Longevity Briefs: Clearing Up Liver Fat With Exosomes

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:

As we age, our livers gradually lose their ability to process fats efficiently, which increases the risk of a condition called non alcoholic fatty liver disease (NAFLD). This is when fat accumulates in liver cells, triggering inflammation, liver damage and scarring that eventually leaves the liver unable to fulfil its functions. One probable reason why fatty liver disease becomes more common with age is that cells lose the ability to carry out autophagy – the process in which cells degrade and recycle internal components, including fat stores.

Previous research has shown that autophagy can be enhanced by delivering exosomes obtained from stem cells. Exosomes are microscopic membrane-bound ‘packages’ containing genetic information and signalling molecules. They are released by cells, pass into the blood, and are absorbed by other cells in distant tissues, acting as a form of ‘long distance communication’. Research suggests that many of the previously observed benefits of stem cell therapy might actually be the result of the exosomes released by those stem cells, not the cells themselves. In this study, researchers investigate whether exosomes might have potential for reversing fatty liver disease.

The discovery:

First, researchers isolated exosomes from stem cells derived from human umbilical cords. They then tested these exosomes in two ways: in living mice and in laboratory-grown liver cells. For the animal study, they used three groups of 6 mice each: young mice (8 weeks old, equivalent to roughly 20 ‘human years’), naturally aged mice (18 months old, equivalent to around 56 ‘human years’), and aged mice treated with exosomes. The aged mice that were treated received exosome injections every 3 days for 12 weeks.

They found that aged mice treated with exosomes showed significantly reduced body weight, improved markers of liver function, improved sensitivity to the blood sugar-lowering hormone insulin and decreased liver fat deposits. They also observed enhanced autophagy in the livers of treated mice compared to untreated aged mice, reinforcing the hypothesis that exosomes could reduce liver fat via autophagy. Exosome treatment also resulted in reduced markers of senescence (where cells permanently stop dividing).

In parallel, researchers cultured human liver cells and treated them with palmitic acid, a saturated fat that mimics age-related damage and fat accumulation. Treating these cells with exosomes had effects that were consistent with the results from live animals, suggesting that the benefits of exosomes might carry over to humans. Using advanced protein analysis, researchers were also able to pinpoint the specific signalling molecule within the exosomes that was responsible for the bulk of these effects: a protein called thrombospondin-1 (THBS1). This became clear when it was found that removing THBS1 from the exosomes caused the therapeutic benefits to disappear. Further investigation revealed that THBS1 works by activating a cellular signalling pathway called PPAR, a master regulator of fat metabolism and autophagy.

The implications:

This research suggests that exosomes are effective at reversing age-related metabolic decline of the liver, at least in mice, via a mechanism that also exists in human liver cells. It also identifies a specific protein that seems to be sufficient to reproduce most of the benefits of exosomes, which makes eventual clinical application more realistic – it is a lot easier to make a drug that mimics the effects of a single protein that it is to harvest a sufficient quantity of exosomes at reasonable cost.

Fat accumulation in the liver can be reversed through lifestyle changes – primarily those which achieve weight loss, since a calorie deficit encourages the liver to mobilise its stored fat for energy (though this won’t reverse most of the liver damage caused by fatty liver disease). However, reversing fatty liver is easier for some than for others -for example, it is often harder for older people to implement the lifestyle changes required due to frailty and increased risk of nutritional deficiencies. For this reason, pharmaceutical options to reduce liver fat would be helpful, but none currently exist.