Longevity Briefs: A One-Time Gene Therapy Extends Lifespan In Mice

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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:

It’s clear that there is a link between the ageing process and cellular metabolism – how cells manage, consume and store energy. ‘Master regulators’ of metabolism – molecules such as mTOR and AMPK – control (among other things) how much energy cells consume and whether that energy is spent on growth or repair, with the latter thought to result in slower ageing. Drugs like rapamycin, which inhibits mTOR, have been shown to extend lifespan in mice.

Meanwhile, conditions that disrupt the management and distribution of energy throughout the body also contribute to ageing and age-related diseases. In insulin resistance, cells become resistant to the blood sugar-lowering hormone insulin, and do not absorb glucose (sugar) from the blood as readily as they should. This means that this glucose ends up being stored as fat within adipose tissue and in the liver. This stresses the liver and eventually causes it to stop responding correctly to the metabolic needs of the rest of the body. Though insulin resistance and high blood sugar are features of type II diabetes, some degree of insulin resistance will develop in old age, even in those who avoid diabetes.

In this study, researchers experiment with gene therapy to make insulin-resistant mice produce FGF21 (fibroblast growth factor 21). FGF21 is a signalling molecule released primarily by the liver when energy is scarce, such as during fasting. It helps organs throughout the body coordinate to stop storing energy as fat, instead using fat as a fuel source to reduce reliance on glucose. While FGF21 gene therapy is already advancing towards human clinical trials for metabolic diseases like diabetes, here researchers wanted to see if it could promote healthy ageing in mice with insulin resistance.

The discovery:

The study’s main lifespan experiment compared 61 male mice given a control treatment (a viral vector that had not been loaded with gene therapy) with 32 male mice given the real treatment, called AAV-FGF21. The gene therapy was targeted to muscle tissue, with the intention of making a subset of muscle cells into permanent FGF21 producers. It was given as an injection when mice were 13 months of age, roughly ‘equivalent’ to middle-aged humans. The mice were then followed up until death.

Overall, the median lifespan (the age by which 50% of mice are dead) was 28.14 months in the control group vs 33.92 months in the treated group – a 20.54% increase in median lifespan. The treated mice also had lower body weight without reducing food intake, improved blood sugar control and insulin sensitivity, reduced inflammation, reduced liver and fat mass alongside several other benefits in late life compared to controls (pictured above). At the cellular level, the function of mitochondria (the ‘power plants’ of the cell responsible for extracting energy from nutrients) was improved in treated mice compared to the controls.

In addition to the increased lifespan and biological markers of improved health, treated mice also showed improved physical and cognitive function in late life. At around 22-24 months of age, treated mice performed significantly better in tests of physical function such as grip strength. They also spent significantly longer exploring new objects over old objects introduced to their environment, which is a measure of memory function.

The implications:

Rather than simply improving insulin sensitivity in insulin resistant mice, FGF21 gene therapy appeared to significantly extend median lifespan and improve physical and cognitive health in old age. This occurred despite the therapy only being given when the mice were 13 months old. Many therapies that have been shown to extend mouse lifespan only work if they are started much earlier in life, which would limit their usefulness in humans.

10% maximum lifespan (that is to say, the age by which 90% of mice are dead) was several months longer among treated mice – in other words, the 10% oldest of the treated mice outlived the 10% oldest control mice. However, only 3 mice in the treatment group were still alive by this time, so it cannot be concluded that treatment extended maximum lifespan, as these three mice could have lived a month or so longer by chance.

There is no telling whether FGF21 gene therapy would have similar benefits in humans to those shown here, but the good news is that we don’t need to wait for gene therapy. Pathways affected here like insulin sensitivity, FGF21, inflammation and mitochondrial function can all be improved via lifestyle factors like a healthy diet, dietary restriction strategies (such as fasting) and exercise.