Longevity Briefs: More Results From The World’s Most Rigorous Mouse Lifespan Extension Testing Program

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Lifespan extension isn’t science fiction – numerous interventions have been shown to correlate with extended lifespan in animal models, but what does it actually mean to ‘prove’ lifespan extension? That’s a more complicated question than it may initially seem, but suffice it to say that a single study showing that mice given drug X live 10% longer on average doesn’t carry that much weight. The ‘gold standard’ for determining whether a compound extends mouse lifespan is called the Interventions Testing Program (ITP). Several factors make studies conducted as part of the ITP particularly reputable:

• They use large numbers of mice, for higher statistical power
• They run three studies in parallel at different locations when testing a compound, to reduce the likelihood of environmental conditions influencing the result
• They use genetically diverse mice, which make better, more human-relevant models than the highly inbred mice used by most studies
• They test each compound in both male and female mice, where the effects on lifespan often differ
• They measure both average lifespan and maximum lifespan, using a method that reduces the risk of outliers swaying the results

The ITP only tests compounds that already have some evidence behind them when it comes to lifespan extension. Despite this, most compounds tested so far have failed to produce significant lifespan extension, at least at the doses studied, though there have been some success stories. Unfortunately, the latest round of testing to come out of the ITP isn’t one of them.

The discovery:

The ITP tested 8 compounds, some of which had already been tested by the ITP at different doses and dose timings. Perhaps most notable among these was alpha-ketoglutarate (AKG), a molecule that plays a role in the production of ATP (the cell’s ‘universal fuel’) and that can suppress inflammation and mimic some of the effects of calorie restriction (a sharp reduction in calories without causing malnutrition). While AKG had previously been found to significantly extend mouse lifespan and delay age-related deterioration when started very early in life, the ITP had previously found no significant benefits when started at 18 months of age (roughly equivalent to a 60 year-old human). This time, AKG was started at 7 months of age, but once again, there was no significant benefit.

Other notable disappointments included astaxanthin (a natural carotenoid with antioxidant properties), meclizine (an antihistamine, anti nausea-drug) and mitoglitazone (which targets insulin sensing). Astaxanthin had previously been shown by the ITP to extend median lifespan (the age by which 50% of mice are dead) by 12% in male mice when started at 12 months of age. This time the ITP tested whether starting it later at 16 months, or earlier at 7 months but at a lower dose, would still result in lifespan extension, and found that neither of these conditions were successful. In the case of meclizine and mitoglitazone, which had both been shown to extend median lifespan in males when started at 12 and 7 months respectively, the ITP found that starting these compounds later in life did not have a significant impact, even when the doses were increased.

None of the other compounds tested showed any significant benefits. Those compounds were pioglitazone (similar to the aforementioned mitoglitazone) mifepristone (a steroid), atorvastatin (a statin) and methotrexate (chemotherapy agent and immune suppressant). Moreover, pioglitazone, mitoglitazone and low-dose astaxanthin were associated with a significant reduction in median lifespan for female mice. Researchers initially thought this could have been because the lifespan of the female control mice at one of the testing sites was unusually long, but when analysis was repeated excluding this site, pioglitazone and mitoglitazone were still associated with reduced survival.

The implications:

This study is a good demonstration of why we need rigorous assessment of lifespan-extending interventions, and why it is necessary to curb our enthusiasm when a new study appears to demonstrate lifespan-extending effects. The dose of a compound, when in life the animals receive it, and the housing conditions of the animals (including random environmental effects that researchers may not even be aware of) can all influence the outcome of a single study. The ITP runs three studies of shared design in parallel at different sites, and even these studies sometimes produce different results. Many lifespan extending compounds only work under specific conditions, such as when administered very early in life or at very high doses, either of which could make them unviable in humans even if they did translate from animal models.