Can blocking fat transport increase lifespan?

"Since we see in the worm that we can extend lifespan by silencing this protein, we reason that that it could be a promising strategy to prevent age-related disease in humans," says Louis Lapierre. Above, a store of mouse fat cells (red) is permeated by blood vessels (green). (Credit: Daniela Malide/NHLBI/NIH)

Animals from tiny worms to human beings have a love-hate relationship with fats and lipids. Cholesterol is a famous example of how they are both essential for health and often have a role in death. A new study reveals another way this may be true.

Researchers working in nematodes and mice report that a naturally occurring protein responsible for transporting fats like cholesterol around the body also hinders essential functions in cells that increase lifespan.

When the scientists genetically blocked production of the worms’ yolk lipoprotein, called vitellogenin (VIT), the nematodes lived up to 40 percent longer, the study shows. Mice, humans, and other mammals produce a directly analogous protein called apolipoprotein B (apoB), and therapies have been developed to reduce apoB to prevent cardiovascular disease.

The new research suggests that there might be a whole other benefit to reducing apoB. Data from the nematodes indicate that apoB’s evolutionary cousin VIT prevents long lifespan by impairing the ability of cells to use and remodel fats for healthier purposes.

“That protein, which has an ortholog in humans, is a major decider of what happens to fat inside intestinal cells,” says Louis Lapierre, assistant professor of molecular biology, cell biology, and biochemistry at Brown University and senior author of the study in the journal Autophagy. “If you reduce the production of these lipoproteins you allow the fat to be reused in different ways.”

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Lipophagy is the process of breaking down large quantities of built-up fats and reusing them for other purposes. The new study shows that the longevity benefits associated with increased lipophagy are hindered by too much VIT.

Lapierre’s team, including lab manager and co-lead author Nicole Seah, demonstrated the link directly. Some experiments, for example, showed that the lifespan benefits of blocking VIT didn’t occur if autophagy was blocked in other ways. They also showed that VIT hinders a related process called lysosomal lipolysis, the endpoint of lipophagy which catalyzes fat breakdown.

Link to dietary restriction

In mice the team connected this effect to another well-known model of increased longevity: dietary restriction. Many studies have shown that animals that eat less live longer. In this study the researchers showed that calorie-restricted mice produced less apoB.

In nematodes, the normal purpose of VIT is thought primarily to involve the transport of fats from the intestine to the reproductive system to nourish eggs and to aid in reproduction. Similarly in mammals, Lapierre says, a purpose of apoB is to transfer fats away from the intestine and liver toward other tissues where they can either be used or stored.

“Altogether our data supports a model in which lipoprotein biogenesis prevents lifespan extension by distributing lipids away from the intestine and by negatively regulating the induction of autophagy-related and lysosomal lipase genes, thereby challenging the animal’s ability to maintain lipid homeostasis and somatic maintenance,” the authors write in the study.

Human lifespan, too?

Of course nematodes and mice are not people, but Lapierre says he is optimistic that these findings could eventually matter to human health. He’s not alone. Other labs are currently investigating the relationships among¬†lipoproteins, autophagy, and lifespan.

“Since we see in the worm that we can extend lifespan by silencing this protein, we reason that that it could be a promising strategy to prevent age-related disease in humans,” Lapierre says.

[Starvation diet puts nematode lifespan on ‘pause’]

In humans, he says, a major unanswered question is what effect silencing apoB would have on fat remodeling in the liver and the intestine.

The new research finds that at least in nematodes, keeping fats in the intestine allows cells to carry out processes that are linked to longer lifespan.

Earlier this year Lapierre earned a grant from the American Federation for Aging Research to continue his work. His lab group is now looking at the global effects of limiting VIT and apoB in animals.

In addition to AFAR, the National Institutes of Health provided funding for the study. Coauthors contributed from the Howard Hughes Medical Institute and Salk Institute.

Source: Brown University