Naked mole-rats, rodents with nearly 40-year lifespans and brains that barely age, carry several times more fat in hippocampal immune cells than mice do, although this is considered a sign of brain aging and damage in mice and humans
Naked mole-rats, rodents with nearly 40-year lifespans and brains that barely age, carry several times more fat in hippocampal immune cells than mice do, although this is considered a sign of brain aging and damage in mice and humans
An international team compared the hippocampus, a brain region involved in memory, in naked mole-rats and mice at comparable life stages. As naked mole-rats age, fat accumulates in the brain's immune cells, called microglia. In mice, it accumulates within neurons.
The mouse-sized naked mole-rat rarely develops common age-related diseases, including cancer, cardiovascular disease, and neurodegeneration. From a young age, its brain contains large amounts of soluble beta-amyloid, a protein associated with Alzheimer's disease in humans, yet it does not form amyloid plaques. It can also survive up to 18 minutes without oxygen reaching its brain, without harm. These traits make it a useful model for studying how the brain can be protected against aging.
A similar finding in 2020 linked fat accumulation to harmful changes. A paper in Nature Neuroscience, since cited more than a thousand times, showed that fat-laden microglia accumulate in the brains of mice and humans with age. These cells are less effective at clearing cellular debris and produce reactive oxygen species and inflammatory signals. Fat in microglia has since been regarded as a marker of brain aging and damage. The same association was later confirmed in human microglia under mitochondrial stress.
A paper in GeroScience, published on September 16, examined the same feature in naked mole-rats and found the opposite pattern. The researchers compared the hippocampus at comparable life stages: 26 and 52–54 weeks in mice, and about 4 and 13 years in naked mole-rats. The proportion of microglia occupied by fat was 5–14 times greater in naked mole-rats than in mice. In naked mole-rats, this proportion increased by another 66% by middle age, while it remained unchanged in mice. In mice, however, fat accumulated within neurons: their lipid droplets grew by 68% by middle age. In naked mole-rats, neuronal lipid droplet size remained unchanged with age.
Naked mole-rat microglia retain their shape and branching patterns as they age. They do not shift into the reactive, proinflammatory state that usually accompanies fat accumulation in mice.
Our results suggest that microglia that accumulate fat are not inherently harmful.
The authors hypothesize that naked mole-rats transfer fat from overloaded neurons into microglia, protecting the neurons from their own excess fat. Free fat that is not stored in droplets is toxic to cells, whereas storage in droplets makes it safe. In mice, this transfer is less effective, leaving fat inside neurons.
Naked mole-rats also have a lower density of blood vessels in the brain: capillaries are 40–66% less abundant in the hippocampus and sensorimotor cortex than in mice, and their numbers do not increase with age as they do in mice. The authors associate this with life in low-oxygen burrows. Naked mole-rats have lower brain metabolism and higher hemoglobin affinity for oxygen, which appears to allow a sparser vascular network to meet their needs.
The authors also propose a more direct connection: a sparse vascular network may itself increase lipid oxidation in the brain, and fat accumulation in microglia may be a direct response to this risk. Markers of this damage are already elevated in young naked mole-rats, but unlike in mice and humans, they do not rise with age. Beta-amyloid follows the same pattern: it is abundant, yet the harm associated with it does not increase with age.
If experiments that directly block this transfer confirm the hypothesis, gerontology will have a specific target: the ability of cells to take up excess fat from vulnerable neurons and store it without becoming a source of inflammation.