Caloric restriction slows brain ageing in mice

For as long as humans have wondered about mortality, food has been central to the conversation. Ancient traditions often linked eating habits with health, longevity, and clarity of mind. In modern science, these ideas take shape through rigorous experiments. One of the most consistent findings across species is that eating less—without depriving the body of nutrients—extends life. This practice, known as caloric restriction, influences not only how long organisms live but also how well their brains function during ageing.

Why the Brain Matters

The brain is especially vulnerable to ageing. Neural circuits weaken, repair mechanisms falter, and inflammatory processes take over. These changes increase the risk of disorders like Alzheimer’s and Parkinson’s, conditions that devastate memory, movement, and identity. Understanding how caloric restriction preserves the brain is therefore more than an academic exercise. It is a step toward therapies that might protect millions from age-related decline.

Modern Tools for Ancient Questions

Until recently, scientists lacked the tools to observe brain ageing at single-cell resolution. Traditional bulk measurements blurred the diversity of cell types into a single average, hiding critical details. Researchers at Rockefeller University overcame this barrier by applying advanced single-cell and spatial transcriptomics. Using EasySci sequencing and a platform called IRISeq, they mapped over half a million brain cells across three age groups. They also reconstructed spatial patterns of gene activity across eleven distinct brain regions. This approach created a cellular atlas of ageing and caloric restriction.

Preserving Cellular Balance

The results were striking. In normal ageing, neural stem and progenitor cells vanish early, reducing the brain’s capacity for repair. At the same time, inflammatory glial cells—often called the brain’s immune sentinels—multiply excessively. Mice under caloric restriction showed a very different pattern. Neural precursors persisted longer, while harmful glial expansion slowed. These findings suggest that caloric restriction actively sustains the balance of cell populations that maintain resilience in the ageing brain.

Turning Back Gene Expression

Beyond cell counts, gene activity revealed deeper effects. Ageing usually amplifies stress-response genes, inflammatory pathways, and signals of cellular exhaustion. In restricted mice, many of these changes were reversed. Genes associated with oxidative phosphorylation, neuroprotection, and repair increased, while those tied to damage and senescence decreased. At twenty-four months—the mouse equivalent of old age—the transcriptional landscape of restricted brains resembled that of much younger animals. This molecular “rewinding” offers a powerful glimpse of how diet can shift biology toward youth.

Regional Nuances Emerge

Not all brain areas responded equally. The ventricles and hypothalamus showed the strongest rejuvenation. In these regions, caloric restriction restored genes linked to neurogenesis, circadian rhythms, and myelin maintenance. The hippocampus and white matter also displayed marked improvement, especially in pathways that protect against degeneration. By contrast, some areas showed modest or delayed responses, reminding us that ageing is a mosaic, with each region following its own timeline.

The Dance of Glial Cells

One of the most telling findings involved microglia and oligodendrocytes. With age, microglia often shift from protective roles to inflammatory states, known as disease-associated microglia. Oligodendrocytes, responsible for producing myelin, also develop stress-prone subtypes during ageing. Caloric restriction disrupted these transitions. Inflammatory microglia failed to dominate, and oligodendrocytes retained healthier profiles. This points to a diet-induced dampening of brain inflammation, a feature long associated with resilience against neurodegeneration.

A Fragile Window of Neurogenesis

Adult neurogenesis—the birth of new neurons—declines early in life. In control mice, few neurogenic cells remained by twelve months. Yet in restricted animals, these cells persisted longer, nearly doubling in number at the same age. This boost arose from enhanced proliferation and delayed differentiation, expanding the pool of progenitors. By eighteen to twenty-four months, however, neurogenesis dwindled even in restricted mice. The findings show that diet can extend the window of plasticity but not halt its eventual closure.

Signatures of Reduced Senescence

Cellular senescence, a state of permanent arrest triggered by stress, accelerates brain ageing. In this study, senescence markers surged with age in microglia and oligodendrocytes. Caloric restriction blunted this surge, lowering the expression of genes tied to DNA damage, inflammation, and oxidative stress. The effect was most pronounced in regions like ventricles and white matter, which also showed preserved cellular populations. This suggests that diet not only prevents decline but also reduces the toxic influence of senescent cells.

The Bigger Picture

Taken together, these discoveries reveal caloric restriction as more than a broad protective measure. It acts with precision, rescuing vulnerable cell types, restoring regional gene networks, and slowing molecular clocks. While the study used mice, the parallels with human brain ageing are clear. Similar pathways govern our own neural health, making these findings a foundation for exploring diet-based interventions in people.

Where Science Goes Next

Important questions remain. This study used only male mice, though caloric restriction can affect sexes differently. The spatial atlas covered late age but not earlier adult stages. Future research must examine how these interventions play out across lifespans, genetic backgrounds, and environments. Still, the roadmap is now clearer. Scientists can track how interventions shape individual cell states, rather than relying on averages that obscure critical dynamics.

What emerges from this work is both humbling and inspiring. A simple change—eating less—reshapes the brain’s trajectory of ageing. By preserving neural precursors, calming inflammatory cells, and rewiring gene networks, caloric restriction slows the brain’s drift into decline. For humanity, the implications extend beyond diet. They invite us to imagine therapies that mimic these effects, offering not just longer lives but sharper, healthier minds deep into old age.

The study is published in the journal Cell Reports. It was led by Junyue Cao from The Rockefeller University.