Imagine a world where we live longer and longer, but where the passage of time affects our brains in the same way it does today. A world populated by old people with a rejuvenated appearance, still vigorous but every day more self-centered, slowed down, dizzy, overwhelmed, morose or worse still, lost or amnesiac. A nightmare. Because even when it escapes neurodegenerative diseases, our brain changes under the influence of age. “A bit like a tree that loses its leaves in the fall, the nerve endings alter,” summarizes Professor Yves Agid, neurologist and co-founder of the Brain and Spinal Cord Institute*. The neurons communicate less well with each other, they become clogged, the blood vessels shrink and deform, the brain volume decreases… The cognitive decline which results from these metamorphoses, more or less rapid depending on the individual, has long seemed inevitable. A time gone by. “Science shows us that we are capable of reversing the aging clocks, in the body but also in the brain,” rejoices Professor Pierre-Marie Lledo, director of the neuroscience department at the Institut Pasteur and research director. at the CNRS.
Hope was born about ten years ago, when a handful of researchers from Harvard University in the United States had the somewhat crazy idea of linking the blood circulation of a young mouse to that of a mouse. old. “At the time, we already knew that it could ‘rejuvenate’ certain organs, but the effects on the brain had never been studied. When I saw the first results, I said to myself that this was going to be a revolution “, remembers Lida Katsimpardi, then a young postdoctoral researcher. With the supply of young blood, the brains of the aged rodents seemed regenerated. Their vascularization improved, as did the production of new neurons. And with them, memory. One molecule seemed particularly involved, GDF11.
Since then, Lida Katsimpardi has continued this promising path, to better understand the role and mechanisms of action of this potential elixir of youth. Work that took her to France, to Professor Lledo’s team at Pasteur, and to Inserm. “We discovered that GDF-11 also reduces excess weight and depression,” summarizes the researcher. The molecule would act by strengthening autophagy, that is to say the ability of neurons to self-clean, to get rid of their metabolic waste. “In the hippocampus, this molecule also eliminates senescent cells, these overly old cells which have stopped dividing and spread toxic inflammatory factors around them. Their disappearance restarts the production of neurons,” adds Professor Lledo . Better yet, this magical molecule appears to have similar properties in humans. “As in mice, concentrations of GDF11 in the blood decrease with age, and the reductions are greater in depressed patients,” reports Professor Lledo from an observational study carried out on around a hundred individuals.
The road ahead remains immense
Since the pioneering work of Lida Katsimpardi, different teams have identified around fifteen other potentially rejuvenating molecules in the blood. A French researcher, Franck Oury, for example, identified a hormone produced by bone, osteocalcin. “We were interested in it because it decreases with age, and is modulated by physical activity and calorie restriction, which have proven effective in slowing cognitive decline,” he explains. A good intuition: in aged mice, an increase in blood concentrations of osteocalcin corrects the slowdown in cognitive functions. Conversely, when an aged rodent receives plasma from a young animal from which osteocalcin has been removed, its recovery is less than if the hormone is present.
Scientists believe there are still other molecules with similar effects to be discovered. In any case, their handling promises to be delicate and transfusions to avoid aging remain strongly discouraged, due to lack of validation in humans. To add to the complexity, the blood of older people conversely contains molecules that accelerate cognitive decline, which should be eliminated. “It is unlikely that a single therapy will be enough. As aging trajectories vary between individuals, it will be necessary to define biomarkers and offer personalized treatments, including lifestyle changes, rejuvenating molecules and molecules inhibiting aging factors. decline,” writes Saul Villeda of the University of Southern California in the journal Nature neuroscience published at the beginning of the year.
The dogma of a brain inaccessible to intervention may have fallen, but the road ahead remains immense. We could hope that the “rejuvenating” treatments planned for the rest of the body also act on the brain. Nothing is less certain: “We already know that this is the case for some of them, but not for others,” notes Coleen T. Murphy, director of a research laboratory on aging at the Princeton University (United States) and brain specialist. Many avenues are open, from the quest for molecules emitted during physical activity, whose neuroprotective virtues are proven, to attempts to reprogram neurons. “A lot of progress has been made, but in truth, the complexity of our brain is such that we do not even know if our knowledge represents a thousandth or a millionth of all there is to know,” Yves Agid puts into perspective. In fact, research on brain aging has so far attracted less funding than work on Alzheimer’s or Parkinson’s.
Better understanding “normal” cognitive decline could, however, in return, open up new avenues to fight against neurodegenerative pathologies, or at least prevent them. This is the bet of David Furman, associate professor at the Buck Institute for research on aging and researcher at Stanford University (United States). “Studies on a cohort of 1,500 people on the one hand and on animals on the other hand show a correlation between accelerated aging of the brain and the appearance of these diseases,” notes the scientist. Based on these results, he used artificial intelligence tools to identify molecules potentially capable of slowing down this aging. He is now testing them on cerebral organoids (models derived from reprogrammed stem cells that mimic the structure of parts of the brain) and on mice. Among these molecules, many old drugs. Including Viagra “which could have the capacity to reverse the molecular signatures of Alzheimer’s and brain aging”, assures the researcher. The art of combining business with pleasure…
* I’m having fun growing old, 291 pages, Odile Jacob, 2020, 22.90 euros.
.