Low Dose Naltrexone Produces a Small Extension of Life in Nematodes

Over the past decade, researchers have put a great deal of effort into automating and otherwise reducing the costs of studies of aging in nematode worms. A properly equipped team can now screen thousands of compounds in a year in nematodes, while obtaining good data on life span and pace of decline with age via a range of metrics. Sadly, short-lived species such as nematodes have life spans that are far more plastic in response to interventions than is the case for longer-lived species such as our own. A 10-20% increase in nematode life span is likely irrelevant to humans; some interventions that probably do little in humans have increased nematode life span by 100% or more. It is worth bearing this in mind when reading papers such as the one noted here.

There is increasing interest in the concept of aging as a druggable target to prevent age-related diseases. However, developing new drugs to address human aging presents challenges in conducting clinical trials. In the absence of validated risk biomarkers, a large and initially healthy population would need to be treated over an extended period, making it difficult to conduct trials. Therefore, repurposing existing drugs with a good safety profile is a more practical short-term solution than developing new drugs.

Naltrexone is a prescription medication approved by the US Food and Drug Administration (FDA) in 1984 for the treatment of alcohol use disorder and opioid use disorder. It belongs to a class of drugs called opioid antagonists. In recent years, there have been several significant findings regarding a specific dosage of naltrexone called low-dose naltrexone (LDN). LDN has been shown to have immune-modulating properties that could reduce various oncogenic and inflammatory autoimmune processes and alleviate symptoms of certain mental ailments.

Here, we studied the potential benefits of low-dose naltrexone (LDN) in promoting healthy aging using Caenorhabditis elegans as a model organism. We found that LDN treatment extended both healthspan and lifespan in worms, while high-dose naltrexone did not produce the same effects. Further metabolomics analysis revealed that LDN treatment induced metabolic changes that led to increased activity of both amino acid and glucose metabolism, but the longevity effect was independent of the DAF-16/FOXO3 signaling.

We then tested various mutant strains and found that the lifespan extension induced by LDN treatment was dependent on the SKN-1/NRF2 transcription factor. We also observed that LDN treatment not only increased the expression of innate immune genes but also upregulated the oxidative stress response, in line with a role for SKN-1/NRF2 in LDN's lifespan promoting effects. Inhibiting the nuclear translocation of SKN-1 from the cytosol could attenuate the LDN-mediated innate immune gene expression and oxidative stress response. Overall, our study highlights the potential of LDN as a therapeutic agent for promoting healthy aging and identifies its mechanism of action.

Link: https://doi.org/10.1016/j.isci.2024.109949