In an article published in the journal Nature Aging on February 2, a group of researchers from Brazil and France described a new possible biological cause of depression: the loss of neurons’ ability to recycle their old or damaged components. When properly controlled, the process of breaking down and reusing components—dubbed autophagy, which means “self-devouring” in Greek—is essential to the health and functioning of cells. The connection with depression was identified by a team led by French neuroscientist Pierre-Marie Lledo of the Pasteur Institute in Paris, in partnership with a group led by Brazilian psychiatrist Flávio Kapczinski of the Federal University of Rio Grande do Sul (UFRGS).
A reduced capacity for autophagy is just one of the biological factors linked to the onset of depression, a psychiatric illness characterized by prolonged periods of sadness that may affect up to 20% of people at some point in their lives. Two others have already been associated with the illness: low replacement of brain cells (in particular, neurons) and reduced connections between these cells. These factors alone, however, do not explain all cases of depression, which like other psychiatric disorders, results from a combination of the individual’s biological characteristics and their social, economic, psychological, and cultural conditions.
There was a bit of luck involved in Kapczinski and Lledo’s discovery that autophagy may be a contributing cause. Some years ago, they began collaborating to investigate the effects on neuron health of a protein called growth differentiation factor 11 (GDF11). This protein stimulates the development of the brain, blood vessels, and other tissues in the embryo and continues to be produced by the body until adulthood. In human beings, its synthesis begins declining from the age of 70.
The Brazilian scientist had been gathering evidence, through tests on animals and humans, that successive episodes of depression gradually cause damage to neurons and other brain cells, a little like an accelerated aging process—a phenomenon that Kapczinski called neuroprogression (see Pesquisa FAPESP issue nº 197). “At a conference held at Pasteur in 2018, I presented the hypothesis of neuroprogression and learned that Lledo’s group knew of a molecule that functions as a neuron rejuvenator,” says the researcher, who is part of Brazil’s National Science and Technology Institute for Translational Medicine (INCT-TM), funded by FAPESP and the Brazilian National Council for Scientific and Technological Development (CNPq).
That molecule was GDF11, whose restorative action in the brain had been demonstrated by Greek neuroscientist Lida Katsimpardi during a postdoctoral fellowship at Harvard University, USA. In an article published in Science in 2014, Katsimpardi proved that the protein reversed the effect of aging in rodents by promoting the formation of new neurons (neurogenesis). Later, at Pasteur, she suggested evaluating GDF11’s effects on depression and a symptom that frequently accompanies it and is also common in old age: memory loss.
The results of the experiments, presented in Nature Aging, showed that administering GDF11 over a number of weeks to elderly mice, which naturally have lower levels of this growth factor, prevented memory decline and the characteristic symptoms of depression. The treated animals began to perform similarly to young rodents. In young rodents, the protein prevented signs of depression induced by the rodent stress hormone corticosterone.
The scientists also found that in animals given GDF11, the hippocampus—the part of the brain associated with mood regulation and memory acquisition—functioned better, but for a different reason than expected. “We thought GDF11 had an impact due to neurogenesis, which would compensate for the loss of these cells observed in depression and aging,” says Kapczinski.
Analyses of how GDF11 affected the neurons, however, showed that the improvements did not occur as a result of neurogenesis. At least, not fully. When injected into the bloodstream, GDF11 does promote the formation of new neurons, but only indirectly by stimulating the release of other compounds that trigger neurogenesis. When injected into the brain, it did not lead to neuron proliferation, despite leading to memory improvements and reduced symptoms of depression.
The scientists realized that the beneficial effect of GDF11 was a result of increased autophagy, which contributes to the elimination of toxins. Neurons grown in the lab and treated with the growth factor functioned better and made more connections with other neurons. Evidence that autophagy was behind the result came from another experiment. When one of the proteins involved in autophagy was genetically inactivated or completely blocked using chemical compounds, the protective effect did not occur.
“Uncovering this role for GDF11 advances our understanding of the connection between aging, memory, and mood disorders, and perhaps most excitingly, raises the prospect of using GDF11 to improve the diagnosis and treatment of these problems,” wrote Patrick Piantadosi and Andrew Holmes, both from the US National Institutes of Health (NIH), in a review of the study published in the same issue of the journal.
“This study is important for three reasons,” says Brazilian psychiatrist Elisa Brietzke of Queen’s University in Canada, who was not involved in the research. “Firstly, it shows that there are multiple mechanisms involved in depression, which cannot be explained solely by a lack of neurotransmitters, such as serotonin. Secondly, it suggests that this mental disorder does not only cause changes in the brain, but in the whole body. And lastly, it offers the potential for a treatment that increases GDF11 levels to fight both depression and memory problems, which is a common symptom of the illness that is not improved by current antidepressants,” she explains.
Although Kapczinski and his team observed that blood GDF11 levels are lower in people with depression, there is still a long way to go before a therapy is developed to increase levels of the growth factor in the body. “Proteins such as GDF11 act on various organs and tissues, and when administered directly they can have beneficial effects on some and harmful effects on others,” warns Brietzke. Understanding how GDF11 acts in cells, however, could lead to the development of compounds that act on the same molecular targets while remaining efficient, safe, and well tolerated.
Scientific article
MOIGNEU, C. et al. Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy. Nature Aging. Feb. 2, 2023.
