Scientists Confirm Three New Lifespan-Extending Compounds (In Mice)

Getting your Trinity Audio player ready...

Researchers recently published results suggesting that three compounds significantly extend mouse lifespan. Let’s take a look at these results and their implications.

The ITP

These results come from the Interventions Testing Program (ITP), considered by most to be the ‘gold standard’ when it comes to determining whether a compound extends lifespan in mice. You can read more about the strengths of the ITP here. In brief, the ITP runs three separate experiments at three different sites when testing a compound for lifespan extension, making it less likely that specific environmental conditions within a given lab will skew the results. It also uses large sample sizes of genetically diverse mice, as opposed to the highly inbred mice that are plagued by health problems used in many studies. The ITP also tracks lifespan in male and female mice separately, which is essential given that lifespan-extending compounds often work better in one or other sex.

The main metrics of success are median lifespan (the age by which 50% of mice are dead) and p90 lifespan (the age by which 90% of the mice are dead). The latter is an approximation of whether the compound extends the maximum age to which the mice are likely to live, as opposed to simply increasing average lifespan.

What Worked

Out of six compounds examined in this round of testing, the ITP identified three compounds with promise:

• Epicatechin, a type of flavonoid (plant compounds with antioxidant properties) extended median lifespan by 5% and p90 lifespan by 6%, but only in males. The median lifespan increase was only statistically significant when pooling data across all three sites. There was no statistically significant effect in female mice.
• Halofuginone, an antiparasitic drug with metabolic effects that mimic those of amino acid restriction (which has been shown to extend lifespan). It extended median lifespan by 9% and p90 lifespan by 7%, but only in males. When analysed by site, these increases were only statistically significant at one of the three sites. There was no statistically significant effect in female mice.
• Mitoglitazone, a drug that targets metabolism in the mitochondria (the structures within the cell that generate ATP, the cell’s main energy source) and has been investigated for the treatment of type II diabetes and Alzheimer’s disease. It extended median lifespan by 9% in male mice, but had no significant effect on p90 lifespan in males or on either measurement in females. When analysed by site, the median lifespan increase in males was only statistically significant at one of the three sites. There was also a non-significant trend towards decreased median lifespan in female mice.

For comparison, the highest increases in median and p90 lifespan were 28% and 20% respectively, both achieved by rapamycin in female mice.

What Didn’t Work

The three other tested compounds were 2BAct (which helps protect against cellular stress), dichloroacetate (which boosts mitochondrial function), and forskolin (which regulates programmed cell death and mitochondrial function). None of them produced a statistically significant effect in either male or female mice, but forskolin was associated with an 8% increase in median lifespan in male mice. This is enough of a trend not to rule out forskolin just yet – the authors suggest that varying the dose might achieve more impressive effects.

A Closer Look at the Winners

The graphs above show the percentage of surviving mice for the three successful compounds and their controls, with male mice on the left and female mice on the right. You can see from the graphs for epicatechin (EPI) and halofuginone (HAL) that survival rates for treated and control mice are similar until the mice are around 750 days old, after which the control mice start to die off faster than the treated mice. This suggests that these compounds are mainly benefiting the mice in later life. By contrast, mitoglitazone (MIT) appears to work differently – treated mice survive better in early life, but the control mice ‘catch up’ with them later on as the treated mice die of faster in later life.

These differences could be because mitoglitazone is working in a fundamentally different way to the other two drugs. It is also possible that the mice metabolised mitoglitazone differently as they aged, resulting in a decreased effect.

Why Didn’t They Work in Female Mice?

It’s impossible to say from these studies alone why lifespan extension only occurred in male mice, as the ITP doesn’t focus on the mechanisms of the drugs that they test. While there are some compounds that extend lifespan more in females (such as rapamycin, which achieved the greatest increase in both median and maximum lifespan to date), the ITP has so far observed that most compounds work better in males, and in some cases only work in males, while they have yet to observe a compound that only works in females. This could be partly because male mice live shorter natural lifespans, so there is more ‘room for improvement’, but this doesn’t explain why treated male mice sometimes outlive treated female mice, or why female lifespan sometimes decreases while male lifespan increases. There are still sex-specific difference in ageing that need further study.

Sources of Epicatechin

Epicatechin is the only naturally available successful compound from these studies. Cocoa powder contains the highest epicatechin content per gram, so chocolate (the darker and less processed the better) is one dietary source of epicatechin. Other sources include tea (especially green), blackberries and black grapes, apples, pears and raspberries.

Forskolin is extracted from Coleus forskohlii roots and is mostly consumed in supplement form.