## Key findings

- Reserpine extends Drosophila lifespan in a dose-dependent manner.
- Reserpine-treated flies show reduced locomotion and impaired heat-stress survival.
- Reserpine induces a low-energy state and blunts protective gene responses to heat stress.

## Abstract

Pharmacological modulation of monoaminergic signaling, a process targeted by many therapeutic and recreational drugs via receptors, transporters, degradation enzymes, or reuptake mechanisms, is emerging as a promising aging intervention and as a strategy to treat various maladies. Monoamines (including dopamine, serotonin, and norepinephrine) are central to the regulation of mood, movement, sleep, memory, and systemic physiology. Here, we demonstrate that Reserpine, chronic inhibitor of the vesicular monoamine transporter (VMAT), robustly extends lifespan in Drosophila melanogaster in a dose-dependent manner. However, reserpine-treated flies also exhibit reduced locomotor activity and impaired survival under acute heat-stress, indicating a context-dependent trade-off between lifespan extension and stress resilience. Transcriptomic profiling revealed that reserpine induces a transcriptionally repressed, low-energy state characterized by downregulation of metabolic, immune, and stress-response genes in treated aged animals. Notably, under heat-stress, reserpine blunts the induction of canonical protective genes, including heat shock proteins and antioxidant genes, resulting in increased proteotoxic vulnerability. These findings highlight the potential trade-offs of monoaminergic modulation and support further investigation of VMAT inhibitors, monoamine modulators and other hypertension drugs as geroprotective agents.