New results are in from the Interventions Testing Program (ITP), our current gold standard for determining whether a drug extends lifespan in mice. They show that two commercially available compounds – astaxanthin and meclizine – significantly extend mouse lifespan. Let’s take a closer look at these findings and why they are important.
The ITP is held in high regard for a few reasons. Unlike many studies, the ITP does not test drugs on inbred mice. Inbred mice develop many health problems, meaning research using them can generate results that are not applicable to normal, healthy mice. The ITP instead uses a type of genetically heterogeneous mice called UM-HET3. These are mice whose grandparents each come from a different inbred strain. This means that any group of mice used by the ITP will share the same pool of genes, but individual mice are genetically different and not crippled by genetic diseases.
Additionally, when the ITP tests a drug, it doesn’t just use one group of mice in one lab. Even when scientists attempt to replicate the conditions of a previous experiment, different labs can and do introduce variables into an experiment that can influence the outcome. The ITP runs experiments at three different labs in the US simultaneously, which immediately tells us whether any lifespan extending effects are reproducible or not.
These practices make the bar for demonstrating lifespan extension higher. Several drugs that have previously been shown to extend lifespan in mice, such as the antidiabetic drug metformin, have failed to show significant benefits in the ITP.
Astaxanthin (Asta) is a naturally occurring carotenoid – yellow, orange and red pigments that give certain plants their colour, including (as their name suggests) carrots. Asta has been proposed to slow ageing. It’s a potent antioxidant and anti-inflammatory compound that can regulate multiple genes associated with protection against ageing and age-related diseases.
Meclizine (Mec) has a more surprising origin: it’s a drug used to treat nausea, vomiting, and dizziness caused by motion sickness and vertigo. What makes it interesting is that it binds and inhibits a signalling molecule called mTOR, which is thought to play an important role in the ageing process. mTOR is also inhibited by a drug called rapamycin, which has previously been shown to significantly extend mouse lifespan in the ITP, and is arguably one of our most promising drugs for slowing the ageing process.
Asta treatment, when started at 12 months of age, increased median mouse lifespan in males at all three testing sites. The median lifespan is the age by which 50% of the mice have died. The average increase in median male lifespan was 12%, from 817 days to 911 days. Asta also increased the lifespan of the 90th percentile (10% of mice live longer than this) for male mice by 6% on average, from 1092 days to 1159 days, but this increase wasn’t statistically significant.
Mec treatment, on the other hand, only increased median male lifespan in two testing sites, with an overall average increase of 8%, from 817 days to 885 days. 90th percentile lifespan increased by 6%, from 1092 days to 1156 days, but again this wasn’t statistically significant.
Both treatments fell significantly short of their target dose. For example, the actual amount of Asta in the mices’ diet was less than half of what researchers were aiming for, so the longevity benefits could have fallen short of their true potential.
Asta and Mec had no significant effects on the lifespans of female mice. This is something that has previously been observed in ITP studies with other drugs, which often find that female mice benefit less or not at all from lifespan-extending drugs in comparison to males. It’s still not fully clear why this is, and the explanation may be different in each case. In this particular study, researchers noted that males achieved higher blood levels of Mec, which may have contributed to the sex difference for this drug’s effectiveness.
5 other drugs of interest were also tested: fisetin, SG1002, dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. Unfortunately, none of them had a significant effect on mouse lifespan apart from 4-phenylbutyrate, which actually decreased lifespan in female mice.
Asta and Mec look like promising candidates as lifespan extending compounds. While the effects on mouse lifespan were not as strong as some other drugs, these are the first lifespan extending compounds to be validated by the ITP that the general public can already buy. Both have good human safety, with Mec sharing mechanisms of action with rapamycin while having fewer side effects. However, Mec also has effects on the central nervous system, and could be working in ways that are completely unrelated to the mechanisms of rapamycin.
As for the negative results, the most disappointing is perhaps the failure of fisetin, which had previously been shown to extend mouse lifespan in other studies. Fisetin is an antioxidant that has been found to reduce the burden of senescent cells – these are ‘zombie cells’ that have lost the ability to divide, but refuse to die. However, the ITP study found that fisetin did not significantly reduce senescent cell numbers or increase mouse lifespan.
In all cases, there is room to experiment with optimal doses. More work will also be needed to figure out the mechanisms behind lifespan extension with Asta and Mec, which remain vague.
Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used https://doi.org/10.1007/s11357-023-01011-0
Title image by Ricky Kharawala, Upslash