Scientists have learned that plasmalogens, obscure but important lipids, serve as a mediator of neurogenesis and synaptic health and can reverse age-related cognitive decline in mice .
Plasmalogens and membranes
Plasmalogens are a subtype of phospholipids, the molecules that cellular membranes are mostly made of. Plasmalogens are especially abundant in brain, heart, and immune cells, where they constitute as much as 20% of the total phospholipids in cell membranes. Their function is not well understood, but it is becoming evident that plasmalogens protect cells from stress and that their depletion decreases cellular viability. Diet-wise, plasmalogens can be found mostly in seafood, such as scallops and mussels; a limited number of commercial plasmalogen supplements is already available.
The levels of plasmalogens decline with age, especially in patients with Alzheimer’s disease . Plasmalogen supplementation has been tested before in a handful of studies, including one double-blind, placebo-controlled trial in humans that showed that two-month plasmalogen supplementation significantly improves measures of memory in people with Alzheimer’s and mild cognitive impairment, especially in women .
Prettier and smarter
For this new study, aimed at improving our understanding of how plasmalogens work, researchers used 40 16-month-old naturally aging female mice. The mice were divided evenly into two groups, and the study group received plasmalogens with drinking water for two months. Additional 15 mice were used as young controls.
The first thing the researchers noticed was an improvement in the mice’s appearance. Plasmalogen-fed mice looked healthier than their similarly aged controls, with glossier and thicker body hair. The researchers even detected new hair growth:
After the treatment, the mice’s cognitive abilities were assessed via a water maze test, where they are required to navigate a maze filled with water until they find the platform they can use to get out. Healthy mice should quickly learn the location of the platform, as the young controls did. The learning ability was significantly impaired in old controls but restored by the plasmalogen treatment, almost to youthful levels.
The researchers then dived deeper into the workings of plasmalogens. It has been previously suggested that plasmalogens are abundant in synapses where they help to form synaptic vesicles, the tiny bubbles that carry neurotransmitters between neurons . Synaptic structures were equally abundant in young controls and in old plasmalogen-treated mice, much more than in old controls. The number of synaptic vesicles in plasmalogen-fed mice was lower than in young controls but much higher than in old controls. These results strongly suggest that plasmalogens alleviate age-related synaptic loss.
This was confirmed by transcriptomic analysis that revealed significant upregulation of synapse-related genes in the study group. Other upregulated genes were related to neural stem cell proliferation, neurogenesis, and production of neurotrophins, which are molecules that affect synaptic plasticity – a quality that makes learning possible. In particular, the expression of synaptophysin, a key mediator of synaptic plasticity, was significantly decreased in old controls compared to young controls in two regions of the hippocampus but almost completely rescued in the study group:
Less neuroinflammation, more neurogenesis
Neuroinflammation is thought to be a major cause of age-related cognitive decline . It is mostly promoted by overactivation of microglia, the immune cells of the brain. When activated, microglia produce a cocktail of pro-inflammatory cytokines. The researchers analyzed the levels of three of them: TNF-α, IL-1β and IL-6. For all three, the levels shot up with age but were almost completely reversed by the treatment. Activated microglia also morphologically differ from quiescent ones, as they are larger and have fewer extremities. Those differences were mostly rolled back by plasmalogens as well.
Neurogenesis, the creation of new neurons, occurs in a few discrete niches in mammalian brains, but its rate steadily declines with aging . Keeping the production of new neurons up is very important for preserving cognitive ability. In the study, the number of neuronal stem cells that express Sox2, a marker of differentiation, was significantly reduced in old controls versus young controls, showing an age-related decrease in neurogenesis that was partially alleviated by the treatment:
Plasmalogen deficiency looks increasingly interesting as a target for treating Alzheimer’s disease and other types of age-related cognitive decline. Plasmalogen levels are so well-correlated with Alzheimer’s that scientists have proposed using them as a diagnostic tool. While Phase 1 human studies are required, oral supplementation of plasmalogens is likely to be safe and, as we learn from studies like this one, effective. Since some anti-aging interventions work in a sex-specific manner, we hope to see a study in mice of both sexes. It would also be interesting to know whether plasmalogen supplementation has any effect on lifespan.
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